You can say one thing about mast cell activation syndrome (MCAS) – it’s weird! In some ways, it seems tailor-made for rejection by the medical community. Its proponents claim it can cause virtually every symptom in the book (big red flag), yet it lacks good or even half-good measurable diagnostic markers (bigger red flag).
Amber Walker, who has written several excellent books on MCAS, wrote that she felt like she was faced “with the colossal challenge of summarizing something that is a black hole of possibilities with very few concrete, research-based facts”. She underlined the fact that we need to keep in mind that “MCAS research is still very much in its infancy. There is a lot we don’t know and a lot that will change.”
MCAS decidedly did not luck out with its often not so illuminating laboratory tests, but it did luck out in one way: the treatments for it – as we know them now – are generally cheap and safe – which means doctors can bypass the testing phase and use a response to treatment instead. If a treatment helps, the diagnosis is made.
This blog used Amber Walker’s book, “Mast Cells United: A Holistic Approach to Mast Cell Activation Syndrome“, a recent YouTube presentation by the Bateman Horne Center’s Dr. Yellman (see below), an interview with Dr. Bela Chedda done several years ago, and a review paper by Theoharis Theorharides to inform it.
Amber Walker’s Story
Before getting into the nitty-gritty of mast cells, the first part of Amber Walker’s fascinating story must be told.
At the age of 30, Amber Walker had a realization – while exploring Colombia no less. She had to see the world – and right now. She sold her stuff, bought a one-way ticket to Australia, and set off on the backpacking trip of a lifetime – by herself.
As a windup for the Boston Marathon, she began a running tour of Australia, New Zealand, Indonesia, and Thailand (while checking out the hot surfing spots, of course).
The event that helped to trigger the collapse of her health occurred near the end of her trip, when after a baby monkey attached itself to her shoulder, she was attacked and bitten by the momma monkey. She had a strong reaction to the first and second rabies vaccine shots. That wasn’t particularly surprising, and maybe what happened next wasn’t either. She wasn’t about to miss the Boston Marathon, so three days after her last vaccine shot, she lined up at the starting line, feeling terrible.
Suffering from strange muscle sensations, dizziness, and gut pain ,she barely made it through the race. How barely? It took three hours for her to walk a mile from the finish line to get her gear bag. She vomited and had diarrhea for several hours. She now suspects she was in a “mast cell storm” and that the combination of the rabies vaccine, the international travel, and the marathon pushed her over the edge.
It turned out, though, that our seemingly healthy marathoner, adventurer, and world traveler wasn’t in such good shape after all. In fact, she was already pretty much of a mess and had been for quite some time. Unbeknownst to her, she’d been suffering from symptoms of MCAS for almost her entire life.
They occurred early. Digestive issues, abdominal pain, constipation, hives, rashes (she was diagnosed with chronic urticaria and took daily antihistamines), extremely sensitive skin, dermatographia, asthma, allergic reactions to dogs, horses, hamsters, rabbits and cats, foods (pine nuts, chocolate, shellfish), repeated sinus infections (countless antibiotics), Raynaud’s disease: they all showed up pretty early.
Abdominal pains were a constant for her entire life, but in her teens, she began having abdominal attacks – intense periods of abdominal pain that felt like glass was cutting her insides – which left her experiencing mental confusion, anxiety, and even delirium, and sometimes left her unable to eat or drink anything for days. Numerous diets had no effect.
Next, a car accident was followed by swollen neck and groin lymph nodes, fatigue, and iron-deficiency anemia. She had her first, but not nearly last, experience with anaphylactic shock and a trip to the hospital after being stung by a yellow jacket. Then came chest pain, heart palpitations, low blood pressure, near-fainting episodes, urinary tract infections, severe cold intolerance and occasional heat intolerance, and constant sinus infections.
All this while being a competitive swimmer at the college level – training 2-4 hours a day. She was living proof that your immune system can be a mess without impairing one’s ability to exercise. After her eardrum ruptured, sending blood and pus flying during an airplane flight – she swam the next day. After she found herself gasping for air during a slow warmup, she checked herself into an urgent care clinic and found she had pneumonia. She recovered enough to enter her (last) swimming meet – but her lungs were never the same.
Despite having good oral hygiene, her gums receded to the point where her front teeth became loose and she had to have a gum grafting procedure. (Unfortunately, she couldn’t tolerate the pain medication – something that had started long before.)
In her 20s, she began experiencing numbness and tingling and episodes of weakness and vision, and problems with balance and vertigo. Sometimes they came for a while and then mysteriously disappeared. Brittle nails, white coating on her tongue, hair loss, night sweats, anxiety and depression, jaw pain, TMJ, frequent joint subluxations, IT band pain, knee meniscus problems, ankle and wrist sprains, plantar fasciitis – they all added up. A car accident left her with severe neck instability. In an odd accident, she fractured her tailbone while doing a jump into the river that her friends accomplished easily. (People with MCAS appear to be at increased risk of osteoporosis.)
Over time, she saw countless doctors… She also completed graduate school and traveled and worked in Peru, picked up some parasitic infections, was exposed to bed bugs, and flea infestations, was attacked by wild dogs, and was even kidnapped. Coming back home, her abdominal attacks worsened – and then she went on her trip to Australia.
Another blog will sort out what happened afterward – the collapse of her health, her MCAS diagnosis, and the gut diagnosis which finally cleared that mystery up and ultimately, her return to at least acceptable health. Her story demonstrates the many signs of MCAS that may be present long before someone reaches the point where their functionality is dramatically affected.
Amber clearly didn’t have ME/CFS at this point. I was struck that with all the health problems she had, she was still able to competitively swim and run and backpack. (I, on the other hand, didn’t have any health problems prior to ME/CFS and can’t do any of those. Go figure.) MCAS does not necessarily, then, produce exercise intolerance and ME/CFS. On the other hand, it’s clearly a big deal in ME/CFS. Learning why it’s such a common comorbidity in ME/CFS will undoubtedly help us understand both diseases.
Mast Cell Activation Syndrome Makes Good
Dr. Bateman, of the Bateman Horne Center, is the last person one would associate with ‘woo-woo” treatments. Her sober, careful manner and focus on conservative, evidence-based treatments has enabled her to be able to speak to a wide variety of audiences. In a word, she is trusted.
The fact that she and her colleague, Dr. Yellman, fully embrace MCAS despite the wretched diagnostic tests really says something about the potential efficacy of MCAS treatments in chronic fatigue syndrome (ME/CFS). Indeed, the list of ME/CFS practitioners that employ MCAS treatments from Dr. Chheda to Dr. Kaufman, to Dr. Klimas and Dr. Bateman, is a long one.
Dr. Bateman went so far as to say that MCAS is found frequently in the post-viral syndrome population (ME/CFS), in Ehlers Danlos and hypermobility patients – and now she’s seeing it “in spades” in long COVID. She actually said, being careful, that “something that appears to be (:)) mast cell activation tends to be very, very frequent”. She said that it’s been “really gratifying” to be able to include MCAS treatments in her list of supportive treatments. Note the word “supportive” – not curative – but definitely helpful.
Long COVID, ME/CFS/FM and Mast Cells in the Research Arena
It’s not surprising, given the lack of good laboratory tests to diagnose, that the few MCAS/long-COVID papers that exist tend to focus on symptoms, or are hypothesis papers. It’s clear, though, that acute COVID-19 (and presumably other infections) releases a vast array of immune mediators (120 and counting), and there’s no doubt that mast cell activation occurs during the infection. With regard to long COVID, early studies have shown a dramatic symptom overlap in people with long COVID and people with documented mast cell activation syndrome. That’s about the end of the story, though.
The situation is not much better in ME/CFS and fibromyalgia where no studies that I could find have quantified the prevalence of MCAS in either disorder. Despite the fact that MCAS is a major clinical concern in ME/CFS/FM, it has yet to make a dent in the ME/CFS/FM research world.
Mast cells are white blood cells found in the connective tissue (it’s everywhere) in the body. They’re most prominent in the boundary between the outside world and us (skin, mucous membranes, digestive tract, nose, lungs, etc.).
When activated, they can release a variety of immune mediators (histamine, tryptase, cytokines, chemokines, leukotrienes) – each of which has different effects. While one person’s mast cell might release ‘X’ mediator – another might release ‘Y’ mediator.
Theoharides reports that “histamine is associated with headaches, hypotension, and pruritus (itching), tryptase with inflammation and fibrinogen lysis; cytokines and chemokines with… symptoms of generalized inflammation and fatigue, PGD2 with flushing, and leukotrienes with bronchoconstriction.”
These mediators trigger symptoms by activating nerve fibers in the skin, gut, etc., which relay pain signals through the dorsal root ganglion into the spinal cord, and into the brainstem. The brainstem then releases substance P and CGRP into the trigeminovascular system, and into dural mast cells found in the connective tissues (the dura) that surrounds the brain and spinal cord.
The trigeminal nerve is a complex nerve that contains both autonomic and sensory nerve fibers and regulates eye movement, the nose, and chewing. It’s the nerve that goes bonkers in migraine, and Yellman noted that central pain sensitization can clearly be activated by mast cells.
Theoharides calls mast cells “the immune gateway to the brain“, and notes that mast cell activation can degrade the blood-brain barrier. Mast cells in one area are able to trigger mast cell activation in sometimes distant locations.
Mast cell activation syndrome (MCAS) occurs when too many mast cells are present, and/or those which do occur are twitchy; hypersensitive, and overactive. The result, in either case, is too much mast cell activity and therefore increased inflammation via the release of a wide variety of immune activators (histamine, leukotrienes, prostaglandins, tryptase, proteoglycans, platelet activation factor, TNF-a, interleukins, and others).
These factors can produce just about any symptom in the ME/CFS/FM/long-COVID book: fatigue, muscle pain, dizziness, fainting, brain fog, headache, chest pain, rapid heart rate, irritable bowel, acid reflux, breathing problems, hives, flushing, osteoporosis, uterine cramps/bleeding, skin irritation (dermatographism).
These sometimes twitchy mast cells can also potentially be triggered by just about everything: from temperature changes to stress (of any kind), to infection, to exercise, to different foods, to drugs, to odors, to insect bites, to skin irritation to sunlight – they all can activate mast cells in different patients. Noting that symptom surveys by the Mastocytosis Society point to “stress”, especially emotional stress, Theorides called stress a key trigger. He did not mention foods in his key trigger list but did include drugs such as antibiotics, NSAIDS, opioids, and estrogen.
Mast cell activation has been associated with many diseases such as fibromyalgia, bladder pain syndrome, vulvodynia, migraine, irritable bowel syndrome, ME/CFS, postural orthostatic tachycardia syndrome (POTS), rheumatoid arthritis, lupus, chemical sensitivities, Ehlers Danlos Syndrome, and early osteoporosis. Theoharides, who now works with Nancy Klimas at the Center for Neuroimmune Studies, noted its particularly high rate of incidence in ME/CFS.
Doctors identify MCAS in three ways: via symptoms, treatment, and laboratory markers.
The symptoms tend to be episodic and need to affect two or more of the following systems:
- Skin – hives, flushing, edema, dermatographia
- Gut – nausea, vomiting, cramping, diarrhea
- Cardiovascular – dizziness, fainting, rapid heartbeats
- Respiratory – wheezing
- Naso-ocular – itching, nasal stuffiness.
Elevation of Laboratory Markers
Total serum tryptase – Yellman reported that serum tryptase is VERY specific for mast cell activation – but is hard to run and has poor sensitivity; i.e. while a positive test does indicate MCAS, a negative result does not rule it out. In an earlier interview, Dr. Bella Chheda noted that only a small percentage of people have elevated tryptase, and when tryptase levels are elevated, they’re usually borderline elevated (13-20)
Plasma prostaglandins – Dr. Chheda reported that the two main MCAS markers she uses involve the prostaglandins. Prostaglandin D2 is the most helpful marker, but because it can have diurnal variations, it may take several tests to capture the elevation. F2 alpha – which is a breakdown product from other cells, as well as mast cells – is moderately diagnostic.
N-methylhistamine, 11B, leukotriene E4 – 24 hour urine tests.
Biopsy tissues – GI tissue – if you’ve had an endoscopy done – you can ask them to stain for the mast cells.
Dr. Bela Chheda told Health Rising several years ago that these lab tests can be more problems than they are worth, and often it’s best to try out the treatments and see if they work. Dr. Yellman clearly agrees.
A General Approach
Amber Walker noted that a trial-and-error process seems almost inevitable with mast cell medications and other treatments. Medications that are questionably helpful should not be continued: only medications that are clearly helpful should be.
She reported that Dr. Afrin agrees, who stated:
“If at any point it is thought that a given medication is no longer providing significant benefit, it should be stopped or weaned to see what happens. No patient with any disease should be taking one milligram of one more medication if it is not clearly providing significant help.”
First Dr. Yellman focused on two possibilities – low histamine diets and diamine oxidase. He noted that while low histamine diets can be difficult, they can be helpful for some. Walker was rather sanguine about low histamine diets, calling them “one of the most controversial topics” in MCAS, and reporting studies that cast doubt on their effectiveness.
Dr. Afrin – a seminal figure in the field – stated that “there is no one “low histamine diet that works for everyone – every patient is different”, and that, like other treatments, finding the right diet is a “big trial-and-error process”. Most patients should know within a month if a diet is working.
Dr. Yellman noted that diamine oxidase can help patients tolerate more foods. Dr. Brown, a pulmonologist, said low histamine diets can be successful in “some” patients and they’re hard to adhere to. She echoed Dr. Afrin when she said that it “really depends on what people find helpful”.
Walker noted that twice daily use of H1 and H2 antihistamines are often recommended for MCAS. When used together, they’ve been shown to reduce inflammation in people with hives. A review asserted that the dosage of these drugs can be increased two to four times the typical dose in urticaria (hives).
Chheda reported that 2 antihistamines are often needed to have an effect, and relayed the story of a patient with a classic case of ME/CFS who did not appear at first blush to have MCAS. An antihistamine trial told the tale, though; while neither 1-2 antihistamines a day made a difference, adding a third one did – it completely removed her anxiety.
Amber Walker noted that three generations of antihistamines exist. (Other sources lop the 2nd and 3rd generations together.)
H1 Receptor Antagonists – suppress generalized histamine releases. First-generation antihistamines were developed as far back as the 1940s (diphenhydramine (Benadryl), chlorpheniramine (Chlor-Trimeton), doxepin hydrochloride (Sinequan), and others were effective but sedating. The problem was that they crossed the blood-brain barrier and whacked some areas of the brain. Benadryl and Chlor-Timeton also have anti-cholinergic properties – and Benadryl has been associated with an increased risk of dementia. Walker recommended that these drugs be used in flareups unless other antihistamines are not effective.
Second-generation antihistamines – (loratadine (Claritin), cetirizine (Zyrtec), levocetirizine (Xyzal), desloratadine (Clarinex), ketotifen (Zaditor/Zaditen in Europe), developed in the 1980s, were also more focused on the H1 receptors, worked for longer periods of time, had more anti-inflammatory effects, produced less drowsiness and fogginess, and have fewer cardiovascular side-effects.
Third-generation antihistamines – fexofenadine (Allegra) – removed the cardiovascular risk. Note that second and third-generation antihistamines, while better, can still cause drowsiness.
- famotidine (Pepcid), ranitidine (Zantac), cimetidine (Tagamet), nizatidine (Axid).
Walker reported that H2 receptor antagonists suppress gastric acid secretion by blocking histamine receptors in the stomach and are commonly used for acid reflux but can also help in people with chronic mast cell activation. They are different from proton-pump inhibitors.
One worry is that regular use may contribute to Vitamin B-12 deficiency. Earlier, an increased risk of dementia was a concern, but later studies have not found an association.
Leukotriene Inhibitors and Leukotriene-receptor Antagonists
- Montelukast (Singulair), zileuton (Zyflo), zafirlukast (Accolate).
These drugs hit mast cells early in their development – reducing their development in the bone marrow and their recruitment into the tissues. They also appear to have significant anti-inflammatory properties via their impact on innate immune system cells like monocytes and neutrophils.
They appear to help most with respiratory symptoms and general mast cell activation symptoms. People with elevated prostaglandins may see the most benefit. They are widely used to suppress hives and help with asthma, and are reportedly well tolerated.
Tumor Necrosis Factor Antagonists
- Etanercept (Enbrel), adalimumab (Humira), Infliximab (Remicade).
These expensive drugs are typically prescribed for conditions like rheumatoid arthritis, Crohn’s disease, and psoriasis. They are not usually used in MCAS, but in theory, they should be helpful.
Mast Cell Stabilizers
Dr. Yellman said he likes to hit people hard and fast with mast cell stabilizers and considers them a bit more effective than using H1/H2 blockers alone. He included compounded cromolyn sodium or ketotifen, and over-the-counter quercetin.
Cromolyn Sodium – One of the more commonly prescribed mast cell drugs, cromolyn has its challenges. Well absorbed in the gut, the liquid version is poorly absorbed in the rest of the body. Walker reports that it’s expensive, can take weeks to months to have an effect, and should be taken 30 minutes before meals, often 3-4 times/day. Doses are also slowly titrated up over time. Theoharides reported that cromolyn can cause severe diarrhea in about 15% of patients, and hair loss in about 10% of patients.
Walker states that cromolyn can be very helpful for people with food sensitivities and chronic gut symptoms. Yellman reports that liquid cromolyn or Gastrocom – taken 15-20 minutes before eating – can make an enormous difference in gut symptoms. Compounded cromolyn provides more systemic relief – and he uses it more for symptoms such as migraines and neuroinflammation, and craniocervical instability. People who have trouble tolerating the compounded cromolyn can get benefits by taking the liquid cromolyn/Gastrocom 15-20 minutes before taking the compounded cromolyn.
Ketotifen – Ketotifen is a compounded antihistamine that Dr. Chheda said she uses regularly. It requires a prescription and is used in a variety of related conditions including asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, mast cell activation syndrome (MCAS), allergic and nonallergic anaphylaxis, and food allergy.
Quercetin and the Flavonoids – Quercetin is a flavonoid which (like other flavonoids apigenin and kaempferol) may reduce mast cell degranulation by inhibiting certain pathways. Animal studies suggest these flavonoids are able to reduce the release of numerous mast cell mediators. Able to affect the brain, quercetin was able to return brain glutathione levels to normal in stress-induced, sleep-deprived mice. Culture studies suggest that quercetin, which is considerably cheaper and easier to use, is more effective than cromolyn at both reducing mast cell activation and release, and at reducing cytokine levels.
Quercetin, though, has in the past had poor bioavailability. Liposomal or enteric formulations (NeuroProtek, Quercetin Phytosome (Thorne) that are available today appear to have mostly solved that problem. Note that it can take 1-6 months for the benefits to show up.
Amber Walker proposed that “it’s entirely possible that a flavonoid supplement could be as or more effective than a regimen of mainstream prescription medications – and could come at a reduced price in the long run.”
Luteolin – Walker noted that luteolin is a transcription factor inhibitor that is able to cross the blood-brain barrier and may also be able to reduce inflammation and microglial activation. Theoharides reported that luteolin is a mast cell inhibitor and can decrease histamine secretion.
Nancy Klimas noted that luteolin is able to cross the blood-brain barrier and may be able to help with brain fog. In culture experiments, both quercetin and luteolin have been able to inhibit the release of many mast cell factors.
Theoharides recommended that luteolin be used in conjunction with a tetramethoxyluteolin-containing skin lotion and noted that a few weeks are required before mast cells are sufficiently inhibited. It may also be combined with vitamin D3.
Omalzumab (Zolair) – Waker calls Zolair a “commonly utilized treatment option” that is considered a 3rd-line treatment; i.e. something to be considered if other options don’t work. Zolair binds to free IgE – thus stopping an allergic inflammation cascade from the beginning. It’s expensive, but is used in people with chronic hives, asthma, and other conditions.
Yellman reported that Zolair can be very effective in those who do not respond to other treatments, but he’s only rarely had to reach for it. A pulmonologist called getting biologics approved “one of those most challenging things”.
Allergy desensitization process is, in Yellman’s opinion, a kind of fool’s errand.
Walker noted a raft of other possible treatments that may not ordinarily be thought of as MCAS treatments. Benzodiazepines (lorazepam, clonazepam, alprazolam) appear to be able to reduce mast cell-induced anxiety in some MCAS patients. Immunomodulators such as azathioprine, methotrexate, cyclosporine, and prednisone (used on a short-term basis) have been used in MCAS as well. Stem cell transplantation and tyrosine kinase inhibitors (4th line treatments) are two other possibilities that are clearly rarely used.
Cannabidiol (CBD) and CBD oil – Cannabinoid receptors are abundant on mast cells and CBD appears to be able to reduce the production of cytokines produced by mast cells. Among many other things, CBD oil has been associated with a reduction in allergy symptoms, and can be helpful with asthma. Walker wrote that anecdotal reports suggest CBD oil may be particularly helpful in people experiencing high pain levels, inflammation, and insomnia.
Other Supplements – Walker reports on many other supplements that may be able to help. Note that virtually all studies showing impacts on mast cells are culture or animal studies. They include NAC (general aid), Vitamin C, Vitamin D and magnesium (decreases mast cell activation/ low levels of either leave the door open to MCAS (?)), alpha lipoic acid (good for nerve-related pain), bromelain (inhibits prostaglandin synthesis – pair with quercetin), curcumin (suppresses mast cell degranulation), mangosteen (mast cell stabilizer/inhibitor), khellin (long cited as mast cell stabilizer), resveratrol (reduces prostaglandin synthesis), milk thistle extract (reduces prostaglandin and leukotriene synthesis), melatonin (mast cell secretion), pancreatic enzymes, omega-3 fatty acids, probiotics/fecal transplants,
Better antihistamines are under development and, at least in one case, are available for some.
H3 receptor antagonists block histamine release in the brain as well as the peripheral nervous system. Instead of being sedating, though, H3 antagonists have stimulating effects and are being researched in neurodegenerative conditions like Alzheimer’s disease. Because they’re found in high densities in several areas of the brain (basal ganglia, hippocampus) associated with cognition, they may have positive cognitive effects (!).
Pitolisant (Wakix) accesses the brain and is being used to maintain a wakeful state in narcolepsy – an interesting effect given the decidedly unwakeful state often found ME/CFS. It’s also being considered in attention deficit disorder – another common problem in ME/CFS and FM.
- Amber Walker’s Origin Wellness website – states Amber Walker “specializes in working with patients who suffer from chronic conditions including fibromyalgia, dysautonomia, mast cell activation disease, covid and vaccine complications, Ehlers-Danlos syndrome, migraine headaches, inflammation from mold, and chronic viral, gastrointestinal, and bacterial issues that influence immune system function.”
MCAS is a huge field and this is only an introduction to it. Some things do stand out, though. Although MCAS is not well studied in ME/CFS/FM, long COVID, and similar diseases, it’s clearly common, and while not a cure-all, can be quite amenable to treatment. Plus, the most commonly used treatments are readily available, are often cheap, and usually produce few side-effects; i.e. it’s amenable to self-experimentation to some extent.
Coming up – the conclusion of Amber Walker’s story. We’ll watch Amber as she gets sicker and sicker, develops chemical sensitivities, neurological problems, an ME/CFS/FM-like condition, etc., but ultimately recovers – not all the way – but a large part of the way using a variety of techniques, including several that are not directly MCAS-related and one, in particular, that I had never heard of before, which made a huge difference.
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