Low Vasopressin In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2025, Huhmar/Bragée/Polo

Fancymyblood said:
I stumbled upon this paper because I'm experiencing a severe crash and had some private blood work done. As usual (and frustratingly) all seemed normal except Copeptin (2,36) and serum osmolality (330). High osmolality suggests dehydration but than Copeptin should be way higher as a compensation mechanism. ChatGTP claims this is highly suggestive (95-100% specificity and sensitivity) of central diabetes inspidus. A friend endocrinologist agreed but had some reservations about the accuracy of the tests as the blood was send by mail.

I'm now getting a retest including urine osmolality and then probably a copeptin stimulation test at the hospital.

After a 20 year struggle I hope to have finally found the silver bullet.!It does make sense. As long as I remember I've been drinking 5-10 liter water per day, it all started with orthostatic symptoms, never had the myalgia aspect always pee in 0,5-1l increments and since this crash I've been experiencing extremely dry skin and a huge increase in orthostatic symptoms.

These researchers might be on to something, at least in a subset of patients!
Click to expand...
Hi @Fancymyblood!
Was diabetes insipidus confirmed in your case?
 
Low Vasopressin In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Helena M Huhmar; Lauri S Soinne; Bo Christer Bertilson; Per Hamid Ghatan; Björn A Bragée; Olli J Polo

OBJECTIVE
The complex clinical picture of ME/CFS includes orthostatic intolerance with symptoms and signs suggesting abnormal water homeostasis and hypovolemia. Since many ME/CFS patients report polyuria-polydipsia, we conducted an observational study based on series of plasma and urine osmolality (P-Osm and U-Osm) as well as plasma levels of vasopressin (P-VP) or copeptin in consecutive patients diagnosed with ME/CFS according to the International Consensus Criteria.

METHODS
P-VP as well as P-Osm and U-Osm were measured in 111 patients after 10 hour overnight fasting and fluid deprivation. Additional 13 patients were assessed for copeptin, when P-VP measurements were no longer available. The clinical routine also included brain MRI and blood chemistry.

RESULTS
P-Osm was abnormally high (>292 mOsm/kg) in 71/124 (57.3%) and U-Osm below the reference interval (< 750 mOsm/kg) in 82/124 (66.1%) patients. P-VP was below the level of detection (<1.6 pg/mL) in 91/111 (82.0%) patients. A normal P-VP level compared with their P-Osm was found in 11/111 (9.9%) patients. Copeptin levels were all within the given reference range, albeit in the lower end in most patients. No indication of relevant pathology in either hypothalamus or hypophysis was present.

CONCLUSIONS
Our findings suggest that chronic down-regulation of VP mimicking central diabetes insipidus is an important measurable part of the disease mechanism that potentially contributes to criterial symptoms of ME/CFS.

HIGHLIGHTS
• orthostatic intolerance and polyuria-polydipsia typify disabling forms of ME/CFS

• in a consecutive series of ME-CFS patients, majority had very low vasopressin levels, relatively high plasma osmolality and low urine osmolality, in absence of overt hypothalamic or hypophyseal pathology

• chronic down-regulation of vasopressin mimicking central diabetes insipidus may contribute to the core symptoms of ME/CFS

Web | DOI | PDF | Endocrine Practice | Open Access
 
Our results reveal a high prevalence of low P-VP, low urine osmolality and high plasma osmolality after overnight water restriction. These findings are in line with polydipsia polyuria (PP), which is a common complaint when specifically asked about during the clinical interview. PP often appears at the beginning of illness, and the manifestations may be constant and monophasic, transient, or intermittent, and it seems to be often overlooked in the patientphysician communication. The combination of high P-Osm with low P-VP excludes both psychogenic polydipsia and renal resistance to VP. Instead, it indicates a central VP deficiency resembling central diabetes insipidus (cDI)
Click to expand...

This all rings many bells for me. Here are some comments from the saline infusion thread discussion.

Kitty said:
In PEM my fluid intake goes up a lot, and in the catastrophic crashes I had before I was diagnosed, it was bizarre. I needed 10 to 12 litres of water a day, and my skin still looked dehydrated. Last time round I even asked our stage manager to get me rehydration salts to add to it, because I was worried about washing out too many nutrients. I don't know whether it made any difference, and the only thing that reduced the need for fluids was when I began to recover.
Click to expand...

SNT Gatchaman said:
Although I had no idea what was going on then, I had a warning moderate PEM crash six months before I crashed out to severe, but the second crash was astonishingly dramatic. One of its features was a sudden massive diuresis and I simply could not keep up with the losses. I would drink water but I would pee it out within 15-20 minutes - faster than I would expect one could absorb, but maybe it was the previous glass. This was much more than I'd ever experienced with bog standard past viral illnesses. Eventually this stabilised but it seemed obvious to me that I was now intravascularly depleted in status quo. That improved at around 6 months, either just with time +/- helped along by supplements. Renal function in terms of eGFR has remained normal.
Click to expand...

Midnattsol said:
Dehydration and polyuria has been a common PEM symptom for me. One year I had nocturia as well, and got up once or twice every night to pee. But that only occured for one year nearly on the mark. Since it was a new symptom I had it checked out and nothing was found. Since I had the history of polyuria with PEM I have assumed there was a connection
Click to expand...

@MelbME I'm probably jumping the gun, but I'd be interested on your thoughts on this paper. I would need to read up about copeptin which I'd never heard about before now. They felt the copeptin assay that replaced the vasopressin (radionuclide) assay for the last few of the cohort suffered from too few numbers so no inferences could be drawn. But the results on that assay seemed to be pretty normal in that subgroup. Could that be a clue? Any chance in your saline study that both VP and copeptin be measured to see if there's a mismatch?

I was naively wondering if there was a potential biochemical explanation where the vasopressin is not being produced (or not properly functional) while copeptin still is secreted at normal levels. Some limitation on arginine for VP production eg if there were wider issues with nitrogen metabolism?? Ie I'm wondering if it's possible for the propeptide to be inadequately produced, while the copeptin end is complete and able to be cleaved, and then measured as normal. Edit: vs peripheral increased enzymatic breakdown or sequestration.
 
Last edited:
They say high electrolyte content due to low vasopressin might lead to over-excitability of neurons.
Furthermore, hyperosmolality may even contribute to sensitization of neurons, an essential feature in ME/CFS pathophysiology, since influx of cations into shrinking neurons might shift the resting potential closer to the threshold of action potential. The resulting excessive irritability of different types of neurons could explain a wide range of neurological symptoms such as spontaneous pain and oversensitivity to light and sound.
Click to expand...
 
Good to see this paper that confirms the possible cause for the chronic hypovolemia. I have had a significant improvement in my quality of life from getting weekly IV fluids. I am in the US and insurance covers this because of my diagnosis of ME with hypovolemia.

I was grateful to see these researchers used patient selection based on the ME-ICC (International Consensus Criteria.)

"Between March 2019 and November 2020, our neurologist (HH) met 173 consecutive patients with ME/CFS diagnosed according to the International Consensus Criteria."

Based on those dates it is unlikely those with Long Covid were included in the study. I think this is a good study to share with doctors.
 
The paper refers to previous studies with similar results.
Paper said:
Low VP in chronic fatigue is not a novel finding. As early as in 1993 reported Bakheit and colleagues a low VP despite high P-Osm in nine patients with postviral fatigue.15

Wyller and colleagues had similar findings in sixty-five adolescents with ME/CFS.16

A small controlled study using essentially the same diagnostic criteria but with a considerably younger patient population and a treatment arm found not only significantly lower levels of ADH (VP) and renin activity but also consistently lower cardiac parameters and stroke volume index.17
Click to expand...

Quotes from referenced papers:

15. Bakheit et al. Abnormal arginine-vasopressin secretion and water metabolism in patients with postviral fatigue syndrome. Acta Neurologica Scandinavica. 1993. [Article] [S4ME]
Secretion of arginine-vasopressin (AVP) was erratic in these patients as shown by lack of correlation between serum and urine osmolality and the corresponding plasma AVP levels. Patients with PVFS had significantly low baseline arginine-vasopressin levels when compared with healthy subjects.
Click to expand...

16. Wyller et al. Hormonal alterations in adolescent chronic fatigue syndrome. Acta Paediatrica. 2010. [Article] [S4ME]
Among patients, plasma antidiuretic hormone [vasopressin] was significantly decreased and serum osmolality and plasma renin activity were significantly increased (p ≤ 0.001).
Click to expand...

17. Miwa K. Down-regulation of renin-aldosterone and antidiuretic hormone systems in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Journal of Cardiology. 2017. [Article] [S4ME]
Both the mean plasma aldosterone (104±37pg/ml vs. 157±67pg/ml, p=0.004) and antidiuretic hormone (ADH) [vasopressin] (2.2±1.0pg/ml vs. 3.3±1.5pg/ml, p=0.02) concentrations were significantly lower in the ME group than in the Controls.
Click to expand...
 
Last edited:
A disturbance of ADH production would be another pointer to hypothlamic cell problems that might perhaps tie in with CRH findings and sleep disturbance.

A key question would be whether low ADH might be secondary to inactivity though, since lying flat is associated with reduced blood volume. That should be testable by correlating with step counts etc.
 
Two things that my be yellow flags are that 'Endocrine Practice' seems a pretty obscure journal, suggesting tht this has been rejected by more mainstream journals, and some of the authors have produced underwhelming stuff. Polo presented at a Euromene conference on diagnosing ME/CFS (or maybe EDS, it wasn't very clear) on the number of rolls of fat the patient had on their belly. Bragee produced a paper on neck changes with some implausible figures.
 
The initial abstract (first post in this thread) was in Neurology. It would be good to know what the peer review concerns were.

Jonathan Edwards said:
A key question would be whether low ADH might be secondary to inactivity though, since lying flat is associated with reduced blood volume. That should be testable by correlating with step counts etc.
Click to expand...

For what it's worth, my history would suggest this isn't the explanation. I was active up until the day before my major disabling crash, that presented with a major diuresis. The orthostatic intolerance then immediately followed and I was bed-bound.
 
SNT Gatchaman said:
I was active up until the day before my major disabling crash, that presented with a major diuresis. The orthostatic intolerance then immediately followed and I was bed-bound.
Click to expand...
For me, at least these days, I’m always very inactive, but the periods of peeing loads correlate with crashes.

Edit: It could be interesting to have some longitudinal studies of some of these hormones, tracked with activity, crashes, etc.
 
Last edited:
forestglip said:
The paper refers to previous studies with similar results.


Quotes from referenced papers:

15. Bakheit et al. Abnormal arginine-vasopressin secretion and water metabolism in patients with postviral fatigue syndrome. Acta Neurologica Scandinavica. 1993. [Article] [S4ME]


16. Wyller et al. Hormonal alterations in adolescent chronic fatigue syndrome. Acta Paediatrica. 2010. [Article] [S4ME]


17. Miwa K. Down-regulation of renin-aldosterone and antidiuretic hormone systems in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Journal of Cardiology. 2017. [Article] [S4ME]
Click to expand...
1993!! 2017
If there had been follow up on these papers, I probably could have been "helped" 25 - 30 years ago.
Now I still can't get my blood volume tested. I asked for it 4 times. But specialists don't know no nothing, but always know better.
I still think low blood volume is my main problem and in 34 years I was not bedbound, just the first 3 days.
 
I’m not sure, but is there a reliable way to test for low blood volume (hypovolemia)?
Has this ever been properly investigated in ME/CFS?
I’m only aware of a hypothesis paper where it is mentioned as a possible mechanism, but without it actually being tested.
 
SNT Gatchaman said:
The initial abstract (first post in this thread) was in Neurology. It would be good to know what the peer review concerns were.



For what it's worth, my history would suggest this isn't the explanation. I was active up until the day before my major disabling crash, that presented with a major diuresis. The orthostatic intolerance then immediately followed and I was bed-bound.
Click to expand...
I developed excessive thirst and diuresis a long time before I became bedbound or even was significantly ill/disabled. I caught a vomiting bug when I was 17 and developed it afterwards from what I recall, and have struggled with it (and eczema) ever since, but when my ME/CFS hit properly at 26 it got worse, and has been generally worse with worse severity and in crashes.
 
Last edited:
On inactivity - I still get polyuria episodes despite having an activity level well within normal ranges. They correlate with crashes although they are sometimes my only symptom (ie I have overexerted but it never goes further than the polyuria). I also have crashes without polyuria. Nocturia as was mentioned in a quoted post of mine is still a none-issue since the year it was nightly.
 
Blood volume meaurements have been made in ME/CFS and reported as low. The problem is that blood volume perse is not necessarily what matters - it is more whether the blood volume is suitable for the vascular capacity and vasomotor tone. To make sense of things it may be necessary to look at more functional measures - essentially what David Systrom is doing looking at low right atrial filling pressure.

Inadequate ADH ought to produce a shift in osmolarity and that may be a more useful indicator of poor regulation?
 
Might not be a relevant connection, but this preprint links the actual downstream changes induced by vasopressin on collecting duct cells to CREB-family transcription factors, the same ones that control CRH transcription (discussed in this thread):


[edit: maybe the problem is downstream and causing a regulatory feedback issue?]

(Initially misread one point in the abstract, edited to correct my thought)
 
Just adding my experience: my onset was very gradual, and diuresis began early in that process. As I have continued to decline, it has essentially remained steady - I have not noticed any increase or decrease in urine production when in a crash. I don't know if it could be related, but I am aware of a sudden "drying out" as a symptom of having over done things - my eyes and mouth with dry right up, like I've been starring at the desert sun, slack-jawed and open-mouthed for hours. The urination is just pretty much constant no matter how I'm feeling though.
 
You must log in or register to reply here.
Back
Top Bottom