Why ME/CFS is a result of the histaminergic system in overdrive

[redo]

So, any theory of ME/CFS must seek to explain the following (and please do add things to this list if you can think of any)

• Why the disease has increased in prevalence the last fifty years or so.
• Why ME/CFS affects more women than men.
• Why sensory stimuli can make the symptoms so much worse.
• Why transient and unrelated stressors like extreme stress, giardiasis and mononucleosis can trigger ME/CFS.

I'll make a separate thread of this some time later this year. I think we should add these to the list.

• Why so many ME/CFS patients also have MCS
• Why so many ME/CFS patients also have IBS
• Why ME/CFS patients get PEM

If an overactive histaminergic system is at the core of ME/CFS then mechanisms such as these could certainly explain PEM. "The findings represent the first documentation of increased urinary levels of 9alpha,11beta-prostaglandin F2 in adults following exercise challenge and provides clear evidence for mast cell activation during exercise-induced bronchoconstriction in asthmatics."

If asthmatics can get their mast cells activated by exercise, there is no reason why people with other mast cell disorders couldn't also get their mast cells activated by exercise.

Regarding the triggers, in such a summary list, it should be noted that getting the recent pandemic influenza A (H1N1) was associated with a more than two-fold increased risk of getting CFS/ME.

 

[jimells]

If asthmatics can get their mast cells activated by exercise, there is no reason why people with other mast cell disorders couldn't also get their mast cells activated by exercise.

I'm sure that for me, just waking up or standing up activates mast cells. For example, before I started anti-histamines, just standing up was enough activity to cause widespread itching. Another example: taking a shower caused itching.

Nearly every day around 4 AM I would waken with night sweats and one hour after waking I would experience a "hot flash", and these symptoms have also stopped. Yes it could be coincidence, but since I had those symptoms *for years*, I suggest "just coincidental" is unlikely.

Purely speculative, since no one has bothered to look, but I strongly suspect extracellular ATP is a major player in activating my mast cells, as Naviaux's Cell Danger Response theory suggests (his theory involves extracellular ATP, not mast cells specifically). I vaguely recall reading someplace that red blood cells can also deliver ATP along with the oxygen, so that could be another trigger for mast cell activation.

There is research showing that Corticotropin-releasing hormone (CRH) both activates mast cells and is released by mast cells; that could be a bad positive-feedback loop. CRH is released by the hypothalamus in order to tell the pituitary gland to produce ACTH, which tells the adrenal glands to make more cortisol, epinephrine, norepinehprine, etc. If I understand correctly, CRH is released as part of waking up in the morning, which is why I think that early-AM CRH is activating my brain mast cells.

I also have a few IGE activated food allergies; some of them appear to be delayed hypersensitivies. It makes me wonder if PEM is a delayed type hypersensitivity.

While mast cells are commonly understood to be located primarily at interfaces to the outside world (such as mouth, gut, lungs, and skin), they are also found in the brain, located near the hypothalamus:

Chronic Fatigue Syndrome, Mast Cells, and Tricyclic Antidepressants

Theoharides et al, 2006

“Tricyclic antidepressants have been reported to be helpful [for CFS] at concentrations lower than those typically used to treat depression.”

“We hypothesize that corticotropin-releasing hormone (CRH) and other related peptides secreted by acute stress, activate diencephalic [a part of the brain that includes the hypothalamus] mast cells, either directly or through neurotensin (NT), leading to the release of proinflammatory cytokines that contribute to CFS pathogenesis”.

“Mast cells and their mediators have been implicated in diseases that are comorbid with CFS; in fact, there may be altered mast cell function in some tissues of CFS patients.”

Full text at Sci-Hub.

@Janet Dafoe (Rose49) I sure hope that someone on Dr Davis' team can look at the role of mast cells in ME someday soon. To me it is such an obvious avenue of inquiry that I can't understand why there is so little interest on the part of researchers and even most patients. Maybe I'm just biased by the fact that antihistamines and aspirin make the difference between me being homebound and being bedbound.

 

[redo]

So, any theory of ME/CFS must seek to explain the following

• (...)
• Why transient and unrelated stressors like extreme stress, giardiasis and mononucleosis can trigger ME/CFS.

Okay. So I've looked around a bit, and see that a common denominator of extreme stress, giardiasis and viruses is that they can activate mast cells.

Mast cell activation by stress. https://www.ncbi.nlm.nih.gov/pubmed/16110169

Viruses. Scroll down to "How are Mast Cells Activated by Viruses?" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435071/#!po=31.1321
The article doesn't specifically mention mononucleosis. I've done a PubMed search without finding anything, neither disproving or validating that there is a connection.

I found a study which states that "mast cells are important for the rapid control of Giardia infections in mice". If I look around more I am sure there's more to be found. But this at least shows there can be a connection.

 

[Wishful]

While I'm not convinced yet that mast cells are part of the issue, for the question of 'why does ME affect women more than men', recent findings claim that testosterone affects how mast cells respond to inflammatory events, protecting males.

 

[redo]

If the hypothesis held true that people with ME/CFS are "only mentally ill and stressed", then we would expect that the gender ratio of depression and ME/CFS would somewhat match. The gender ratio when it comes to depression is 1.7 women for every man. But the gender ratio of ME/CFS is 4 women for every man. That is a huge difference. And makes the "ME/CFS patients are only mentally ill" hypothesis less plausible.

UPDATE. The theory that ME/CFS is just "stressed out people" should rather be matched with the gender ratio for PTSD. "The lifetime prevalence of PTSD is about 10–12% in women and 5–6% in men." So 2 women for every man have PTSD. Closer, but still not close to 4 women for every man. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632782/

While I'm not convinced yet that mast cells are part of the issue, for the question of 'why does ME affect women more than men', recent findings claim that testosterone affects how mast cells respond to inflammatory events, protecting males.

Yes!

And on top of that we have this:

"Experiments in rodents confirm an effect of estrogens on mast cell activation and allergic sensitization, while progesterone is shown to suppress histamine release but potentiate IgE induction" https://www.ncbi.nlm.nih.gov/pubmed/18925878

Later I will look at various allergic diseases and see if there is one with a mathing gender ratio of ME/CFS, and also look at various psychiatric diseases and look for a gender ratio matching ME/CFS.

You're not convinced, Wishful? Me neither! But I am looking for something that makes the hypothesis seem less likely. So far I haven't found it. If you can think of anything, then please post.

 

[Wishful]

If you want to test the hypothesis, look for drugs or foods/supplements/activities that affect mast cells and test to see if they affect ME symptoms. If there's a drug that strongly inhibits mast cell activation or operation and it doesn't seem to have much effect on ME patients, that would be fairly strong evidence against it. I don't feel up to doing that search myself right now, so I'll leave it to you.

 

[ljimbo423]

@redo-

Interesting thread!

So, any theory of ME/CFS must seek to explain the following (and please do add things to this list if you can think of any)

• Why the disease has increased in prevalence the last fifty years or so.
• Why ME/CFS affects more women than men.
• Why sensory stimuli can make the symptoms so much worse.
• Why transient and unrelated stressors like extreme stress, giardiasis and mononucleosis can trigger ME/CFS.

I think the main reasons why the disease has increased in prevalence the last fifty years or so are, #1- antibiotics but also higher levels of toxins in our food, water and air = everywhere!

Antibiotics cause dysbiosis and dysbiosis increases intestinal permeability. This allows lipopolysaccharides (LPS) from gram negative bacteria in the gut to get into the bloodstream and cause an immune system reaction.

Toxins increase inflammation, which in turns increases intestinal permeability and causes an immune system reaction and symptoms. There are an enormous amount of mast cells in the gut which could be causing many of the mast cell symptoms in CFS.

I don't know why women are more effected than men but there could be many reasons.

Why sensory stimuli can make the symptoms so much worse. Neuro-inflammation I think is probably the biggest reason. LPS from the gut I think also causes the neuro-inflammation. Neuro-inflammation causes a magnifying of sounds, light, etc.

Why transient and unrelated stressors like extreme stress, giardiasis and mononucleosis can trigger ME/CFS.

I think anything that can significantly increase inflammation can increase intestinal permeability, causing symptoms.

EDIT- Stress causes inflammation, as does mononucleosis (and any other viral infection) and a Giardia infection often causes significant gut damage that can take a long time to reverse.

Here is quote from a leading CFS researcher, Maureen Hanson, from her 2016 study on the gut microbiome and increased microbial translocation -

Taken together, our results suggest an ongoing damage to the gut mucosa, leading to increased microbial translocation in ME/CFS, which in turn could alter antimicrobial regulators and disregulate the innate immune system.

LINK

This is a quote from another leading CFS reseacher, Chris Armstrong-

"Well we all experience a bacteremia when we exercise. The type of bacteria that enter your bloodstream are usually quite controllable by your immune system but if your gut is further compromised they may release more bacteria into your blood or more pathogenic species or your immune system may already be depleted.

This is the concept for the chronic sepsis or SIRS and this is what I think may be behind PEM."

LINK

This video at 14 mins in shows that the gene expression pattern on CFS is a 100% match to systemic inflammatory response syndrome (SIRS). Which is what happens when lipopolysaccharides get into the bloodstream.LINK

Just a few thoughts!

Jim

 

[Learner1]

If you want to test the hypothesis, look for drugs or foods/supplements/activities that affect mast cells and test to see if they affect ME symptoms. If there's a drug that strongly inhibits mast cell activation or operation and it doesn't seem to have much effect on ME patients, that would be fairly strong evidence against it. I don't feel up to doing that search myself right now, so I'll leave it to you.

I have both ME/CFS and MCAS, as several others around here do. They seem to be comorbid conditions, with MCAS exacerbating ME/CFS symptoms. Some of the things I take for MCAS help reduce my ME/CFS symptoms. I'm not sure there's a lot of concrete science out there, though...

 

[redo]

I have both ME/CFS and MCAS, as several others around here do. They seem to be comorbid conditions, with MCAS exacerbating ME/CFS symptoms. Some of the things I take for MCAS help reduce my ME/CFS symptoms. I'm not sure there's a lot of concrete science out there, though...

Yes, that's my impression too. Many have both MCAS and ME/CFS, but alas there's not a lot of concrete science. When it comes to MCAS and ME/CFS it should be fairly easy to do blinded studies: if patients know what makes them worse (but not horribly worse) one could then put it in a capsule and then have other capsules with intert material and do a trial.

Maybe I am wrong, but I really have the impression that most GPs think of MCAS as "complaints a lot" instead of "reacts to a lot". So we could really use some more studies.

 

[Learner1]

MCAS has labs that identify it. My doctors ran tests for tryptase, histamine, prostaglandin D2, and Chromagranin A.

 

[Wishful]

@redo-
I think the main reasons why the disease has increased in prevalence the last fifty years or so are, #1- antibiotics but also higher levels of toxins in our food, water and air = everywhere!

Is there actually any statistical evidence for increased prevalence of ME/CFS? We still don't have an official lab test for it, so we can't have reliable figures for how many people have it. There's certainly been a rise in the number of people who believe they fit the criteria. Earlier, people were diagnosed as 'lazy' or 'malingering' or having a variety of illnesses that couldn't be proven true or false.

I'm not claiming that the incidence hasn't increased; just that we lack the tools and historical data to answer the question.

 

[redo]

Is there actually any statistical evidence for increased prevalence of ME/CFS? We still don't have an official lab test for it, so we can't have reliable figures for how many people have it. There's certainly been a rise in the number of people who believe they fit the criteria. Earlier, people were diagnosed as 'lazy' or 'malingering' or having a variety of illnesses that couldn't be proven true or false.

I'm not claiming that the incidence hasn't increased; just that we lack the tools and historical data to answer the question.

There are other people better fit to answer that than me. I haven't studied the literature enough to know whether there is either flimsy or sound evidence of the increase in incidence. Anyone who has an opinion on this, please chime in.

When it comes to the of understanding "syndromes" like ME/CFS and fibromyalgia, we have lumpers and splitters. I am a lumper, and think there is a common thread between them. That if we'd have a perfect understanding of one, we would have a clear understanding of the other. Perhaps it's the same mechanisms, perhaps not. But if we widen the net a bit, and see that many autoimmune illness have increased in incidece (have they? I haven't studied it) then that would be at least an indication that it's also the case for ME/CFS, if there is a lack of studies proving ME/CFS increased in incidence.

It would also be useful to know whether IBS has increased in incideces, since X % of IBS patients also have ME/CFS, and some 50 % av ME/CFS patients also has IBS. It would be just circumstansial evidence, but better than nothing.

Anyways, what I can say is that I know several doctors personally, who is now either just retired or will retire soon, and what they say is that it's their impression after a long life as doctors that there are many more now than before who come with the type of symptoms we call ME/CFS. This is of course not sound evidence, so chime in anyone who has a perspective on this.

I think it would be useful for the ME/CFS community if we would build a set of questions a hypothesis of ME/CFS must answer. A set of questions anyone who has a hypothesis of ME/CFS, either their name is Wessely or Lipkin, Jane or John Doe, agree that their ME/CFS hypothesis must seek to answer.

If we assume ME/CFS is just some sort of stress reaction, that would mesh with the gender ratio of PTSD. But the PEM is a complete mystery if ME/CFS is just a PTSD like illness, as virtually all studies on PTSD show that exercise is a great PTSD medicine which gives relief.

Without going into detail, using the mast cell / histamine hypothesis we could think of PEM somewhat like patients with asthma who deteriorate after exercise.

(EDIT: If I had more time, I would have written a shorter post)

 

[Wishful]

I think of PEM as a response to immune system activation as a result of various activities. IFN-g rises 24 hrs after physical exertion, so that could be the trigger, though there's probably a whole cascade of cytokines released, some of which might also have that 24-hr delay. Does asthma have such a precise consistent delay? If not, it's not a good analogy.

 

[redo]

I think of PEM as a response to immune system activation as a result of various activities. IFN-g rises 24 hrs after physical exertion, so that could be the trigger, though there's probably a whole cascade of cytokines released, some of which might also have that 24-hr delay. Does asthma have such a precise consistent delay? If not, it's not a good analogy.

When I wrote somewhat like asthma, I meant that we know exercise triggers an immune reaction in some ninety percent of asthma patients. Their airways tighten. So it's plausible that another type of immune reaction may be triggered by exercise in ME/CFS patients.

If the mast cells are activated, they have "many tricks", such as displayed here:

I was about to write that knowing what a myriad of processes mast cells are involved in, it wouldn't be far fetched to think they might be involved in an IGN-g rise, which then would go slower (I assume) than a regular histamine rush.

But I searched and found this study saying that mast cells regulate IFN-gamma and this one called Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma. So, without going into detail, there may very well be a link between hyper-responsive mast cells and a rise in the interferon gamma levels.

UPDATE. And I found this.
"IFN-gamma induces apoptosis in developing mast cells
Mast cells are critical effectors of allergic disease, and are now implicated in immune responses observed in arthritis, multiple sclerosis, and heart disease. Because of their role in inflammation, understanding how mast cells develop is of clinical importance. In this study we determined the effects of IFN-gamma on mast cell survival."
https://www.ncbi.nlm.nih.gov/pubmed/16116187

And the PEM patiens experience seems to be a mixed bag, just like the mast cells' tricks are a mixed bag. So, many patients get worse immediately, many report being worse the next day, many report feeling it even later. More than 10 % of ME/CFS patients do not get worse from exercise, not all that a different number from asthma.

 

[Learner1]

In the charts above, there isn't the "dead feeling after exercise" as listed in the IOM report.

This article goes through many possible explanations for PEM:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639

 

[kangaSue]

I think I looked at Gastroparesis before and just saw nausea / vomiting and though - naa' not me.

For all intents and purposes, Functional Dyspepsia (FD) is basically Idiopathic Gastroparesis (IGP) without the delayed gastric emptying finding and maybe a less severity of GI dysmotility symptoms and both FD and IGP have been found to involve having an enterovirus in some people with ME/CFS.
http://file.scirp.org/pdf/OJGas_2015040916050357.pdf
https://www.ncbi.nlm.nih.gov/pubmed/27344315

 

[Runner5]

Thank you @kangaSue for the articles! I appreciate them.

 

[kelly8]

MCAS has labs that identify it. My doctors ran tests for tryptase, histamine, prostaglandin D2, and Chromagranin A.

I was diagnosed with mcas as well but they didn't do any of these labs. I'd be interested in seeing if my new Dr would be willing to check this out. The antihistamines they gave me helped with some of my symptoms but not all.

I can now tolerate more foods than before. I also can now tolerate more environmental things too but every once in a while i get a wierd reaction. Even to things i have encountered before...

 

[quent100]

It's an interesting theory - I started having problems with high histamine foods about a year before cfs (itchy skin, couldn't sleep, heart rate increased) - and now if I eat high histamine foods my brain shuts down - literally can't think properly. I attempt to steer clear - but there's just so many damn foods with high histamine!

 

[jimells]

This article goes through many possible explanations for PEM:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639

Thank you for this link. I didn't realize this article actually mentions mast cells:

4. Sleep Dysfunction Domain

Stress can trigger mast cells, which are heavily populated in the thalamus (located next to the sleep/wake center in the hypothalamus), to release the stimulant histamine. Excessive mast cells and their release of stimulants could be one of the reasons that sleep is interrupted in patients with ME and FM.

Mast cells act as an immunologic defense against external pathogens, and there are 5 to 14 fold increases of these cells in the top layer of the skin in 100% of patients with FM. Kindling may impact mast cells and the release of histamine in the thalamus, resulting in disrupted sleep patterns among patients with ME.

I have found Benadryl (diphenhydramine) to be helpful for sleep - more helpful than trazodone. Since it crosses the blood-brain barrier like other early anti-histamines, it can effect the mast cells that I suspect are a major problem for us. I am fascinated that this drug is sometimes marketed as a sleep aid, and sometimes marketed as an allergy remedy. IV Benadryl is also used as a rescue med for people having a severe mast cell episode.

I see where this article also talks about nitric oxide. NO is another mediator sometimes released by mast cells.