What is Mast Cell Activation Syndrome?

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Adam Foster

Director at The Fibro Guy

Adam Foster is the founder of The Fibro Guy and one of the leading voices in hypermobility, EDS, and chronic pain rehabilitation. A former Reconnaissance Soldier, he developed chronic pain after an IED blast in Afghanistan and built his approach from the ground up when the medical system had no answers. Since 2009 he has worked with thousands of people across eight countries, drawing on pain neuroscience, motor learning, and sensorimotor rehabilitation. He co-authored "No Pain, No Pain" with trauma psychologist Dr Mairi Harper, directed the documentary "Invisible Monster," and has been featured in Forbes, BBC Radio 4, ITV News, LiveScience, and The Telegraph.

Latest posts by Adam Foster (see all)

• Teeth, Gums and Jaw Pain in hEDS, and How to Get Through a Dental Appointment - 28 September 2026
• Why ADHD and Hypermobility Keep Turning Up Together - 16 September 2026
• Hypermobility and Early Development: Milestones, Motor Delay, and Predictions - 12 September 2026

Mast cells are immune cells, and they’re concentrated in your skin, your gut, your airways and the other places where your body meets the outside world. Set one off and it empties a load of chemicals into the tissue around it. Histamine is the famous one, however there’s also tryptase, prostaglandins, leukotrienes, heparin and a long list of signalling molecules, and between them they produce the flushing, the swelling, the itch, the cramping and the sudden drop in blood pressure that comes with a proper allergic reaction ^[1]. That’s the machinery working exactly as it’s supposed to. Mast cell activation syndrome, or MCAS, is the name given to that same machinery firing repeatedly, severely, across more than one part of the body, when there was no good reason for it to ^[2][3].

The definition isn’t really the complicated part though. What’s complicated is that MCAS means something quite narrow in an allergy clinic and something a great deal broader online, and the gap between the two is wide enough that the same person can be told she definitely has it and definitely doesn’t, inside a month. If you’re hypermobile you’ve almost certainly met the word already, generally as the third leg of a trio with POTS, and generally presented as settled. It isn’t settled, and the reasons why change what you do next and what you should expect from the appointment.

What Mast Cells Actually Do

Mast cells sit at the borders, so the skin, the gut lining, the airways, anywhere the outside world is trying to get in. They’re stuffed with granules, and when the cell is triggered those granules empty in seconds, which is why an allergic reaction is fast rather than gradual ^[1]. Some of what comes out is stored and ready to go, histamine and tryptase being the obvious two. Some of it gets manufactured on the spot over the following minutes and hours though, which is part of why a reaction can have a second wave hours after you thought the whole thing was over.

The classic trigger is IgE, which is the antibody your immune system builds against one specific allergen, so peanut, bee sting, penicillin. The mast cell carries that antibody on its surface, the allergen turns up, the cell fires. That’s the pathway everybody has heard of and it’s well understood.

What fewer people get told is that a mast cell has a lot of other doorbells on it. It can be set off by a different class of antibody entirely, by the complement system, by cytokines from other immune cells, by signals coming straight off nearby nerve endings, by the sensors your immune system uses to spot an infection, and by purely physical things like pressure, friction, heat, cold and vibration ^[4][5]. Stress signalling does it too, and that’s a real biological pathway rather than a polite way of saying it’s in your head.

That breadth is why the trigger lists people keep are so long and so strange, as they end up covering foods, medications, exercise, a hot bath, a sudden temperature drop, a perfume counter, a tight waistband and a bad fortnight ^[5][6]. None of that is irrational, and none of it requires an allergy in the sense that most people use the word. It’s also, unfortunately, the reason the whole area is so hard to pin down. A cell that answers to twenty different signals is very difficult indeed to test for cleanly.

What Has To Be True Before It’s MCAS

Under the strict consensus criteria, three things all have to be true at once, and this is the part that generally gets lost ^[3][7][8].

– Episodes, not a background hum: Recurrent, severe, episodic symptoms affecting at least two organ systems at once, so skin and gut, or gut and cardiovascular, or airway and skin. The word episodic is doing real work there, as this is meant to describe events with a start and a finish, often looking a great deal like anaphylaxis, rather than a permanent baseline of feeling unwell ^[3][9].

– Something measurable during the event: Objective evidence that the mast cells actually released their contents, taken while it’s happening rather than afterwards. This is the criterion almost nobody manages to satisfy, and the reason why is the whole tryptase problem ^[7].

– It gets better on the drugs: A meaningful response to medication aimed at the mast cells or at the chemicals they release, so not a slight improvement, and not one that could just as easily be the flare passing on its own ^[3][8].

The symptoms that turn up in the confirmed cases are fairly consistent, and they read like a very bad allergic reaction spread across the whole body: flushing, hives, swelling, itching, wheeze, a swollen throat, a racing heart, fainting from low blood pressure, cramping, nausea, vomiting, diarrhoea, headache, streaming eyes and nose ^[9][10]. In one group of people with confirmed idiopathic MCAS, every single one had skin involvement and most had respiratory involvement too ^[10].

Now, fatigue, joint pain, brain fog and long running gut trouble get reported constantly by people who suspect MCAS, and those symptoms are absolutely real. What’s much less clear is whether mast cell chemicals are what’s causing them, as the link between mediators and those chronic complaints is a great deal looser than the link between mediators and a flushing, wheezing, fainting episode ^[11][12]. That distinction matters far more than it sounds like it should, as it’s the difference between a diagnosis that leads somewhere and a label that stops the search.

Tryptase, and Why the Test Is So Easy to Get Wrong

Tryptase is the marker with the best evidence behind it, and there’s a specific threshold for reading it ^[13]. Your tryptase measured during an episode has to come in at least a fifth above your own baseline, and a small fixed amount gets added on top of that as well. That’s there so a trivial wobble in the number doesn’t get counted as a reaction ^[13]. It’s your own baseline that matters here rather than a population range, which is why this takes two blood tests instead of one, taken at different times, with one of them while you’re actually reacting.

That is where the whole thing falls apart in practice. Most of these episodes happen at home, at night, in a car park, or anywhere else that isn’t a phlebotomy room. Tryptase peaks and then falls away within a few hours, and most of the other markers people try instead, the histamine breakdown products, the prostaglandin metabolites, the leukotrienes, are less standardised and considerably fussier to collect, so a mishandled sample reads normal whatever was actually happening in your body ^[1][7]. A normal result from a tube taken three days later tells you almost nothing, and unfortunately it gets used as though it told you everything.

The other half of the problem runs the opposite way, as a high tryptase on its own does not diagnose MCAS, and quite a few people have been told that it does ^[13][14]. Baseline tryptase can be raised by kidney disease, by myeloid blood disorders, by mastocytosis, and most commonly of all by a perfectly ordinary genetic trait called hereditary alpha tryptasemia.

That trait, usually shortened to HαT, just means you carry extra copies of one tryptase gene, so you make more of the protein all of the time, and a few people in every hundred have it ^[15]. It does turn up more often than chance in people with mast cell disease, and in some settings it’s linked to more frequent or more severe anaphylaxis, so it certainly isn’t nothing ^[16]. Plenty of carriers have no symptoms at all though, and carrying it is not evidence of MCAS ^[15][16]. So if somebody has handed you an MCAS diagnosis on the back of a single raised baseline tryptase, that’s a very reasonable thing to go back and ask about.

Three Different Things Wearing One Name

MCAS isn’t one condition, and the classification genuinely matters, as it changes what gets investigated ^[17].

– Primary, or clonal: The mast cells themselves are abnormal, usually carrying a change in a gene called KIT that makes them far too easy to set off. This is the version that sits next to mastocytosis, and it’s the one where a bone marrow test earns its place, particularly if there’s been real anaphylaxis, a high baseline tryptase, or a positive KIT result ^[8][17].

– Secondary, or reactive: The mast cells are normal, but something is provoking them, and a genuine IgE allergy is the usual culprit. Find the trigger and you’ve found the problem.

– Idiopathic: Nothing clonal and no identifiable trigger, despite a proper workup. This is where most of the argument lives, and it’s also the category most people mean when they say MCAS online ^[8][17].

It’s worth knowing which one is actually being discussed, as “you might have MCAS” means something very different indeed if the plan is a bone marrow biopsy than it does if the plan is an antihistamine and a food diary.

How Common It Is, and Who’s Counting

Take the adults referred to a specialist centre specifically because somebody suspected a mast cell disorder, as only a small minority of them turned out to meet the criteria for idiopathic MCAS ^[8], and in a separate group who arrived with suspected MCAS and were then worked up properly from the start, the confirmed share was smaller still ^[18]. Both of those describe people who had already been filtered by a referral though, so they aren’t population rates, and what’s happening in the general public is not something either of them can tell you.

Set against that, on a much broader definition, the syndrome has been proposed to affect something like one person in six ^[19], and that estimate isn’t accepted by the consensus groups, it gets flagged as contested more or less everywhere it turns up ^[20].

So which one is it. Well, in one group of young people with POTS, three different sets of criteria were applied to exactly the same individuals ^[21]. Under the strictest consensus criteria, MCAS turned up in around two per cent of them, a looser consensus approach put it above a third, and symptom based clinical criteria put it close to ninety per cent.

Same people, same symptoms, same blood, and the answer moved from vanishingly rare to nearly universal depending purely on which rulebook happened to be open that morning.

That’s most of the shouting in this field explained in one go, and it’s why your diagnosis can genuinely depend on which clinic door you walked through. It’s also why the looser symptom based criteria get criticised for catching almost anything, as when symptom clusters get tested for how specific they are, the broader alternatives don’t discriminate well ^[22].

None of that means the strict version is automatically right and everyone else is wrong. Researchers genuinely disagree here, and the disagreement is about where the boundary sits rather than about whether the syndrome exists at all ^[11]. One camp argues that the strict criteria miss real, treatable disease, partly because the markers are so hard to capture during a flare, and the other argues that the loose criteria sweep in thousands of people whose problem is something else entirely, and then close the file. Both of those failures happen to real people, unfortunately.

The Hypermobility and POTS Question

Right, the trifecta, which is hypermobile Ehlers-Danlos syndrome or hypermobility spectrum disorder, plus POTS, plus MCAS, all sitting in the same person. You’ll have seen it drawn as three overlapping circles with an air of great certainty about it (and usually in a graphic with far too much pastel in it).

The overlap is genuinely reported, and reported a great deal. In one community allergy clinic, a substantial group of the people seen had both hEDS or HSD and mast cell activation disease ^[23], and when women with HSD and hEDS were asked anonymously, roughly a third said a doctor had diagnosed them with MCAS, and a quarter reported the full set of three ^[24]. Self reported MCAS also turns up more often in hEDS than in HSD ^[25]. All of that is people being asked, and people being seen in the clinics that attract exactly this population, so it records what people have been told and what walks through a particular door, which is a very different thing from a prevalence rate.

Held to strict, validated criteria though, the link between mast cell disorders and POTS or EDS hasn’t been confirmed ^[26]. Current gastroenterology practice guidance goes the same way: the overlap is observed rather than explained, the experimental work behind it is still evolving, and testing every hypermobile person for mast cell disease isn’t supported by what’s there ^[27].

That’s a genuinely useful thing to know before an appointment, as it cuts both ways. A clinician who refuses to even consider mast cell involvement in someone with recurrent flushing, swelling and collapse is out of step with the guidance. So is a place that diagnoses MCAS in every hypermobile person who walks through the door, just in the other direction. That one also costs you money.

Now, where it gets more interesting is the POTS side. In one group of people with confirmed POTS, a sizeable minority had both non-orthostatic symptoms and at least one raised mast cell marker, mostly histamine or prostaglandin related ^[28]. It doesn’t tell you how common mast cell activation actually is though, because of who ends up in that kind of clinic in the first place, and a single abnormal result isn’t definitive on its own ^[28].

The mechanism people reach for is plausible and unproven. Histamine and prostaglandins widen blood vessels and make them leakier, and if your veins are already more distensible than average and you’re already pooling blood on standing, then mediators floating around could reasonably make orthostatic symptoms worse. It’s a decent hypothesis, and it has never been shown to be the main driver ^[27][28]. There’s a competing explanation sitting right next to it as well, which is small fibre nerve damage. In one group of people with hEDS, skin biopsies showed small fibre neuropathy in most of them, and a substantial proportion met POTS criteria too, which is a route into autonomic trouble that doesn’t need mast cells in it at all ^[29].

In our opinion, hypermobility and POTS travelling together is solid and repeatedly observed, and MCAS as the guaranteed third leg is not, as the confidence with which it gets asserted online is running a long way ahead of what’s actually been shown. None of which means you haven’t got it, it means the diagnosis deserves the same scrutiny as any other, and being hypermobile is not itself the evidence.

The Difference Between MCAS and Mastocytosis

These two get used interchangeably all of the time, and they’re genuinely different problems.

Mastocytosis is a blood disorder, as there are simply too many mast cells and they accumulate in tissue, in the bone marrow, the skin, the liver, the spleen and the gut ^[14], and because that’s an accumulation problem, it carries risks tied to the tissue infiltration itself, on top of anything the cells release ^[30].

MCAS is an activation problem, so the number of mast cells can be entirely normal, they’re just firing when they shouldn’t ^[1][30]. Some people have both, and someone with mastocytosis who also gets recurrent systemic mediator episodes can meet the criteria for primary MCAS as well ^[8][17].

In practice, the reason to keep them straight is that mastocytosis is looked for and found with a bone marrow test and a KIT result, and it comes with its own monitoring. MCAS on its own does not, and a normal bone marrow doesn’t rule it out.

What Long COVID Did to All of This

Two things happened after 2020, and they get conflated more or less constantly.

New POTS diagnoses rose sharply, and that’s about as well evidenced as this kind of thing ever gets, as the rise turns up both in very large sets of medical records and in the caseloads the specialist autonomic services reported ^[31]. Some of that will be better recognition rather than new disease, and the data can show the association without proving the cause, however the size and the consistency of it are pretty hard to wave away.

Mast cell activation syndrome is a different story though. Referrals to the specialist mast cell centres have climbed substantially over the last fifteen years, and awareness, allergy and plain internet amplification all get named as drivers of that ^[32]. Long COVID symptom profiles have been reported to look a lot like untreated mast cell activation, with mast cell symptom scores in long COVID coming out similar to a comparison group who had MCAS ^[33]. There’s a reasonable biological story behind it as well, involving persistent inflammation and immune signalling ^[6].

What rose unambiguously, then, is suspicion, referral and labelling. A rise in strictly confirmed cases is a different claim, and it’s one the specialist literature has not made ^[32]. So if you came out of a COVID infection flushing, reacting to foods you were fine with before, and going grey when you stand up, MCAS is an entirely reasonable thing for a doctor to investigate. It isn’t a safe thing for anybody to assume though, and the assumption is being made a great deal at the moment.

What Actually Helps

Treatment is aimed at symptoms rather than at a cure, and nobody writing guidance pretends otherwise.

– H1 antihistamines: The standard first move, the same drugs used for hay fever and hives, usually taken at steady daily doses rather than as and when ^[30][20].

– H2 antihistamines: These block a different histamine receptor, the one that mostly sits in the stomach, so they’re added particularly where the gut symptoms are prominent ^[30].

– Leukotriene targeting drugs and mast cell stabilisers: Leukotrienes are a separate family of mediators, and blocking them helps some people, while cromolyn works differently again, making the mast cell harder to trigger in the first place, and it’s used mostly for gut symptoms ^[30][20].

– Adrenaline: If an episode meets the criteria for anaphylaxis, it gets treated as anaphylaxis, which means adrenaline and emergency care ^[20][30]. If you’ve had episodes anywhere near that severity, the conversation about carrying an auto-injector is one to have.

The controlled evidence behind the antihistamines is considerably thinner than you’d expect for drugs this widely used, as it amounts to a handful of small, old studies, most of them built in ways that make the results easy to doubt. One of them, in adults with mastocytosis, did show real improvement in quality of life and in several of the mediator symptoms though ^[34].

For people who don’t respond to any of that, omalizumab is the drug with the clearest signal. It’s an injected antibody that mops up IgE, and across the pooled reports most people with refractory disease got at least a partial response, a few got a complete one, and no major safety problems were reported ^[35]. All of it is uncontrolled though, so treat it as promising rather than settled.

Now, diet is where the evidence gets thinnest and the advice gets loudest. Trigger avoidance makes sense and it does work for individuals, and where food is clearly involved, structured elimination and then reintroduction is a reasonable thing to try with somebody keeping an eye on your nutrition ^[27][36]. What doesn’t exist is good trial evidence for any specific MCAS diet or low histamine protocol as a general treatment ^[27][36]. So if a plan has you cutting whole food groups indefinitely with no reintroduction stage and no monitoring at all, that’s a plan with a cost and no demonstrated benefit attached to it. Gut symptoms in this population have plenty of other causes that are worth excluding first ^[37].

Where That Leaves You

If you think this might be you, the most valuable thing you can do is get the testing done properly, as a badly collected normal result will follow you around for years.

That means a baseline tryptase taken when you’re well, and a second one taken during an episode, ideally within a couple of hours of it starting ^[13]. Write down what happened, what you’d eaten, what the temperature was doing, what you’d taken, and how long the whole thing lasted. A written record of episodes that repeat across two or more body systems is worth a great deal more to a specialist than any amount of describing how awful you generally feel, and it’s the thing that turns “she thinks she has MCAS” into a workable referral.

Keep the other explanations on the table while you do it, as the differential here is genuinely wide, covering infection, hormonal, cardiac, neurological, autoimmune and gut conditions, and a label applied early has a way of stopping people looking ^[17][8]. That isn’t scepticism aimed at you, it’s the practical risk of getting the wrong answer confidently.

And if the strict criteria don’t fit, that’s information rather than a dismissal. A negative workup doesn’t mean the flushing, the reactions and the exhaustion were imagined, it means the mechanism is something else and the search isn’t over. The burden people report living with while all of this gets sorted out is heavy, and it’s heaviest in the stretch before anybody has a name for it at all: interrupted days, restricted food, unpredictability, and needing help with things that used to be automatic ^[38].

Over the years we’ve watched a lot of people go through this, and what we’d say is be as rigorous about this diagnosis as you’d want a clinician to be about your hypermobility. A label that doesn’t fit won’t get you anywhere, even when it feels a great deal better than not having one.

The Fibro Guy

References

[1] Collins, S., Williams, T., Sanchez, E. and K. Agrawal, D. (2026) ‘Pathophysiological Drivers of Mast Cell Activation Syndrome and Implications for Treatment’, Fortune Journal of Health Sciences. https://doi.org/10.26502/fjhs.427

[2] Valent, P., Hartmann, K., Bonadonna, P., Niedoszytko, M., Triggiani, M., Arock, M. et al. (2022) ‘Mast Cell Activation Syndromes: Collegium Internationale Allergologicum Update 2022’, International Archives of Allergy and Immunology. https://doi.org/10.1159/000524532

[3] Valent, P., Akin, C., Arock, M., Brockow, K., Butterfield, J.H., Carter, M.C. et al. (2011) ‘Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal’, International Archives of Allergy and Immunology. https://doi.org/10.1159/000328760