Gut Check: Jacqueline Squire, MD, on the Gastric Impacts of MCAS

Drs Jacqueline Squire and Brian Lacy review the challenges of accurately diagnosing mast cell activation syndrome, how it affects the gastrointestinal and other organ systems, and how best to treatment this relatively rare and often overdiagnosed autoimmune condition.

Brian Lacy, MD, is a professor of medicine at Mayo Clinic-Florida in Jacksonville, Florida. Jacqueline Squire, MD, is an associate professor of medicine in the Division of Allergy and Immunology at the Mayo Clinic in Jacksonville, Florida.

Mast Cell Activation Syndrome (MCAS): Diagnostic Criteria, Biomarkers, and Practical Management

• A diagnosis of mast cell activation syndrome (MCAS) according to the Vienna consensus requires 3 criteria: (1) recurrent, acute episodes that present simultaneously (within minutes or perhaps hours) that affect ≥2 organ systems (cutaneous, respiratory, GI, cardiovascular); (2) biochemical evidence of mast cell activation, best validated by serum tryptase rise ≥20% + 2 above baseline; and (3) clinical response to mast cell–targeted therapy. Baseline tryptase is typically normal in MCAS but >20 ng/mL suggests systemic mastocytosis, warranting hematology evaluation and bone marrow biopsy.
• Epidemiology and diagnostic pitfalls: True prevalence is unknown; referral-center data show only ~2–4% of suspected cases meet criteria, indicating substantial overdiagnosis. Evidence does not support associations with POTS or Ehlers-Danlos syndrome when validated criteria are applied. Chronic isolated GI symptoms (e.g., bloating) without acute multisystem episodes reduce the pretest probability of MCAS.
• Evaluation and treatment (outpatient setting): Serum tryptase (baseline and during episodes) is the most reliable test; urine mediators are less validated. Avoid nonvalidated tests (e.g., serum serotonin, chromogranin A) and tissue mast cell counts for MCAS diagnosis. First-line therapy includes high-dose second-generation H1 antihistamines (up to 4× standard dose) ± H2 blockers (e.g., famotidine); add montelukast (respiratory), oral cromolyn (up to 200 mg QID) for GI symptoms, or omalizumab for recurrent anaphylaxis. Avoid chronic steroids and routine IV therapies.

Dr Lacy:

Welcome to Gut Check, a podcast from the Gastroenterology Learning Network. My name is Brian Dr Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida, and I am absolutely delighted to be speaking today with Dr. Jacqueline Squier, associate professor of medicine in the Division of Allergy and Immunology at the Mayo Clinic in Jacksonville, Florida. Dr. Squire is an expert in the field of allergy and immunology and is well versed in the evaluation and treatment of patients with suspected mast cell activation syndrome, the topic for today. So Dr. Squire, welcome. Let's begin really simply. What are some of the basic functions of mast cells? What do they really do?

Dr Squire:

It's great to be here. Thank you so much for having me, and hopefully we'll clear up some of those questions your listeners may have. But mast cells, it's a great question. Mast cells are really part of our innate immune system. They're designed to help us identify and target new stimulus in our environment. They are particularly found in our tissues and those tissues that come into contact with the external environment, so our skin, our conjunctiva, the respiratory and GI tracts, they might primarily stay in those areas so that they can come into contact with any sort of stimuli or allergens that may come into those spaces.

Dr Lacy:

And so mast cells play a critical role in allergic conditions, right?

Dr Squire:

Yes, they are primarily activated by allergens. We find that certain things once they've been identified as an allergen are what will trigger the mast cells. When those mast cells are triggered, they'll then release their mediators that are preformed and sitting in the cell. Those include things like histamine, leukotrienes, tryptase. And when they're released in those tissues, they'll cause typically localized, those sometimes more systemic, symptoms. And those would be the typical allergy symptoms you think about if it's in the skin, itching, redness, hives; if it's in the nose or the respiratory tract, sneezing, coughing, wheezing, those sort of symptoms.

Dr Lacy:

So as you've nicely pointed out, mast cells are really important for a normal immune response. They're important for allergic conditions, but sometimes things go awry. And many of our listeners will be aware of a rare condition called mastocytosis where there are an abnormal number of mast cells throughout the body, skin, bone marrow, internal organs, et cetera. So what are some of the typical symptoms of this rare disorder and how can you distinguish that from our topic today of mast cell activation syndrome?

Dr Squire:

That's honestly a little bit of a tricky question. And the reason for that is that systemic mastocytosis, as you mentioned, a rare condition, can have episodes where the patient has actually mast cell activation syndrome or MCAS where all of the mast cells go off and release their mediators. Because actually a common presenting symptom of systemic mastocytosis is venom anaphylaxis where a patient gets stung by an insect such as a wasp or a bee, and then they have a severe episode of anaphylaxis. Those patients should actually be screened and tested for systemic mastocytosis. But what does make systemic mastocytosis different than just—not just—but separately, mast cell activation syndrome is that systemic mastocytosis is caused by clonal or abnormal mast cells. So you can look and find these abnormal mast cells most often in the bone marrow, though they can sometimes be in other tissues. And so that becomes important as we'll talk about in testing that if you were to get an abnormal baseline tryptase, particularly over 20, that's concerning that we've made enough abnormal mast cells that we now have what is considered systemic mastocytosis. And those patients should then go to typically hematology and oncology to get a bone marrow biopsy, which is more so the definitive diagnosis for systemic mastocytosis.

Dr Lacy:

Wonderful. So two great teaching points. One, the clonal theory here, and number two, probably an elevated baseline tryptase level. So as you've already mentioned, mast cell activation syndrome, which we can abbreviate as MCAS as we go through this, is really topical right now. And it's also quite controversial in both the allergy world and the gastroenterology world. How common is true mast cell activation syndrome?

Dr Squire:

This is a great question, and it's a little bit hard as well because the exact prevalence isn't known. We don't have exact data on the number of patients currently in the world that have mast cell activation syndrome or MCAS. And part of that is that we are seeing that there's a fairly large overdiagnosis of this condition if you're not using the validated diagnostic criteria, which of course we'll talk about as well. There have been now a couple of large referral center studies that these are mastocytosis or mast cell activation syndrome centers that evaluated the cohorts of patients that have been referred for evaluation. And out of those large number, several hundred patients, only about 2 to 4% of them actually meet the diagnostic criteria. So it seems like even in patients that are enriched with symptoms that we're concerned about, only 2 to 4% of those are actually meeting the diagnostic criteria.

Along with that, there's also been a lot of information online, and I'm sure has come into clinics as well, that there may be some overlap or some association with other conditions such as postural orthostatic tachycardia syndrome or Ehlers-Danlos syndrome, EDS, POTS and EDS. But there was actually a recent systematic review by Farley et al that took a look at all of the reports that have been published to this point that are saying there may be an association. And what they found was that that evidence does not currently support a link because those studies were not using the validated diagnostic criteria. It was either based on patient report or symptoms that don't really align with the diagnostic criteria. So at this time, we would say there doesn't appear to be enough evidence that supports a link between those conditions as well.

Dr Lacy:

Great explanation. And of course, there's probably some bias because patients with symptoms are coming in, but we don't really know the true prevalence in the general population. So those are great teaching points.

So you mentioned some of the symptoms of somebody with that rare condition of mastocytosis. What are some of the typical symptoms of mast cell activation syndrome?

Dr Squire:

Yes. And in those, it's fairly similar in the sense of when we think of what is the problem in mast cell activation syndrome? It's the mast cells going off typically nonspecifically without a particular cause. It's not food allergy where there's one specific cause—it's only when they eat peanut, then their mast cells are activated and go off. In mast cell activation syndrome, they are inappropriately going off without really a true stimulus or trigger. And so they will then have symptoms of allergic reactions. It can be multiple symptoms at one time, or it should be really, and we'll get into this as well, but it really should be multiple symptoms at one time. So that might include hives, wheezing, significant vomiting or diarrhea, maybe even hypotension or syncope. So it needs to be some combination of those symptoms, and it can be as severe as really anaphylaxis, somebody who's having multiple symptoms at one time.

Dr Lacy:

So this disorder right now is frequently associated with a number of vague gastrointestinal symptoms, nonspecific symptoms such as chronic bloating or chronic abdominal pain. When we consider this diagnosis of MCAS, who's at the greatest risk to develop this?

Dr Squire:

That's a good question. And it's another, it's part of we don't quite know the exact prevalence. At this point in time, we don't necessarily know or it hasn't been identified that there's a select group of patients that are higher risk for this condition versus others. That being said, patients really do present themselves with these episodes of symptoms. I'm not saying patients can't have other chronic symptoms. They may have some chronic symptoms, but they should also have that history of there's an acute episode that my symptoms significantly worsen. They involve multiple symptoms at one time that makes you suspicious that this patient might have MCAS.

Dr Lacy:

I like the way you emphasize the word acute because if we think about somebody with chronic daily bloating or chronic daily abdominal pain, that probably lowers your pretest probability that it could be MCAS. Is that correct?

Dr Squire:

That is correct. It's something, again, I'm not saying patients may not have some chronic symptoms, but I'm really looking for that history of they can tell me there are discrete episodes that are much worse where they're having multiple symptoms at one time that again, should include something from more than one organ system. We'll talk about that when we specifically talk about the diagnostic criteria, but there needs to be more than one organ system. So if it's just GI, they're saying, "Oh, I have these episodes of vomiting and diarrhea," that's limited to one organ system. We should have another organ system involved such as respiratory—coughing, wheezing, stridor—or hives, something on the skin, cutaneous hives, another organ system involved to really make us suspicious for MCAS.

Dr Lacy:

So that's a perfect segue because it's really important that health care providers communicate using the same vocabulary and also with their patients. So you've already mentioned some of the diagnostic criteria, but let's go through those again. And you kind of mentioned discrete episodes and more than 2 organ systems. Could you fine tune this for us?

Dr Squire:

Yes, I can definitely. We have now narrowed it down, and actually this was established back in 2012 by a consensus group that met. They've named this the Vienna consensus criteria. So if you look into that, there are 3 required diagnostic criteria. Number 1 is that the patient has recurrent severe symptoms involving 2 or more organ systems at one time. So that's also the point is someone may have hives and someone may have GI symptoms, but they need to occur at the same point in time. And that usually is within minutes to a few hours of each other, not days apart or something like that. But it's recurrent symptoms involving 2 or more organ systems. Most commonly, those organ systems are cutaneous, so such as hives, flushing is in there as well; respiratory, I mentioned coughing, wheezing; gastrointestinal, so vomiting, abdominal cramps, diarrhea; and cardiovascular such as with low blood pressure or even syncope to that point.

And so a patient would need to have 2 or more organ systems at the same time, such as hives and vomiting or significant diarrhea and syncope at the same time to meet that criteria. So that's number one.

Second criteria is that we do need to demonstrate that the mast cells are involved, that they are releasing their mediators, and that's how we're getting these symptoms. The validated test that has been identified for that is to look at the biomarker tryptase. Tryptase is constitutively produced from our mast cells, but during an episode where the mast cells have activated, they've released their mediators, you should get a rise in that tryptase level. And so there's actually a formula that's been calculated. It's a little bit clunky, but it's an increase above the baseline tryptase of 20% plus 2. So that is the sort of validated marker that has been identified in MCAS specifically. That's criteria number 2.

And then the third is that they should have a clinical response to mast cell targeted therapies, that there should be, if you then put them on medications that target those mast cells, there should be at least a partial, if not complete response to those therapies. And so that makes up the 3 criteria for MCAS.

Dr Lacy:

Perfect. Thank you. And so homing in on this diagnosis, clinicians take a great history, they try to pull this together, but many clinicians and patients like a test. Is there one single test or one single biomarker that consistently and accurately make this diagnosis?

Dr Squire:

Yes. So the single best test, if we're going to do one test, would be the tryptase level, and that's because it is validated specifically in MCAS. Now, I will say, I'm sure your listeners may have seen or heard or they may have read about that additional tests include the urine mast cell mediators. These are N-methylhistamine, leukotriene E4, and prostaglandin F2. These are basically the urine metabolites of, again, those mediators that are released from the mast cells. The urine ones have been found to be the most stable, so we prefer those over any other sort of plasma levels. And those have been used and there is some information about what is a clinically significant rise in those levels, but I will say they're not validated like the tryptase, and so we really would still lean on the tryptase as the level to check.

Dr Lacy:

And so just focusing on that a little bit more, this has been a great explanation. What's the value of routinely checking a baseline tryptase once or twice a year to see what the baseline levels are to see if there's some change over time?

Dr Squire:

That's a great question. We do actually recommend getting a baseline level in all of these patients. And the big reason for that is, as I mentioned in the diagnostic criteria number 2, that change is you need to see a change. It's not necessarily that the baseline is going to be elevated. If the baseline is, particularly getting closer to that 20 level I mentioned before, we're going to lean a little bit more towards this may be systemic mastocytosis and they need to go to hem-onc for a bone marrow biopsy. So most patients with MCAS will have a completely normal baseline level, but we do want that baseline so that we can then compare with an episode, what does that change and does it meet that criteria for a clinically significant change? So it's important to get those.

If I have a patient who has been diagnosed with MCAS, I will check the level once or twice a year to make sure that it's not rising, it's not going higher. But if you've checked it once and the patient doesn't have any other symptoms concerning for systemic mastocytosis or you're not leaning towards that route, or again, maybe you get the baseline and then you get an acute level and it doesn't have a significant change and we've kind of ruled out MCAS at that point, I would say there's not a reason to continue checking it after that.

Dr Lacy:

Wonderful. So one kind of conundrum that many of us face in clinic is that we evaluate a patient who's been told that they might have MCAS, mast cell activation syndrome, and are empirically being treated with a number of agents, antihistamines and mast cell stabilizers such as chromalin and maybe even steroids as well. How do we approach that patient to make the correct diagnosis in clinic? Do the same diagnostic criteria apply to that patient on therapy for a presumed disorder? Do we measure serum tryptase? Is it even accurate?

Dr Squire:

And that's a great question too. It's because it's tricky. As you mentioned, we talked about that there's overdiagnosis and so we do have patients coming in who are being told that that may be what they have and we're trying to clarify. Thankfully, the same diagnostic criteria do apply, so we can still use all of those. And the tryptase is still quite useful because tryptase does not have any medications that directly affect that level. There are no medications that target tryptase specifically, nor would lower that level specifically. So it should be something that we can check their baseline and then again, at least give them an on hand or have it ordered in our system that if they have an acute episode, they can come in and get the level rechecked. And we would still expect to see a rise if they were truly having an episode of MCAS. So it's something that we can still use.

For me, if I have someone that's coming into the clinic who's expressing that they've been diagnosed with this, I just kind of always go back to the beginning, as most of us do. I say, "Tell me what symptoms did you have that kind of led to someone suspecting that you might have MCAS?" And really try to home in, does it seem like these are acute episodes with 2 or more organ systems involved? And then I ask what workup was done? Did we get any other baseline levels? Do I have something I can look back on and see what was done beforehand? Maybe that's the tryptase or maybe even urine levels. And then I move on to, okay, what therapies have we tried and have we had any clinical response to them? And if so, what sort of clinical response have we had?

But if I have someone that's come in and said, "This is where I've been, these were my symptoms, I maybe didn't have any testing, but I tried all these therapies and I'm really not better. I'm not feeling better." I think that we really need to be thinking about other causes for that patient's symptoms if we're not seeing a clinical response in that scenario.

Dr Lacy:

Yeah, I really like the way you said that. And if somebody's not responding to what we think is the correct therapy for this disorder or any others, we should take a step back and say, "Is this the right diagnosis or is this the right therapy for this patient?"

Switching gears just a little bit, let's take that patient who clearly has MCAS. Diagnosis is not in doubt based on all the things you've already mentioned so nicely. Is there a validated treatment algorithm? Do we always start with one agent over another?

Dr Squire:

That's a great question too. And that's where I think a lot of patients and maybe even other clinicians get a little bit hung up as they think, "I don't know how to treat this patient. I don't know where to go." The great news is that the majority of medicines that we use for MCAS really are quote unquote “regular allergy medications.” We're not using anything very fancy or expensive to treat these patients. And most of these medicines are very easily available. You don't have to use a specialty pharmacy or anything like that to get them. And so it's fairly easy to start the treatment and see if you get some response if you had that concern, rather than maybe waiting for them months to get in to see an allergist or something if you don't have availability near you.

There's not a specific algorithm, so that does make it a little bit tricky. There's not a, everybody starts here and then we move down the list over time. It is that we sort of start with a category of medicines, which I'll go through that, and then we kind of target the patient's symptoms. Are they having more predominant GI symptoms? Are they having more predominant respiratory or skin symptoms? And we're going to target those symptoms.

In general, we do start everyone with antihistamines, our good old first H1 and H2 antihistamines. In general, we shy away and allergy in general has moved away, from using first-generation antihistamines, such as the diphenhydramines, the hydroxyzines, quite as much just because they have more of that sedation, drowsiness, they can cross the blood-brain barrier, have more of an effect there. So we really recommend patients limit use of those. We lean towards the second-generation antihistamines, the cetirizines, fexofinidine, loratadine, things in that group of medicines.

Where it does differ a little bit is that in our guidelines for whether it's mast cell activation syndrome, MCAS, or we have another condition called chronic spontaneous urticaria, which is fairly similar, it's the mast cells going off predominantly in the skin. We use actually high-dose second-generation antihistamines. And so that actually includes up going up to 4 times the daily dose. So for fexofinidine or cetirizine, it's up to 4 tablets a day. In general, I would do 2 in the morning and 2 in the evening, 2 tablets twice daily, but that has been well studied and we consider that very safe dosing. So the patients can go up to 4 times the daily dosing on those. Often, and particularly if they have GI symptoms, we'll add in an H2 blocker such as famotidine and usually something like 20 milligrams twice a day to see if that provides them any benefit.

I would say that is my standard for most all patients that I have a concern of MCAS because it's fairly simple, relatively inexpensive medications to start with, and see how they respond. When I then follow them up, that's when I might do more targeted therapy depending on their symptoms. If they have more respiratory or sinus-type symptoms, I would lean towards montelukast because it targets leukotrienes, which are also released from the mast cells.

If they had, as I'm sure many of your listeners are what they're dealing with is more frequent GI or predominant GI symptoms, I tend to lean more towards chromalin. Chromalin's an oral mast cell stabilizer. It comes in typically in a liquid form, kind of coats the GI tract, and so it can be quite helpful for those persistent GI symptoms. With that one, it's generally very well tolerated. We consider it a very safe medication to use. It can have a little bit of GI upset itself when patients start it. So in general, I'll start them on a low dose like 100 milligrams daily, and then they can titrate up to the maximum dose, which is typically 200 milligrams 4 times daily, such as before meals and at bedtime. And the patient can kind of self-titrate, meaning if they get to twice a day and they feel like that dose works for them, then they can stop there. They don't have to go any higher, but they can go up to the 200 four times a day.

Less frequently, though we do have these as options, would be medications like aspirin, because prostaglandins are released from the mast cells as well, so it targets that pathway. Ketodifen, that's another oral mast cell stabilizer. That one's just a little harder to get in the United States.  It has to be compounded at a compound pharmacy, but we also consider it safe. And then the other main one that we use is particularly for patients who are having recurrent anaphylaxis that we're worried about, we might put them on the anti-IgE biologic omalizumab. That's been shown to be very effective for these patients.

Some things that we don't recommend that you may see your patients coming in on, that would be things like chronic steroids. We don't typically recommend chronic prednisone in these patients. And thankfully with all of those things I just mentioned, we don't typically need to. We can usually find some other combination of therapies that works to calm down those mast cells. So in general, we try to get patients off chronic steroids if they are on them. And we also don't generally recommend chronic IV therapy. There may be some patients that come in that have had ports placed maybe for other reasons, but are getting IV fluids and IV diphenhydramine for their symptoms. We don't recommend that as sort of the primary treatment. We would focus on switching them over to some of those other therapies that I mentioned.

Dr Lacy:

Dr. Squire, that was perfect. I can imagine that many of our listeners will listen to that 2 or 3 times because there was so much information there, which is just great.

So let's think about response to therapy. Are there any predictors? Can you predict that a young woman with 1 episode a year will be more likely to respond to medication A or B versus a middle-aged man with 4 episodes a year?

Dr Squire:

No, there honestly hasn't been any data that has shown that age or other patient characteristics are indicative of who's going to respond or who is not. As I mentioned, with that third criteria being response to therapies, there really hasn't been patients I've been familiar with and very few that I'm aware of outside that won't respond to some combination of these therapies. If we're not getting response to these therapies, then again, we really should rethink that diagnosis, re-evaluate. And of course, too, like I mentioned, we do have to think about that systemic mastocytosis. That does become a little bit of a clonal condition. That's why we're checking that tryptase level, make sure it's not climbing over time, because that is something that, again, we would maybe partner with hematology-oncology to treat more of that clonal aspect.

Dr Lacy:

As we wind down here, you already mentioned a few tips about treatment things not to do, like trying not to get people on chronic steroids and not using IV intravenous infusions of Benadryl. How about what we should not be doing in the evaluation of these patients? For example, should we be checking serum serotonin all the time or chromogranin level A all the time because I see that being done?

Dr Squire:

No, that's another good question. And you're right, we don't recommend those levels. As I mentioned, we are checking some of those urine metabolites that are from histamine or these other things, but the caveat is that those plasma levels have just not been shown to be as stable. They also can have kind of diurnal variation. So you can make it a higher level one time a day that's normal for that to happen. And so those aren't as stable as the other tryptase and occasionally those urine levels. So in general, we don't recommend any of the other things that you may have come across such as the serum serotonin, chromogranin A, platelet activating factor—sometimes I'll see patients come in with that—and particularly plasma histamine. So again, we'll look at the breakdown product of it, but we wouldn't recommend that serum level.

The only other thing I would say that I've come across as well is some patients or other clinicians looking at mast cells on biopsies. So looking particularly such as within the GI tract, looking to see if there are evidence of mast cells. And as I'm sure all your listeners are familiar with, there's definitely varying reports of what's quote unquote “normal” to see within the GI tract or what may have been seen with other conditions. So at this point in time, there's not enough data that shows a correlation between the number or increased or what we consider elevated number of mast cells in the GI tract and mast cell activation syndrome itself. So we wouldn't use that as part of the diagnosis. We would still go on the clinical symptoms, the elevated tryptase, and the response to therapy, but I do see that come through at times.

If you were to find those abnormal mast cells in the GI tract, whether they were elevated or maybe they do have some abnormal findings, sometimes they'll be reported as spindle-shaped or other things of that nature, that would lean us a little bit more towards systemic mastocytosis, that clonal issue with the mast cells, which again, we would want to think about getting a bone marrow biopsy to see if that's where those are coming from.

Dr Lacy:

Great teaching point, that clonal proliferation with infiltration of other organs, including the GI tract. So Jacqueline, this has been a wonderful conversation. I know I've learned an awful lot. Any last thoughts for our listeners?

Dr Squire:

Well, thank you so much for having me, and hopefully I didn't make it more confusing and had some good points for you, but I really appreciate the opportunity to review these diagnostic criteria. And just as a parting thought, I would say there are many more patients that are coming into our offices that have a concern for MCAS than will truly meet the diagnostic criteria. So just going back and reviewing those diagnostic criteria to see whether the patient seems to truly meet those. And just knowing that there are certainly other conditions that will have overlapping symptoms such as patients will get flushing and dizziness that is kind of 2 separate organ systems, but that might be more dysautonomia that they're having. So we have to think about those other potential confounding factors. And as allergists, we're really going to go off those evidence-based guidelines, that consensus criteria that's been developed, and we do want to try to obtain that baseline tryptase and then repeat during an episode to make an accurate diagnosis.

But I will say, if you have a patient in front of you that you have a concern about, it's very reasonable to try those first-line therapies that are relatively benign, such as the antihistamines and maybe even chromalin to see if they have a clinical response while you're maybe awaiting some of that lab results.

Dr Lacy:

Dr. Squire, this really has been a wonderful discussion today. Thank you so much for lending your expertise on this important and sometimes controversial topic. To our listeners on Apple, Spotify, and other streaming networks, I'm Brian Lacy, a professor of medicine at the Mayo Clinic in Jacksonville, Florida. You have been listening to Gut Check, a podcast from the Gastroenterology Learning Network. Our guest today was Dr. Jacqueline Squire from the Mayo Clinic in Jacksonville, Florida. I hope you found this just as enjoyable as I did, and I look forward to having you join us for future Gut Check podcasts. Stay well.