The Paradox
An earlier blog focused on the “renin-aldosterone paradox” in chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS). The renin-angiotensin-aldosterone system (RAAS) regulates blood volume and a whole bunch of other factors.
Given the low blood volume regularly found in ME/CFS and POTS, all three factors of the RAAS system (renin, angiotensin and aldosterone) should be high. While angiotensin II levels are high (very high), renin and aldosterone levels are paradoxically low.
That combination of factors can lead to several problems including low blood volume (from low aldosterone levels) and increased sympathetic nervous system activation, blood vessel narrowing (vasoconstriction), inflammation and oxidative stress (from high Ang II levels).
Two studies suggest that the activity of the ACE-2 enzyme which transforms Ang II to Ang (1-7) and angiotensin to Ang (1-9) is reduced, but it’s not clear why. Miwa speculates that a blunted HPA axis (aldosterone is produced by the adrenal glands) could account for the low aldosterone levels.
After two decades of on and off study, why the RAAS system is so paradoxically off in these diseases remains a mystery.
Is the same system being impacted in COVID-19 and ME/CFS?
Then came the SARS-CoV-2 coronavirus and COVID-19 pandemic. The pandemic has offered an opportunity for understanding how infections can morph into diseases like chronic fatigue syndrome (ME/CFS), fibromyalgia and POTS.
Something, however, differentiates the present coronavirus from the other pathogens associated with ME/CFS. The SARS-CoV-2 virus appears to mess with the same renin-angiotensin (RAS) system that has gone whacky in ME/CFS and POTS.
A Tangled Web
This is a tangled web about which little is known with certainty. Only a few studies have been done in POTS, and fewer in ME/CFS, and research into COVID-19 is still just beginning. This blog, then, contains a lot of speculation.
The two arms of the renin-angiotensin (RAS) system:
- Classical (Inflammatory) Arm – the ACE (or ACE1) arm – produces angiotensin II and increases blood pressure, blood vessel vasoconstriction, sympathetic nervous activity and inflammation.
- Anti-inflammatory Arm – the ACE2 arm counteracts the first arm. It breaks up Ang II to produce Ang (1-7) and angiotensin to form Ang (1-9). Ang (1-7). In contrast to the ACE arm, the ACE2 arm is vasodilatory, anti-inflammatory and anti-oxidative.
Could inhibition of ACE-2 be contributing to a bradykinin storm in ME/CFS and POTS?
Several researchers have hypothesized that the dysregulation of the RAS system – specifically an over-activation of the ACE1/Ang II arm – by the SARS coronavirus is “at the center” of the harms caused by COVID-19. The entire hypothesis rides on the inability of the ACE-2 enzyme to keep the inflammatory arm of the virus in check.
Note that thus far the same scenario – reduced ACE2 activation and increased activation of the classical or inflammatory arm of the RAS – is posited for both COVID-19 and ME/CFS/POTS.
It perhaps bears noting that the full implications of ACE2 inhibition are not assessed in the papers focused on blood volume and blood flow issues in POTS. Receptors for ACE-2 are found across the body (central nervous system, airways, blood vessels, gut, lungs, heart liver, eyes, kidneys) and reduced ACE2 activation has been associated with lowered white blood cell counts, impaired oxygen uptake by hemoglobin, increased oxidative stress, leaky gut, problems with lung perfusion, reduced vasodilation of the blood vessels, inflammation, and heart issues in other diseases.
There appears to be plenty of room for ACE2 inhibition, if it is indeed present in ME/CFS and POTS, to have widespread consequences.
The Super Computer Study
ME/CFS and COVID-19 appeared to be oddly on track with each other until the supercomputer study came along. The study, “A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm“, which was published in eLife Science Digests in July, blew a big hole in the ACE2 hypothesis for COVID-19 and ME/CFS. While it was doing that, though, it opened up even more intriguing connections.
Thomas Smith, of Medium, reported that one of the fastest supercomputers in the world at Oakridge National Lab in Tennessee had been sweating data big time earlier this year. Given the task of assessing the expression of 40,000 genes from 17,000 lung samples from COVID-19 patients, it took the supercomputer over a week to complete the analysis. When it did, though, a new hypothesis had emerged: the bradykinin storm hypothesis.
Dr. Jacobson, the lead researcher, called it a “eureka’ moment. Not only could the hypothesis explain the fundamentals of COVID-19, it also potentially explained many of the bizarre elements associated with the disease.
Jacobson’s study, though, suggested that instead of the ACE2 receptors in COVID-19 being downregulated, as van de Veerdonk suggested (and as some studies had shown), they were dramatically upregulated. Ang (1-9) – one of the countervailing forces against Ang II – appeared to be dramatically increased as well. (But then, so was the receptor for Ang II.) Jacobson believed that the angiotensin pathway had been shifted towards Ang (1-9), which gets metabolized to Ang (1-7), which turns on bradykinin – a vasodilator.
Jacobson found that the genes tasked with responding to bradykinin were being expressed at a feverish pitch. So were the genes for the enzymes that activated the kinin pathway that bradykinin is a part of.
Jacobson’s study suggested that the opposite situation to ME/CFS was occurring. ACE2 was elevated, not reduced. Instead of high levels of Ang II sparking vasoconstriction and inflammation, high levels of Ang (1-9) were triggering a bradykinin explosion.
The Bradykinin Connection
While Jacobson’s findings were opposite to what van de Veerdonk had proposed, it’s in van de VeerDonk’s hypothesis that COVID-19 and ME/CFS/POTS perhaps start to merge again.
In his hypothesis, van de Veerdonk went back 15 years to a Nature paper, which found that increased levels of the ACE2 enzyme protected against severe lung damage with the first SARS virus. (High levels of Ang II, on the other hand, worsened lung damage.) Several other studies found reduced ACE2 activation in the first SARS-CoV-2 virus.
van de Veerdonk then linked the reduced ACE2 activation to the lung damage in COVID-19. ACE2, it should be noted, does not itself inactivate bradykinin, but it does the next best thing; it inactivates the activators of bradykinin.
Could COVID-19, ME/CFS and POTS have a fundamental factor in common?
While van de Veerdonk may be wrong about COVID-19, his hypothesis may make sense regarding ME/CFS/POTS. The upshot is that people with COVID-19 and ME/CFS may both have issues with the RAS system – and both could possibly be facing a bradykinin storm.
The real amazing thing is that two years ago, Wirth and Scheibenbogen predicted that bradykinin – a substance rarely associated with ME/CFS – plays a major role in the disease.
- Next up – The Bradykinin Storms in COVID-19 and ME/CFS
One thing that was part of my workup for POTS (at Mayo, AZ) was evaluating the RAS function. It was wayyyyyyy off for me. Low renin and aldosterone. (See first part of the blog before. I talked about it more there.)
Bradykinin release makes sense especially with them coming from mast cells. Those of us with MCAS and POTS, know too well the results of that. They are giving antihistamines for COVID and that turns off the response. I would also think a mast cell stabilizer like GastroCrom would be of help. In an accute situation, it may be necessary to do this. (However, for my day to day MCAS…..Im no longer using histamine blockers but trying to reset my Histamine 2 receptor to turn on and moderate the over response to histamine. Just as the RAS system has receptors that moderate response and turn down over response (Cort called them arms….its receptors) the histamine pathways also have moderators, down the line, to do that too. We have threads on the forum about this and what we are attempting with this. I only use GastroCrom occasionally now. And I have had really bad MCAS to point of being in ICU for my heart due to Kounis syndrome.) But in such an acute situation of mast cell degranulation and bradykinin release, it has to be hit hard and fast. No time to try to reset receptors. Bayard listed a paper on this on the forum too.
There definitely seems to be connections here.
Good job Cort.
Here is thread Bayard posted on COVID and histamine.
https://www.healthrising.org/forums/threads/pathogen-stimulated-histamine-production-and-release-by-neutrophils-as-a-potential-therapeutic-target-in-preventing-progression-of-covid-19.6353/#post-36645
This is for an accute situation.
As mentioned before, I no longer use antihistamines for MCAS. It has been many months since I have needed to. So has taken a long time to reset my receptors and I still have to watch diet closely, but in so many ways, I’m sooooooo much better off them.
I agree with Issie that mast cell activation (MCA) seems to be a big part of the process. I have Kounis syndrome at times, too. But, I began life with mast cell activation symptoms so they have been with me for 68 years. I wonder if have MCA causes patients to have a worsened outcome when they are hit with Covid-19? I restrict high-histamine food and drink and the only med I take for MCA is fomatodine which is something they give Covid patients, I notice.
Thanks. I was surprised to learn of the mast cell connection – how about that? It gets more and more interesting.
Me thinks you do jest sir
Fascinated by the links between ME/CFS and MCAS, is ME actually a type of MCAS that affects the limbic system. Just read the Occam’s Razor MCAS
book by Dr Afrin, the similarities are startling. I’ve set up a private group on facebook in the hope that people can help me further the discourse on this – ‘scuse the slightly cheeky group name 😉 https://www.facebook.com/groups/thegreatmastdebate
@Tom, I don’t tweet or Facebook. Only forum I participate on is Cort Healthrising and occasionally still on DINET. You are welcome to join our discussions on Healthrising. The ongoing threads are listed in the comments of this blog.
Doctor afrin, Janice jonela have made the mcas connections years back. I hope Ron is taking note.
The connection between eds is also known as is the stand Ford 2019 paper on mast cells causing osteoporosis.
There’s lots of evidence.. Jen brea saying that too.
So the knowledge is there but stabling mast cells is not easy
@Oliver, it sure is NOT easy. Me making the decision to experiment and come off antihistamines, with the severity I had with MCAS, was really risky. I thought I’d never get them to settle down. But I’m so much better now, being off of them. Has been many months trying to figure this out. Lots of trial and error. And I still have it come back with surges. But if I’m careful with diet, not getting too hot, too tired, too emotional and staying on the supplements and histamine supporting things……I’m doing pretty good. I found antihistamines were taking my brain function away from me. It was getting scary. Now, my brain is back and I can research again. I feel better all around. MCAS was a key player for me with my POTS. Until I addressed it, I could barely deal with what POTS did to me. Both things are more level and balanced now.
what did you do to treat it once off antihistamines
Hi Cort,
Many of us have a common genetic mutation, an ACE deletion. I believe it’s the insertion (I allele) deletion (D allele) polymorphism of ACE gene (rs4646994). This ACE gene is expressed in bone marrow cells and encodes angiotensin converting enzyme (ACE), converting angiotensin I to angiotensin II, which stimulates proliferation of hematopoietic stem cells.
It is not clear to me how this common polymorphism affects anything in your article. Have you heard of this and do you have any idea?
@Learner, I tried looking that up in my raw data on 23&me, its not there. Any other genetic markers to look at?
I can go into my Selfdecode as he has a report on genetics and COVID and the connections found with ACE. I’ll take a look at that again.
Okay, looked up ACE2 on that report and there are 2 listed for me, both with one allele off. Not sure what these two do, but are connected to ACE2.
I swear, we got a bad hand with our genetics!!!!! Doesn’t mean there is a dysfunction there. Other genes could be assisting and taking up where those fall short. And there sometimes has to be the right combination of polymorphism or mutations to create a full blown problem.
I got some really not desired genes and don’t have what they should predispose me to, thank goodness!!!!!
Takes a brave person to look into genetics, we can sure uncover some things we rather not know.
If this is the “silver lining” coronavirus research brings to the ME field, it could be big.
I am very much encouraged that Scheibenbogen is on the same track. It would be interesting to hear what she thinks about this finding.
Thank you for again illuminating the science, Cort. It would be impossible for me to follow otherwise!
100% Long COVID is Ehlers Danlos Syndrome traits they even look like EDS
There is also a connective tissue connection! Wirth and Scheibenbogen brought that out in their paper and we will hear more about that. Wirth believes it could explain the intracranical hypotension and craniocervical instability and others.
We call it a trilogy……many of us POTS people have POTS, EDS, and MCAS. Its all connected and many, many, many of us have all three. Then throw ME/CFS on top and you have a whole lot of dysfunction.
Sounds right plus new criteria in lots it is not EDS3 but HSD types instead. I would not be surprised they had (HATS) Hereditary Alpha Tryptasemia Syndrome as well in COVID 19 & ME/CFS Fibro HSD
Yes definitely EDS component of it. I am convinced all the long covid and v damaged have EDS.
Did you see jen brea s tweet saying we are gonna learn more about mast cells in the next two years than in the entire history of medicine.
Then she signed out of twitter saying she won’t be back until….
Then there’s Whitney saying something huge has shifted in understanding.
Maybe I’m reading too much into it but I’m pretty sure something is afoot and it at least involves mast cell activation syndrome, bradykinin and perhaps even prusties mitochondrial fragmentatin
“ME/CFS may both have issues with the RAS system – and both could possibly be facing a bradykinin storm.”
I’m going to take a very big leap here, but Issie and I recently started delving deep in the connection between mucus and ME/CFS, FM, POTS, IBS,…
The reasons? I and to some extend Issie too noted that I have “partial cystic fybriosis like” symptoms for much of my life. True cystic fybriosis is a nasty chronic disease with low life expectation when untreated.
True cystic fybriosis is diagnosed by having strong mutations on both CTFR gene legs. Those genes regulate one thing: chloride channels and with it mucus hydration. Mucus is the slimy stuff that lines all sorts of epîthelial cells, ranging from the stomach, gut, lungs, sines, pancreatic duct to the vagina. Good mucus hydration, not too much nor too few, is key to good protection of many of these surfaces exposed to many external factors and pathogens.
From Cort’s blog titled “Surprise Gene Finding Could Give Pathogens and Toxins a Leg Up in ME/CFS” on HR:
“A remarkably large proportion (77-80%) of individuals with ME/CFS were found to have alterations in the genes that produce mucous.”
Cort did a nice job explaining why it could affect our health and immune system so much, so read it up there.
Going back to us observing “partial cystic fybriosis like” symptoms, cystic fybriosis is a mucous disease at its very core. It has it written all over it. The problem with cystic fybriosis is too few mucus hydration creating very dry mucus with very poor quality. Since then, we found that there are quite a few other ways to have too few chlorine secretion by epithelial cells. Too few chlorine secretion leads to too dry mucus.
=> After reading this blog and delving a bit deeper, it turns out that increased Bradikinin… …increases chloride secretion by epiothelial cells and hence increase mucus hydration.
=> Could this supposed bradikinin storm in ME point to a desparate mechanism of our body to increase mucus hydration to protect us from nasty mucous diseases???
I separated the (even deeper) technical stuff in this part.
From a paper titled “Neurophysiological mechanisms of bradykinin-evoked mucosal chloride secretion in guinea pig small intestine ” by ”
Mei-Hua Qu 1 , Wan-Sheng Ji 1 , Ting-Kun Zhao 1 , Chun-Yan Fang 1 , Shu-Mei Mao 1 , Zhi-Qin Gao 1″
“Aim: To investigate the mechanism for bradykinin (BK) to stimulate intestinal secretomotor neurons and intestinal chloride secretion.”
“Conclusion: The results suggest that BK stimulates neurogenic chloride secretion in the guinea pig ileum by activating B2R, through COX increasing PGE2 production.”
=> In more plain English: Bradikinin made the mucus lining the researched part of the small bowel more wet (hydrated).
From a paper with title “Bradykinin increases IL-8 generation in airway epithelial cells via COX-2-derived prostanoids” by authors “Helen C. Rodgers, Linhua Pang, Elaine Holland, Lisa Corbett, Simon Range, and Alan J. Knox”:
“Interleukin (IL)-8, the C-X-C chemokine, is a potent neutrophil chemoattractant that has been implicated in a number of inflammatory airway diseases such as cystic fibrosis. Here we tested the hypothesis that bradykinin, an inflammatory mediator and chloride secretagogue, would increase IL-8 generation in airway epithelial cells through autocrine generation of endogenous prostanoids. Bradykinin increased IL-8 generation in both a non-cystic fibrosis (A549) and cystic fibrosis epithelial cell line”
=> It says IL-8 is increased by bradikinin in all sorts of cells. It also says that increased IL-8 and hence indirectly has been related to (mucuos disease) cystic fibriosis.
From a paper titled “Bradykinin regulation of salt transport across mouse inner medullary collecting duct epithelium involves activation of a Ca2+-dependent Cl− conductance” by authors “H Kose,1 S H Boese,1 M Glanville,1 M A Gray,1 C D A Brown,1 and N L Simmons1,*”:
“bradykinin was shown to activate a transient Cl− selective whole cell current”
“This data suggests that endogenous activation of bradykinin B2 receptors increases Cl− excretion to urine at the collecting duct.”
=> Bradykinin increases Cl- excretion to the urine. As Cl- attracts more water that means larger volumes of urine or reducing hydration and blood volumes.
=> It is in the kidneys, but the kidney filter mechanism AFAIK again uses epithelial cells to trasport chlorine and with it water from one side to the other. This mechanism has IMO strong similarities with how epithelial cells hydrate mucus.
From a paper with title “Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue” from authors “Gordon Broderick 1 , Ben Z Katz, Henrique Fernandes, Mary Ann Fletcher, Nancy Klimas, Frederick A Smith, Maurice R G O’Gorman, Suzanne D Vernon, Renee Taylor”:
=> look at figure 1: IL-8 is 10 to 15 times as high with people who got ME/CFS after EBV infection versus those who recovered after EBV infection. EBV sure is a bad friend of many of us.
There is also a paper titled “MRP transporters as membrane machinery in the bradykinin-inducible export of ATP ”
=> Ron Davis said that our (energy depleted) cells dumping their (hard won) ATP is a unique feature in our disease. Bradikinin might play a role in this too it seems.
Edit: “It also says that increased IL-8 and hence *** bradikinin *** indirectly has been related to (mucuos disease) cystic fibriosis.”
Another potential connection – and an entirely different one – how about that! Thanks DeJurgen. 🙂 The research community lost a big player when you got ME/CFS. At least you’re still able to draw these potential connections for us and others. (Who knows who may be reading this stuff.)
Here’s a link to the blog 🙂
https://www.healthrising.org/blog/2020/07/11/mucosal-genes-chronic-fatigue-syndrome/
Cort, I’d say the ME/CFS community GAINED a big player when we got Dejurgen. ?
Had he not gotten it, he and I neither one would be researching together. He has a brilliant brain.
I just hate anyone has to have this. But thankful and grateful that some who do, can help to delve deep into the science.
Thanks Dejurgen!
After 34 yrs. of ME/CFS, I’ve been having more shortness of breath and more mucus issues. Now I can’t figure out if I have COPD or asthma, or if these new symptoms are part of the ME/CFS. So far the 2 chest x-rays indicated hyperinflated lungs, flattened diaphragms indicative of emphysema. But, the CT scan didn’t show these. My recent symptoms have been on the more serious side with difficulty breathing (not PEM)/mucus. I have to get the pulmonary function texts next (dreading those) since we’re told not to use any bronchodilators 8 hrs. prior to testing.
I have been wondering if the MUC19 gene is behind all of this. I checked my genetic data and have all 5 “rsd” locations that Dr. Klimas’s group found in her patients.
Is anyone else experiencing significant breathing/lung issues? Hearing about hydration problems with mucus makes me curious. If we have genetic variants does that mean our mucus is not able to hydrate properly? It could be causing a number of problems.
I clearly do have breathing difficulties. They get worse at night.
Going to a good physical therapist and doing breathing exercises plus circulation exercises (light exercises to improve blood flood throughout the body) helped me quite a bit with breathing.
Getting up at night when I wake up and doing those exercises too helped me also a whole lot, but in the beginning it was massively challenging as I had to get up over a dozen times to do those and break my sleep badly. Yet, impaired as I was before it didn’t made me worse but rather improved my health.
It costed truckloads of will power to make that one part of my nightly routine though. Luckily, it helped me with sleeping and waking up less too :-).
In the above comment, I tried to link RAS and bradikinin problems in ME to mucus (hydration) problems. As many might find it a very big leap, let me add the following to catch many women’s attention:
Females make up 75% of ME / FM / POTS / MCAS /… patients.
Research also did find “A remarkably large proportion (77-80%) of individuals with ME/CFS were found to have alterations in the genes that produce mucous.”
Add to this the finding that estrogen is a really strong and key regulator of mucus hydration and quality.
Add to this the hypothesis / idea that excesive high bradikinin levels, likely seen in many ME cases, can increase mucus hydration significantly.
(too say it far too plain, (excessive) inflammation can create quite a bit of water pooling (where needed badly or desired in our case?))
=> Are our diseases tightly linked to mucus hydration problems, even up to the extend that they could be mucus hydration diseases?
Why would women be more prone then men to mucus hydration problems? Because woman need strong differences in mucus hydration and properties depending on different phases of their life (ovulation versus period, pregnant versus non pregnant).
That sort of “forces” their body to chance the mucus quality and hydration away from the “optimal” if those factors would not have to be taken into consideration. With men, ovulation and pregnancy are absent so their mucus doesn’t have to be modified *away from the optimal for personal health and immune functioning*.
Many woman report strong swings of ME / FM / migraine symptoms over their cycle. Estrogen and mucus quality varies a lot during their cycle too.
Many women with IBS, a disease strongly related to the gut lining and with it also to gut mucus, report strong variations in gut symptoms and cramping during there cycle.
Many women report strong variations during pregnancy of their symptoms. Many see a strong reduction of symptoms, while some see an upswing. I must admit the evolution of estrogen and its impact on mucus during pregnancy doesn’t goes exactly as I would expect, but keep in mind that estrogen levels vary wildly during different phases of pregnancy. Also, estrogen is not a single hormone but a collection of hormones and those vary even more. So it’s complicated…
Also, menopauze is said to be often a period of strong differences in ME / FM / POTS symptom strength.
Important note: I did find info that estrogen affects the hydration of *all* epithelial cells, not just those involved in the reproductive system. So swings in estrogen would create swings in mucus quality in the gut, lungs, sines, pancreatic duct, stomach… and possibly even modify kidney functioning.
From Wikipedia(Mucus)
”
Reproductive system
In the human female reproductive system, cervical mucus prevents infection and provides lubrication during sexual intercourse. The consistency of cervical mucus varies depending on the stage of a woman’s menstrual cycle. At ovulation cervical mucus is clear, runny, and conducive to sperm; post-ovulation, mucus becomes thicker and is more likely to block sperm. Several Fertility Awareness methods rely on observation of cervical mucus, as one of three primary fertility signs, to identify a woman’s fertile time at the mid-point of the cycle. Awareness of the woman’s fertile time allows a couple to time intercourse to improve the odds of pregnancy.”
So my thoughts were: would estrogen affect *all* mucus in a womans body?
From a paper with title “Estrogen modulates intestinal mucus physiochemical properties and protects against oxidant injury” from authors “Mark E Diebel 1 , Lawrence N Diebel, Charles W Manke, David M Liberati”
“Results: There were nearly 50% increases in the mucin content of both the nonadherent and adherent mucus layer(s) in HT29-MTX cells exposed to estrogen. Estrogen treatment also resulted in a twofold and eightfold increase in mucus viscosity and elasticity versus HT29-MTX cells with no estrogen exposure, respectively. Oxygen radical damage to the mucus layer caused by H₂O₂ was significantly reduced by E₂ compared with HT29-MTX + H₂O₂ without estrogen. Estrogen treatment resulted in significant reductions in both apoptosis and permeability seen after H₂O₂ challenge.
Conclusion: The results of this study suggest that sex differences in gut barrier function following trauma/hemorrhage shock may in part be related to differences in intestinal mucus content and the resultant physiochemical and oxidant-resistant properties of the mucus layer.”
=> So also affecting other mucus then vaginal only, including gut mucus. The amount that mucus properties swing under influence of estrogen is staggering to me.
Also during pregnancy:
From a blog called “mucus-in-stool-while-pregnant-should-you-be-worried”
“What are the Possible Causes of Mucus in Stool while Pregnant?
Usually, digestive problems can lead to mucus in your poop. Some of the causes of mucus in poop are mentioned below.
A hormone imbalance in your body can cause mucus in your stool.
Another common cause for the presence of mucus in your body during pregnancy could be the prenatal vitamins you take. If these vitamins have an excess of iron or calcium, you may notice mucus in your poop.
The expansion of your uterus commonly also displaces your intestines and this can also lead to mucus excretion in your body.
If you have food allergies associated with nuts or lactose, it can cause mucus in your stool.”
It relates mucus changes in the gut to pregnancy and thus likely links gut mucus to estrogen.
Number four also relates mucus to food intolerances. That’s a common thing in ME, FM… even migraines. OK, it says if you have food allergies you might excrete more mucus. But what if that mucus was subpar? It seems that extra mucus is excreted in order to protect the gut. Would you become more easily prone too these allergies and intolerances if mucus was subpar?
Bradikinin is one of several neurotransmitters and inflammatory mediators released when trigger points become activated. I have always linked mucous production with trigger point activation. I have trigger points from head to toe. I am menopausal and have also suffered for the last 18 years from frequent adrenal spirts/hot flashes and whenever these occur, I become enveloped in pain and start choking on increased mucous production. I also get runny and/or thick mucous production in my nose with post-nasal drip whenever I have neglected to keep my sternocleidomastoid trigger points in a latent state.
Your brain just keeps spinning and spinning spitting out interesting possibilities! So good to see. 🙂
Dejurgen is trying to connect some of his symptoms and find his WHYs and then a “purple bandaid” to help with it. We had noticed his issues with mucus and sinus issues.
With further checking we uncovered that estrogen plays a part with mucus. I have had a hypothesis in regard to males with ME/CFS and/or POTS that there may be an imbalance in estrogen to testosterone ratios. It could explain why these illnesses are predominantly females. But WHY some men get the illnesses too. We all have estrogen and testosterone in our bodies. Its the balance that is key.
Over the years I have asked many males if they had their estrogen levels checked. Some have, most haven’t. Some have found their estrogen levels were in range but have lowish testosterone levels. They say, No my estrogen is normal. BUT, if the testosterone is low…….you are then Estrogen Dominant. The balance swings too high for estrogen to a lowish testosterone level.
Dejurgen, is bringing out about estrogen as it plays a key role in mucus production. And now he uncovered that bradykinin plays a part in mucus too.
With COVID, there is too much bradykinin and lots of mucus issues. Could this be because of the pathogens it is trying to eliminate? And this over response that doesn’t turn off, goes too far and then we have a problem. Like with MCAS, an over response to histamine. (The H2R turns down the degranulation response and triggers T cells to activate the immune system. Histamine is now being used to treat MS, Parkinson, Alzheimer’s and narcolepsy.) The receptors that should halt this over response is not working. In an acute and life threatening response, we need to turn things off right then, in a hurry. But it may be a response of what may need to happen, but on a smaller scale than it does.
The connection here is that mast cells release both histamine and bradykinin. Both beneficial for the purpose they are supposed to serve. The problem is over doing a good thing and the moderator receptors not turning on properly. Two systems, both connected. Histamine receptors and RAS pathways.
My husband had symptoms of oestrogen dominance – little boobies and abdominal obesity. He also had a psa of 13 which I believe means his prostate was working overtime to convert testosterone into DHT (a form of testosterone that does not convert to oestrogen) and his testosterone levels were higher than normal. Once he started on pregnenolone 200mg, his testosterone levels returned to normal. It difficult here in Australia to get the medical practitioners to test for oestrogen.
It is difficult to get the doctors to check males estrogen. They look at you like……and WHY????? But, it is very important to keep the balance.
Another thing to note, taking testosterone can also make it convert into estrogen and it go down the wrong pathway. (Aromatase conversion.) You have to also take something to keep it from doing that. For example: DIM, DHEA and/or Saw Palmetto.
This article gives good advice how to correct this.
https://chriskresser.com/estrogen-in-men-why-you-need-to-balance-your-hormones-as-you-age/
Dr. Klimas’s modeling team has highlighted the protective roles that testosterone plays in ME/CFS and some doctors are even prescribing it in women with fibromyalgia.
Male Trouble: the Testosterone Connection in Fibromyalgia
https://www.healthrising.org/blog/2015/06/12/testosterone-connection-fibromyalgia/
Both hormones figure in pain
Sex (Hormones) and Fibromyalgia: The Pain Connection
https://www.healthrising.org/blog/2018/05/11/sex-hormones-and-fibromyalgia-the-pain-connection/
Plus here’s what an overtraining syndrome study found:
reduced testosterone levels (possibly causing reduced muscle mass).
increased estradiol levels without a concurrent increase in testosterone (reduced testosterone-to-estradiol ratio) (possibly caused by metabolic abnormalities; body composition changes found).
https://www.healthrising.org/blog/2019/09/28/overtraining-syndrome-chronic-fatigue-two-similar-diseases/
I’m glad to hear it is being looked into. I’ve been thinking this was a connection for guys, for years.
I thank the guys who had the courage to answer my question, when I asked it, with honesty. May be a “purple bandaid”? for you guys.
AND, for us girls……even for those of us past menopause. Taking a look at hormones may play a part here.
Many ways to be exposed to estrogen. In our foods, plastic, chemicals, medicines, even being over “fluffy”. Estrogen can be in our fat too.
Key here is ratio between them all.
Been there, done that, Cort. I have been experimenting with hormones since I went into menopause 18 years ago and suffered horrific hot flashes. I’ve been on progesterone, oestrogen and testosterone all at the same time and was not satisfied with the result. Taking the individual hormones appeared to be too complicated so I searched for the precursor to all the steroid hormones, pregnenolone, and started taking that thinking that the body might decide the right balance. It did help a lot but certainly not a cure. I then found out about “pregnenolone steal” where in chronic stress, the pregnenolone is diverted to the cortisol pathway away from the sex hormone pathway and realised that with an overactive sympathetic nervous system, I had no chance of ever completely fixing the problem, especially since pregnenolone is produced in the mitochondria where we also have problems. I even tried DHEA for a while but the only real difference I noticed was that my hair went very oily.I have now been taking 700mg of pregnenolone for some years, finding that to be the best dose for me but I still get hot flashes and they get more intense and frequent the more active I am. However, I now very rarely get severe crashes that put me in bed for a couple of days but I still have only a limited amount of energy each day.
https://www.drmyhill.co.uk/wiki/Common_Hormonal_Problems_in_CFS_-_Adrenal
The above article states that the pregnenolone is stolen from the anabolic pathways and diverted to the catabolic pathways but maybe it is possible that in cases of severe shortage of pregnenolone that the aldosterone pathway may be stolen from in favour of cortisol production.
@Tricia, I hear you! Having had a hysterectomy (8th abdominal surgery, long story) at a young age and not being able to go on replacement for many, many months afterwards……it was most miserable. Then I didn’t tolerate what was tried.
We found a transdermal Estriol that helped some and then Red Clover that was more helpful for flashes. Tried DHEA and Pregnenolone too. Progesterone was really awful for me, gave me horrible hot flashes.
Then by much trial and lots of error, figured out a lot of what appeared to be hormonal issues and menopause related was MCAS. (Mast cell degranulation.) Appears hormones can also trigger that.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377947/
Addressing mast cell, made it all so much better. Having lower estrogen was better for me than trying to up it.
I had been told I would have menopause symptoms until my normal time clock was supposed to naturally be through that……that turned out to be true. The continuation of those symptoms, past that time, appeared to be mast cell connected.
One of my first signs of a mast cell degranulation is a hot flash coming on. If I get on top of my first symptoms, which includes my face to start to go numb on one side and losing my color (pallor), I can stop it usually before it happens in a really bad way. I have to be tuned in and aware and have my remedies handy. I’m doing much better now in so many ways. Still have MCAS, but I’m as good off antihistamines as I was on them. Way less rebound and have much clearer brain function. (I found when the antihistamines wore off, rebound comeback was horrible.)
Hi Issie, thanks for the article. Looks like I suffer from MCAS like you do. I will get myself more informed. Luckily I do have low oestrogen level. Antihistamines don’t seem to work for me either. I’m sorry to hear you have been through so much suffering.
@Tricia, be sure at look up the threads on the forum that are listed here on MCAS. I may have added some on a thread Dejurgen and I have going too. Been awhile since it was added to.
The approach I’m using is soooooooo not the usual approach. Quite the opposite. I educated myself well first, (thanks to Bayard). And then it has been months of experiments and timing things. But I’ve about got it. I did put what I’m using on there. I’ll see if I need to update it.
“Simply put, there is no known adrenal pool of pregnenolone for one cell to steal away from another, and no known mechanism has been described that could facilitate the transfer of pregnenolone between the mitochondria of different cells (in this case, from the mitochondria of cells within the zona reticularis to those within the zona fasciculata). Unfortunately, the most common figures used to teach steroidogenesis show a common pathway and typically do not specify the differential regulation of available enzymes between different steroidogenic tissues. This leads many to incorrectly assume there is a single “pool” of pregnenolone available for all steroid hormone synthesis within the adrenal.” https://www.zrtlab.com/blog/archive/reassessing-pregnenolone-steal/
Hi Remy, sounds like a great theory but doesn’t explain why taking pregnenolone raises my blood pressure and my progesterone levels whereas it lowers my husband’s blood pressure and his testosterone levels.
@Maureen, you may enjoy Bayard thread on Histamine and learning more about the receptors connected to MCAS. The medicine you take is an H2R blocker. This actually is the receptor that would “turn down” histamine. We want that one working. That is the one I’m trying to reset. Has taken months, but I about have it figured out. Believe it or not, I actually add histamine to do this. Trying to get my own body to not dump its histamine, doing so with either herbals, foods or transdermal, triggering H2R to kick in.
https://www.healthrising.org/forums/threads/mast-cell-histamine-immunotherapy-with-histamine.6233/
Bradykinin is also part of the DOMS reaction, delayed onset muscle soreness. DOMS is the only other body thing that I know of that has that consistent 24-hour delay, like post-exertional malaise. That delay is such a unique feature of ME/CFS, it’s always at the top of my mind. Whatever the biochemical trigger is, the PEM reaction has that delay built in. Seems like that should narrow the possibilities. Brain is not up to looking at the DOMS/ME bradykinin parallels right now though.
I looked this up, had not heard of it. Has to do with exercise and type fibers used. They also figured out a way to prevent the delayed muscle soreness in rats.
This was something I hadn’t heard of, but for sure sounds like PEM. And this DOM is connected to Bradykinin, according to this research, and not lactic acid.
https://link.springer.com/article/10.1007/s12576-015-0397-0
And to prevent it……
https://pubmed.ncbi.nlm.nih.gov/22381959/
Dr. Afrin, Dr Weinstock (you may remember him as the doctor that Cort posted about re: novel treatment for MCAS/POTS, he’s a bit of a rockstar with EDS patients that come to him for gastro issues) and Dr. Molderings on Covid 19:
“Covid-19 Hyperinflammation and Post-Covid-19 Illness May Be Rooted in Mast Cell Activation Syndrome”
https://www.sciencedirect.com/science/article/pii/S1201971220307323#!
—* “None of our treated MCAS patients suffering Covid-19 had severe courses or mortality.”
Note that Dr. Afrin also supports the folate cycle in his approach to MCAS…
Whoa! Thanks Meirav 🙂
Yesterday was science crash day. Getting my thoughts out is an accomplishment on those days. Now here is the English summary.
With ME, we have many perplexing and baffling symptoms. They very often make no sense at all. When we find something that can reduce a symptom, we often take it, get one or two days of relieve and symptoms are back. We increase the dose, get a day of symptom relief and they’re back again. It looks often like our bodies want to keep us ill.
Issie and I more and more are looking at it in a different way. Would our bodies need to do those weird things in order to safe us from something even worse? If so, what are they trying to accomplish?
Compare it with being intolerant to a food. Eat it, and you might get a nasty skin rash. Keep eating it and it will get worse. You can try using plenty of potions or medicine, but the rash is there to stay. Even if you finally manage to suppress the rash, likely even worse symptoms will pop up.
One way is to suppress those symptoms, the other way is trying to work your way back and trying to determine what beneficial properties that rash has. In our example, it could be expelling chemicals you can’t easily dispose of in another way. Then trying to track it back to you being intolerant to that food is leading to a potential solution.
Rather then trying to suppress the symptoms and leave the body unable to excrete that toxic stuff from your body, trying to reduce the need to expell the toxic stuff through your skin is the way to go. Removing the need to expell that toxic stuff, by no longer eating that particular food in this example, often leads to a spontanuous slow decline in those particular symptoms.
ME is often cursed not only by its patients but also by doctors and researchers. It is “the impossible diseasse”. So much things are going on that shouldn’t be going on or often are thought to be impossibly correct.
Rather then seeing that as a curse, we learned to see it as an opportunity. If our bodies would do something so outrages as having a potential chronic bradikinin storm, then would our bodies be either utterly dumb to do such stupid thing or would they be so desparate to even consider doing that?
We believe most often our bodies are that desparate to do that. We have blood volumes low enough to kill many healthy people if they have so few blood as us left by bleeding after an injury. We *might* have a chronic bradikinin storm at our hands not so much less intense then a short lasting one that kills plenty of healthier people if they get Covid.
It’s clear that such low blood volumes and such potential chronic bradikinin storm has very few potential advantages. That’s actually the good news. For each of those symptoms there are very few possible good enough reasons to be found as to why our bodies would be willing to take such harsh, long lasting and devastating measures.
When we have a few different of those “impossible contradictions” and very few “good reasons” to do all of them combined for years then few sensible options remain. That eliminates so many possiblities that they often point to a likely reason as to why that happens.
For such possible chronic bradikinin storm, having to fight a very strong persistent chronic pathogen is one possible reason. Even then, other options then having a chronic bradikinin storm to fight a strong chronic pathogen might exist. So this may not be the main reason. Having a very strong need to work around defect mucus hydration is another one.
Those two come together in the disability to hydrate mucus the normal way: you need to find another way around it while it likely still will be only partially effective as it was never meant to be done that way. If our mucus layers still remain too dehydrated, pathogens are way more difficult to fight off.
There may be other reasons as to why such potential bradikin storm would have a much needed benefit. But they are likely very few. Combine that with:
* previous research showing that almost 80% of ME patients has genetic mutations related to mucus problems
* mucus quality very strongly being altered by estrogen levels and the specific extrogen mix
* women making up 75% of ME / FM / POTS… patients
* women very often showing clear variations in diseasse intensity with varying estrogen levels and specific estrogen mixes during their life
* ME patients showing many symptoms like IBS, difficulty breathing (COPD is partly mucus related too), sine problems that can be caused by nothing but mucus problems already
=> All of that makes mucus problems a strong to very strong candidate to make us prone to very prone to ME and related diseases and playing a core part in them.
If so, then trying to work around those mucus problems might be an important thing to consider. We are trying to see if we can get that working for us.
Always ask why something is happening? A compensation for another problem? Wirth and Scheibenbogen believe amped up sympathetic nervous system is narrowing blood vessels causing bradykinin release (vasodilator) in attempt to open them up again.
That makes sense. I’ve always thought, and said, I felt the seeming over response of the Sympathetic nervous system is a compensation in POTS. One I didn’t feel should be turned off or completely turned down. Having more nor-epinphrine and epinephrine causing a faster heartbeat, helps pumping of the blood to vital places. Though very uncomfortable, is probably the lessor of the two evils.
That is a possibility, but I don’t “feel it”. I know that argument is low in science, but science intuition helped me more then once.
It seems to me that there are a lot more other chemicals that can take up that role and with less disadvantages. Using vasodilator drugs to try and compensate for the underlying problem has mixed results to say the least too. That is my main source of doubt.
But I might be wrong and I’ll gladly be proven wrong if that would come with a cure or a good helpfull drug ;-).
With my having HyperPOTS and it causing me to have much higher NE levels with standing, I have always felt the need to slightly vasodilate.
Having faulty connective tissue with EDS and that too affecting vein function. And my having too thick blood and low blood volume more need not only to thin my blood (I use herbs and enzymes to do that) but the need of that extra help of NE to help increase that blood flow to vital areas.
I always felt that the traditional medicine given for POTS that constricts the veins was all wrong for me. And get this, that medicine (Florineff) is a synthetic aldosterone that constricts the veins and makes the kidneys retain salt in an attempt to up fluid volume of the blood.
See the pattern……low aldosterone a possible compensation for me. Connect the RAS system…….compensation? Lessor of two evils?
Histamine…….compensation, lessor of two evils?????
Balance and getting receptors to work correctly.
Find out the WHYs, then find the perfect “purple bandaid”. ? Our “symptoms” may in fact be compensations.
There are however some illnesses that would present with low aldosterone (Addison Disease) that would be a dysfunction in the adrenals. What I’m speaking of is unexplained and has ruled out other possible reasons for those dysfunctions as an issue.
I was looked at for Pheo due to my high NE levels. They looked for tumors and any other dysfunction markers. Other things have to be ruled out. Don’t just assume its a compensation. It could very well be an illness that needs addressing.
All so interesting but I can’t keep up! I’ll try and do my homework before the next blog…
The upregulation of ACE2 receptors in lung samples is likely a compensation due to antagonism by spike protein fragments.
As such, this evidence on it’s own doesn’t suggest the “opposite situation”.
Bradykinin itself isn’t hyper elevated either, I’d prefer if researchers and journalists stopped talking about “cytokine storms” and “bradykinin storms” when there is no evidence of hyper-elevation of such levels.
They are calling this a hypothesis, which means suspected but yet to be firmly researched and determined. They are interesting reads.
https://elemental.medium.com/a-supercomputer-analyzed-covid-19-and-an-interesting-new-theory-has-emerged-31cb8eba9d63
https://elifesciences.org/articles/59177
Interesting about ACE2 upregulation in the lung tissues being possibly a compensatory reaction. The hypothesis was generated out of quite an extensive study but it’s still speculation at this point – and as Snow Leopard points out – it was all done on lung tissue samples.
I agree about cytokines in ME/CFS- no sign of a storm and not too many clouds either 🙂
Bradykinin, though, really hard to measure as it disappears so quickly. One of the researchers reported he was going to use NMR spectroscopy, I think it was, in attempt to assess it.
I didn’t. But will be really nice to have more WHYs, science is advancing and more of the pieces of the puzzle are coming together…… hopefully, the picture will come more clear into view.
Gives us all HOPE for positive change.
This above was a reply to @Oliver and it got kicked to the bottom.
This is really interesting. As a kid I was diagnosed with asthma at age 5 and multiple allergies. Then at 18, I got a virus and the ME/CFS began. Two of the major issues I first experienced, beyond fatigue, were IBS and recurrent chest infections. It is not an exaggeration to say I have had 200 plus chest infections and many more colds over my lifetime. One doctor told me that sticky mucus makes it easier for the bugs to take hold. In fact, I get a lot of infections at every mucosal barrier. As far as I am aware the histamine issues came before the mucosal problems but the virus at 18 may have merely unmasked a pre-existing issue. I agree that it is possible mucus, histamine, bradykinin and RAS are linked. A quick google search showed histamine is high in cystic fibrosis.
I would like to thank every single person who contributed to this interesting and challenging discussion of ACE 2 receptors, estrogen issues, mucous, gender issues, etc. Every time I go to my general practitioner, I leave there frustrated, disappointed, angry and so bewildered at their utter lack of curiosity about this illness whereas their staff condescendingly calls my case “chronic” and dismisses it, whereas I suffer so much. It really helped to feel less “crazy” because of your discussion tonight. I must say “Hats off” to the intellectual prowess your have demonstrated. It goes light years beyond that of my doctor!!!!!!! Thank you, everyone.
Brain Fog and Bradykinin
https://www.researchgate.net/project/COVID-19-PATHOGENESIS
Cort, did you write a third part to this?