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

Discussion in 'General ME/CFS Discussion' started by redo, Jan 22, 2018.

  1. redo

    redo Senior Member

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    Please be the devil's advocate and tell me why the hypothesis is unlikely.

    Here goes.

    I was among those who got Rituximab for my ME/CFS symptoms. It did nothing for me. But quite unexpectedly my symptoms were ameliorated when I got a IV antihistamine at the time of the infusions. Also when taken orally, a high dose of antihistamines makes my symptoms much more bearable.

    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.
    We know that in just about the same period as ME/CFS has increased in prevalence, allergies have increased in prevalence. For the last half century, allergies of peanuts, pollen, apples, cats, dogs have become more widespread. We know that women disproportionately get allergies.

    It is hypothesized that the increase in allergies is due to the fact that we are so much more hygienic now than before. Kids growing up today are washed and bathed and showered regularly, and this new hygiene regime gives our immune system so few intruders to fight off. When a intruder "finally" comes, the system can go into overdrive. Never mind that the intruder can be something as innocuous as birch pollen or the hair of a dog. And we know that the immune system can actually attack specific receptors in the brain, such as with Anti-NMDA receptor encephalitis.

    Knowing that, we could hypothesize that the histamine system could actually react to a rush of catecholamines. This would certainly explain why people with ME/CFS can get worse from any sort of trivial sensory stimuli. This happens behind the blood-brain-barrier, so regular antihistamines in regular doses would do little to nothing.

    The common denominator of extreme stress, giardiasis and mononucleosis is that they all affect our immune system. Could it be that such "triggers" kick-start an immune reaction that never stops?

    And at last, if it indeed is so that we have an overactive histaminergic system, that would certainly explain why so many ME/CFS patients often get abnormal reactions to otherwise normal things, whether that be drugs or foods.

    If this hypothesis is correct, for many of those given the diagnosis ME/CFS, then we'd expect that antihistamines in regular doses dose nothing. But megadosing could help, and the drug Xolair which brings down the antihistamine response with 90 % in vitro, may certainly help. I haven't found that many reports of ME/CFS patients using Xolair, but of the few I've found there has been some with no effect, and some that have benefited greatly, such as this patient: "I have been using Xolair for 5 months for CFS, not asthma, with incredible results"

    This is a bold hypothesis, and I wrote it mostly to sort my own thoughts. So input is welcome.
     
    Last edited: Jan 27, 2018
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  2. Runner5

    Runner5 Senior Member

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    I grew up on a red neck farm with a family that was pretty darn backward. No hand soap - that was one of those rich people items. I had allergies though from the word go. I spent a lot of time out doors and barefoot. ;-P
     
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  3. jpcv

    jpcv Senior Member

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    1- I don´t know, also there seems to be a lower frequency of outbreaks lately. why?
    2-hormones, that modulate the imune system/microbiome
    3- I don´t know
    4- that´s the most importante question, no answer avaiable as far as I know.

    Histaminergic system doesn´t work alone, it´s conected to other pathways,maybe some people with many allergic symptom will benefit most from anti histaminergic drugs.
     
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  4. gregh286

    gregh286 Senior Member

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    think there is some overlap.
    I have angioedema since 1994, always go "fluey" after an attack, like we get with PEM, flu like sometimes.
    antihistamine do little for it.
    the IV antihistamine maybe its breaking up excess histamine in serum.....helping blood flow, etc.? Maybe its a dilator.....
    So much to this disorder.
     
    Sancar likes this.
  5. redo

    redo Senior Member

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    Thanks, Runner5. After reading your post I looked up comorbidity.

    I see one paper stating that some fifty percent of those with CFS have IBS. Fifty percent is way more than can be explained by chance. And I can see that mast cells (which release histamine) play a central pathophysiological role in IBS. So, if the simplest explanation is the most likely, then whatever is driving IBS is also driving CFS. And if a histamine system in overdrive is causing ME/CFS, then that could also explain why many ME/CFS patients experience multiple chemical sensitivites.

    I think of the hygiene hypothesis of allergies as a way to explain, on a population level, why allergies are more prevalent today. That be if hygiene is a major cause, or one of the major causes. Your own experiences don't mesh with the hygiene hypothesis of allergies. But what's true on a population basis isn't necessarily true on an individual basis. I assume that's why you added the winky smiley.

    To your comments on point 1. There have been outbreaks, such as with the cases of giardiasis in Bergen, Norway. But my impression is that the vast majority of those on these boards haven't gotten ill following a specific outbreak.

    But I think it's safe to assume that more people have symptoms of ME/CFS in 2018 than in 1918. Taking into account that we've got way better routines of monitoring how many people have such symptoms now than we had then.

    Anyways, I think a list as to what a ME/CFS hypothesis must seek to explain is of vital importance. Regardless of whether the hypothesis of this thread holds true.

    We have the camp who think that ME/CFS is merely a stress disorder. "Our nervous system is in overdrive," they think, and therefore we are ill. That could mesh with several points below, but it crashes fundamentally with point four, and therefore the stress hypothesis should be refuted or fall into the category "plausible, but unlikely".

    (1) Why the disease has increased in prevalence the last fifty years or so.
    (2) Why women are more prone to get ME/CFS than men.
    (3) Why sensory stimuli can make the symptoms so much worse.
    (4) Why transient and unrelated stressors like giardiasis and mononucleosis can trigger ME/CFS.

    When multiple chemical sensitivity seems to be a comorbid condition of ME/CFS, I wonder whether that should go on the list as well. That a hypothesis of ME/CFS must seek to explain why there is this comorbidity.


    If the hypothesis I put forth holds true, then regular doses of antihistamines would do little. There are studies of other diseases where they give very large doses, like 20 times a regular dose, and thereby sufficient amounts of the drug are able to penetrate the so-called blood-brain barrier to affect the histamine system in the brain.
     
    Last edited: Jan 22, 2018
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  6. Wishful

    Wishful Senior Member

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    ME seems to be triggered more by t-cell activation, which doesn't involve histamines. I haven't seen any clear link to immunoglobulin activation. If antihistamines helped you, it was likely a remote link, by altering some chemical balance which in turn altered some other balance, for some number of links. The body is incredibly complicated, with all sorts of interactions, so it's not surprising that something that affects one aspect of your body's function will affect ME too.
     
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  7. Runner5

    Runner5 Senior Member

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    @redo -- I see where you're going with this. Wheat might play a significant role and I don't really say that from a "omg gluten" and paranoid standpoint, nor from the standpoint of "evil scientistis!" (Not blaming science) I'm being very dogmatic because I realize that it requires a lot of work to feed the globe and I don't exactly want billions of people starving to death -- but if you hybridize and engineer a plant to produce substances that work against pests and work with your brand name herbicide maybe you introduce proteins that are extremely inflammatory to some people. Or maybe some substances were always inflammatory but we dealt with them differently.

    Another option is the vast use of Soy products these days which have estrogenic properties (how much so is very argued, probably not enough to matter).

    Probably however -- there is a certain Zeitgeist at work, we can't see outside our own box and the answer is within a framework we just don't have yet.

    Some people are using "Helminth Therapy" (aka hook worms or good old Ascaris) to calm down the allergic system. Do a Google Search for Youtube you'll find a wide variety of people voluntarily taking on intestinal parasites to calm down inflammation and cure allergies.

    It's really fascinating stuff. I have reactions every single time I eat which has lead me to do fasting several times a week these days.
     
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  8. Wishful

    Wishful Senior Member

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    Are your food reactions type I allergies (histamine), or type IV (t-cells)? My ME started as a type IV food sensitivity: 48 hr delay between eating and symptoms.
     
  9. Runner5

    Runner5 Senior Member

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    I'm not sure I'm allergic @Wishful but I get sick within 20 minutes of eating most things. A few things are safer than others. I can usually safely enjoy a banana and PB2 (dried peanut butter) or a bowl of corn chex cereal -- but most everything else is like taking a tranquelizer and totally makes me foggy, tired and sick feeling. The only time I feel well enough to do anything is if I don't eat.
     
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  10. kangaSue

    kangaSue Senior Member

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    The majority of mast cells come from the gut as does DAO (Diamine Oxidase) enzymes that breaks down excess histamine. Mast cells in the GI tract can be over-produced in a disturbed GI system while DAO can become deficient at the same time and when DAO enzyme activity is low, it leads to an alteration in the metabolism of food histamine.

    Don't bother with getting tested for your DAO enzyme level in the blood as it fluctuates greatly over the course of a day and is not a reliable indicator of deficiency.
     
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  11. tyson oberle

    tyson oberle Senior Member

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    What symptoms did you have that were ameliorated when you got IV antihistamines? And what specific oral antihistamines at high doses have helped? And at what dose?
     
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  12. Prefect

    Prefect Senior Member

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    This is not a new disease by any stretch:

    https://en.wikipedia.org/wiki/Neurasthenia

    I think the only reason we're seeing more chronic illness now is because people are living longer.

    CFS/ME tends to happen more to people from certain socio economical backgrounds, mostly professionals or affluent people, which is why it used to be called the Yuppy Flu.

    I think it's because there is a difference between the stress posture of affluence (restrained, shallow breathing, internalizing, stoicism, more mental stress than physical) and that of blue collar (externalizing, breathing deep and low - you always know when your plumber has arrived, his breathing sounds like that of a bear, acting out with adrenaline, more physical stress than mental).

    The former slowly sets your HPA axis towards a pathological trend that gets it ready for hypofunction as soon as a major stressor (such as an infection) is introduced.

    The latter is more in line with how we've evolved on this rock, high octane stress that is very physical, and I believe the physicality of the stress offsets the effect of stress hormones through higher opioid release, preventing HPA dysfunction. This type of stress may give you a heart attack by the time you're 50, but you're less likely to develop aberration in your autonomic system and HPA response.

    I believe the answer to this disease is resetting the HPA axis. All we have for this so far are SSRIs and an abortion drug, which is pathetic.
     
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  13. Wishful

    Wishful Senior Member

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    Is that a precise and consistent 20 minutes, or can it occur within a few minutes of the first bite? Just curious, because I very often feel lousier a precise and consistent 20 minutes (+/- a few minutes) after eating quickly-digested starchy food. I believe it's due to insulin increasing tryptophan transport into the brain and thus increasing kynurenine production. If your delay can be as short as a few minutes, it's probably type I allergy. Type III takes hours, and type IV typically takes days to develop.
     
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  14. halcyon

    halcyon Senior Member

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    Let's start by questioning your assumptions:
    1) I don't think it's just been the last fifty years. Yes, there was a noted global pandemic in the 1980s, but there also was one in the 1950s as well that was arguably worse.
    2) I don't think they are more prone to get it, they are more prone to not recover. In several outbreaks, the strike ratio was 1:1, but it was noted that the ratio rises to 5:1 over time.
    3) This does seem to be true in many cases.
    4) The evidence for this is extremely limited and what exists is not very convincing for these agents as a cause of literal ME. Do they both cause a prolonged fatigue syndrome consistent with CFS? Most likely. Is this the same exact thing as ME? Unlikely, I think.

    I don't think so, no. Why is it that the various cold viruses, influenza, etc. have never been convincingly linked to ME or CFS then? The immune cascade requires constant antigen stimulation to keep going (and even then, there are built in feedback mechanisms to stop a runaway reaction.) So far, ME and CFS have only been linked with pathogens that can persist indefinitely in the body or GI tract.

    Generally, if we assume these diseases are caused by persistent immune stimulation, then it isn't surprising that there will also be increased histamine release as the cells that release it will also be recruited by the immune response and take part in it. I also think a major part of it is caused by persistent increased sympathetic autonomic outflow. This is either a result of dysautonomia caused by damage or dysfunction in the brain, or as a normal response to infection, or both.

    I don't think long term high doses of antihistamines is a safe route to take. You're not getting at the root cause and you might also be making the original problem worse in the long run due to the anticholingeric effects of most antihistamines. People like Michael VanElzakker recommend against it, see this thread:
     
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  15. Wishful

    Wishful Senior Member

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    I don't think that's true. Many of us were triggered by vaccinations, which may have used inactivated pathogens, so no persistent infection. I'm pretty sure I've read some postings from people claiming to have gotten ME from viral infections such as influenza. If there are no clinically proven reports about ME caused by temporary immune activation events, that doesn't mean that it doesn't happen. ME/CFS has hardly had a lot of research funding and interest to date. The immune cascade may _normally_ require constant antigen stimulation, but ME isn't 'normal function'. I think it's quite reasonable for there to be a positive feedback loop that is keeping us in this abnormal state after an immune activation event.
     
  16. halcyon

    halcyon Senior Member

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    Nobody lives in a bubble. Imagine that you’re exposed to a pathogen while your immune system is dealing with the vaccine and adjuvents.

    I’ve not seen any reports of confirmed ME following a lab confirmed influenza infection. Yes many people report onset after a flu like illness but many other infections are mistakenly believed to be flu.

    We don’t know that ME isn’t ‘normal function’. I’d love to hear some proposed models for your hit and run theory.
     
  17. Runner5

    Runner5 Senior Member

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    Yes, plus or minus one or two minutes, but usually right at 20. Whole grains are the worst culprits except corn and not so much rice. Oats always cause me problems.
     
    Last edited: Jan 23, 2018
  18. Wishful

    Wishful Senior Member

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    I'm delighted to find someone else showing the same 20 minute response. Maybe if we find a few more people showing the same response, some researchers will look into it. Something with such a precise and consistent effect should mean something.

    I differ in that it seems to be refined starches that affect me the most. Starches that are slower to digest (lots of bran) usually don't show the response; maybe the effect is slowed and/or spread out. I'm not sure whether significant amounts of fat with it makes a difference.

    I usually read and have coffee while eating, so what I notice is that at some point, my attention seems to fade and I realize that I'm not actually following the book. I mark that as 'fading' in my diary, and it is usually 20 minutes after starting the meal.
     
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  19. Wishful

    Wishful Senior Member

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    I don't have a detailed model. It just seems plausible that there might be a feedback loop in our microglial cells or mitochondria that gets pushed over a threshold by immune activation and then stays in that abnormal state. My background is engineering, so I think in terms of feedback loops, bistate systems, etc. Plenty of electrical or mechanical systems can operate normally for a while, and then get locked into positive feedback by a signal that exceeds some threshold.

    Why we might have a positive feedback loop after a threshold is something for the researchers to look for. Maybe we have less of receptors (or producers) that provide negative feedback, or more of the ones giving positive feedback. Maybe we're missing a mechanism that otherwise returns us to the normal state.

    When my disorder started (as a type IV food sensitivity developed not long after a tetanus booster), I had spontaneous remissions once in a while, lasting hours. Those got less frequent, then stopped altogether. My guess is that whatever balance there was in the feedback loop was getting worse (probably with age). A few drugs/supplements seemed to trigger remission, but again, just temporary. I take that to mean that this isn't permanent degeneration of cells, but rather a shift in levels of something. I also consider it evidence against chronic infection. It doesn't completely rule it out, but doesn't seem to support it either. If it was chronic infection, the responses to immunomodulators should be more pronounced, and the changes should probably take longer. My responses are usually quite abrupt (getting better or worse over the space of minutes); I assume that viral or bacterial flare-ups or die-offs should take longer.
     
  20. Runner5

    Runner5 Senior Member

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    @Wishful -- I've never seen someone have 20 minute problem before, that is interesting.

    I've been experimenting with fasting, trying to reboot the system. Give it room to heal. At first you know the cortisol takes over (which is energy central) and it's stressful but the body gets used to that and you get adapted to fasting and the cortisol stops being a big issue. It has increased my energy but really hit / miss. Sometimes I have more energy on a fasting day - but not always. What I've been trying to find out is -- is this a food problem?

    I think maybe I'm still eating something I'm allergic to but it's hard to figure out what. Like you my responses are abrupt - like yesterday at 10am I suddenly had some energy and was able to clean up my living room and Yoga it was miraculous -- but today all bets are off. Loads of fatigue and trouble focusing. Ginger almost always makes symptoms better. Also - don't know why figure maybe because it is doing double duty as a digestive enzyme.

    Processed food seems more problematic to me than other types of foods.

    I have a lot of problems with digestion in particular getting amino acids that I need - how about you? I can't sleep without L-Tryptophan at night, and I take a variety of aminos during the day.

    Please keep me in the loop on what you're trying and if you need a fellow guinea pig. I'm always experimenting.
     

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