People think mast cells are only involved in allergy, but there’s so much more!

Watch my presentation 2022 Integrative Healthcare Symposium titled ‘Mast Cell Activation Syndrome : The Interplay Between Immunity and Neuroinflammation’.



Dr. Tania Dempsey: (00:00)

I’m so excited to be here. I was thinking about the first time I was at IHS. It was probably around 2010, and it was the first integrative conference I had ever been to. I wasn’t even aware of what I was going to encounter here. The energy was palpable. I felt like I was with my people. This was the best conference.


I think it was Jay Lombard that year that I remember sitting and listening to and thinking: “Oh, I can’t wait to be up there and talk about something that I’m really passionate about. He’s so passionate about what he talks about. I want to do the same.” Well, here I am to talk about something that I’m not only passionate about, but I’m also a little bit obsessed with—I’ll admit it. And that’s mast cells. It’s hard not to be obsessed with them because they’re really so important when we look at all our chronically ill patients with multisystem disorders.


I have a lot of things that I want to cover, but I’m going to start with some of the basics. Let me set the stage for what mast cells do when they are normal. Everybody has normal mast cells, so let’s talk about what their function is. Then let’s talk about mast cell activation syndrome, which is the dysfunction of mast cells. Let’s understand what happens when they become dysfunctional. We’re going to look at the various disorders that MCAS—dysfunctional mast cells—can cause. We’re going to look at the nervous system and we’re going to discuss neuroinflammation. We’re going to look at things like chemical intolerance and a variety of other manifestations that we see from MCAS.


I think it’s important that we look at all of it and not just think about the things that some people think mast cells are involved in and that’s allergy. There’s so much more. I’m going to end with a case. I did a brief study of some patients in my practice. I’m going to report the findings, and then I’m going to review a case so you get a sense of how I approach patients like this and give you some tools to bring back to the office on Monday.


I apologize if some of this is a repeat of what you already know. But again, it’s nice to hear it again because it puts it together and makes it easier to understand the harder stuff of why things are going awry. Mast cells are from the bone marrow. They’re produced in the bone marrow, they’re released into the bloodstream, and then they go into the peripheral tissues. They’re in the organs. Anything that’s vascularized is where they are finishing up their maturation process. Their maturation is controlled by their environment. I think this is a very important point, and I’ll hit on it a little bit further along: they can get mutated; they can get affected by epigenetic phenomena. Where the mast cells are, what’s happening, what they’re exposed to, what kind of toxins, what kind of infections, etc., are going to control whether they stay normal or whether they become abnormal and aberrant. So there are a variety of receptors on the mast cell surface. There are probably even close to a thousand receptors. They can bind allergens, can bind toxins, can bind lots of things. They synthesize these granules of cytokines and mediate other mediators.


There are probably over a thousand mediators that mast cells can make. Basically, one part of the way mast cells work is that they release their granules, their mediators upon response to a trigger. The trigger could be anything, and we’re going to talk about that as well. They also have other functions that we don’t talk about as much. They can actually phagocytize bacteria, metals, or foreign debris. They’re really in high concentration at the interfaces of the environment. They’re there because they’re part of the innate immune system and they’re there to protect us. So they’re in every place that you can imagine that is going to have to deal with the environment—[that’s] where they are. They’re located where they can locate pathogens.


I bring that point up because while there are a lot of things that we talk about in the mast cell world that could be triggers for mast activation syndrome, part of the focus of my practice is infection. We know that they’re involved. They’re very heterogeneous; I think this is an important point. Not all mast cells make all the thousand mediators that I mentioned; they’re different. They can be different within one patient. The mast cells in their gut could be releasing certain types of mediators. The mast cells in their respiratory tract could be producing other mediators. It’s actually sometimes very hard when we have to treat these patients, how we focus on them systematically, when there may be differences within them, and then between patients, of course. I mentioned they’re in all tissues, but I want to make a point that they are associated with blood vessels, lymphatics, and smooth muscle. So you can imagine the far-reaching effects their mediators can have, affecting things like the flow of blood or lymph, secretion, and contraction of many sites, influencing healing, proliferation, and remodeling.


I just want to point out this website. I encourage you all to check it out: It’s essentially an encyclopedia for nerds—an encyclopedia of cytokines. We’re working with Dr. Ibelgaufts, who has really put together this tremendous array of cytokines. But what’s really interesting is [that for] the mast cell portion of his encyclopedia, he has scoured the literature, he has found every reference to mast cells, and he has found over a thousand mast cell mediators and receptors. It’s just really cool to pull it up and just see it.


Now, I can’t cover all of them, but this is just a little idea of some of the types of things that mast cells produce. And again, the effects they’re going to have on the body are dependent on these particular mediators or cytokines. I think it was interesting—I think Dr. Patterson mentioned this morning that he’s noticing a correlation between the cytokines that they’re finding in COVID-19 and the symptomatology. So you could sort of say the same thing. There are these preformed mediators like histamine and serotonin that are going to have a particular effect: vasoconstriction, vasodilation. And there are other types of cytokines that influence other cells basically, leading to, let’s say, tissue infiltration of leukocytes, growth, and remodeling. So, again, it’s far-reaching.


So the heterogeneity of the mast cells—and I mentioned again that they’re different in different parts of the body—may be producing different types of mediators. A lot of it has to do with the local environment that the mast cells are in. In women, we see an association between hormonal shifts and mast cells. Actually, we would say the same for men, but maybe different hormones. But there are physiological conditions that can affect the mast cells at baseline. And then, we’re going to talk about dysfunctional mast cells. So we know that hormonal shifts affect pathologic conditions like infection, which I mentioned. Epigenetics is a really key player.


This just gives you a quick overview. I have a lot of slides, so feel free to check them all out later. But this is just an example of what mast cells can do, what they produce, and then the effects on the various organs. Now, in the immune system—because we’re going to really concentrate on the immune system and the nervous system—to me, they’re really very, very interconnected. You can’t have one without the other. Mast cells in the immune system talk to other cells, other immune cells. They have that job in the innate immune system where they’re degranulating, releasing their chemicals, and trying to fight what they see as foreign. But they also act in the adaptive immune system. I think this is an important point because they can present antigen, for instance, to B cells, causing the production of autoantibodies—very often there could be other antibodies. But some of those antibodies may not actually be functional antibodies. So the signal is sent from the mast cell to the B cell to produce the antibody. Maybe this is why in many of our patients we’re seeing increased levels of autoantibodies, ANA, etc. Maybe some of it is driven by the mast cells, and there’s some research to support that idea.


Mast cells in the nervous system reside near the nerve fibers. I like to visualize it. I draw this for my patients. I draw a nerve fiber and I draw the mast cells literally lining the nerve. You can imagine that if the mast cell has a degranulating event and there’s a flare, it’s going to release these mediators. It’s going to send a signal to the nerves. It’s going to send the signal to the other cells in the nervous system. They’re going to release their cytokines and inflammatory mediators, and then there’s going to be this back-and-forth vicious cycle essentially of inflammation.


I think I have something here that sort of demonstrates how, in this case, a bacteria or virus—we can replace that; it could be Lyme, it could be COVID-19—affects the mast cell, how the mast cells then affect neurons, the microglia, the astrocytes, and again, the feedback back to the mast cell.


I thought of this slide as I was listening to Dr. Gordon this morning because he was talking about stress and trauma and how they affect us on so many levels. Every organ in the body is probably affected by trauma. In the nervous system, you can see how trauma and stress activate these various parts of the nervous system; the astrocyte, the microglia, and the mast cells right there all feeding back on each other. What’s the end result? It’s inflammation.


I have some references for you there. We have some literature that has looked at the effects of mast cell activation syndrome—dysfunctional mast cells—on neurologic and psychiatric diseases. I want to shift gears a little bit. I want to give you a little bit of a historical perspective on mast activation syndrome because it’s a new disease that was recently identified but obviously has probably been around for much longer. But it sort of sets the stage for how we diagnose mast cell [activation syndrome] and the other things that we have to think about when we’re looking at patients with this. [The historical perspective of] mast cell diseases commonly included allergy and mastocytosis, which is rare. That’s sort of what we thought this was.


So, 2007 was really the first report of mast activation syndrome. Then there were consensus criteria that were put forth in like 2010 and 2012 that looked at: How do we diagnose these patients? What is this syndrome really about? I think that was really pioneering work. I think we’ve gone beyond that at this point, which is good. But again, this is not that long. Some of the things that we talk about here [such as] Lyme disease [for example, we’ve been talking about it] longer than [since] 2010, right? So it’s new, but it’s clearly affecting a lot of people. I would argue that the incidence is probably going to go up as our world becomes more toxic and as we become more exposed to COVID and other infections. I think we better understand this better now. So they finally came up with this term, MCAS. It was around 2010.


There’s one study in 2013—this is, I think, a really important pioneering work by Dr. Gerhard Molderings in Germany. I think that it will hopefully be replicated here. He wasn’t looking at MCAS patients, he was looking at the general population and found that 17% had MCAS. Maybe we go up a little bit and we say, maybe it’s like 20%, because did he really capture everybody? One in five people could have MCAS. I would argue that in our population of patients, it’s half or more. In my practice, it’s 95%, but in many of yours it may be quite a number, and many of them are undiagnosed and not recognized.


I want to bring up a couple of points with this. This is sort of a classification system. So we have at the top, mast cell activation disease. Then under that, we have this mastocytosis or cancer of the mast cell. Then we have the MCAS. Then we have various forms of MCAS, which I’m going to cover. But there are two other things that I wanted to bring up that I’m recognizing more and more in the last year or two, and that is this hereditary syndrome, hereditary alpha tryptasemia, which is HaT, and there is a genetic test for that. That is just an increased number of tryptase genes that basically code for tryptase. Those patients have high levels of tryptase but don’t have mastocytosis. They may have MCAS, but the point is that they may represent a slightly different population.


And then autoinflammatory syndromes, which we’ve been testing a lot of our patients on, we think may also be associated with MCAS, maybe a driver for MCAS. So I just wanted to make a point. It really depends on who you talk to about these classifications, but I like to think of it this way: There’s primary MCAS, there’s secondary, and then there’s idiopathic. Primary [MCAS] is the root cause of the patient’s problem. It best explains their constellation of symptoms. It’s monoclonal, meaning that there was a mutation probably in the bone marrow that led to this clone or many clones of the mast cell. We know what mediators that’s producing and what effects it’s having on the body.


Secondary MCAS is really a secondary problem. So mast cell activation syndrome is occurring because of exposure to a toxin, an infection, or a medication—something that is driving activation of the mast cell. But that could be reversed if you eliminate the problem. So these are the patients that might have mast cell activation syndrome, let’s say, and Lyme disease. We treat their Lyme and their MCAS improves. I would say the majority of my patients fall into the idiopathic [MCAS classification]. It’s not clear whether it’s primary or secondary. I would argue that many of our patients have a predisposition to MCAS at baseline genetically, and then they’ve had a series of events over the course of their lifetime that have escalated it and brought them to the point where they’re seeing you.


There are three themes [to] MCAS. Now again, a lot of people know about the allergic type, or allergy, right? But I want to be very clear: patients can have MCAS and have no allergic symptoms. You do not need that for the diagnosis. Generally speaking, the patients could have allergic reactions [or] they may not. I would say the majority have inflammation. That, by far, to me, is the overriding symptom—it’s inflammation in just about any organ. But they can also have aberrant growth development or dystrophisms. So I think of that as cyst growth, tumors, thyroid nodules, things that shouldn’t be growing but are growing abnormally. The mast cells probably have a role there. They play a role in normal growth. So abnormal mast cells, mast cells that are dysfunctional, will then have an issue with aberrant growth. I like looking at it this way: What do they do at baseline? And then, what do they do when they’re activated inappropriately?


An MCAS patient must have symptoms consistent with chronic mast cell activation, which is abnormal at baseline and reactive to triggers. There are patients that are completely normal at baseline, and then they have an event. So they were normal, they had COVID, they activated their mast cells and their macrophages and lots of other immune cells, and then they got better and they returned to baseline. In mast cell activation syndrome, the patients probably have abnormal mast cells at baseline. They are always sort of on alert. Then there are these additional triggers—sometimes they’re not identifiable, though—that will bring it out. We say that they should really have symptoms in at least two organ systems, and they must not have some other disease that better accounts for the full range of observed symptoms and signs.


These patients are usually under the age of 20. Again, I mentioned that they’re inflammatory. The symptoms wax and wane. Sometimes there’s no rhyme or reason for why they might be symptomatic now when they weren’t yesterday. Sometimes they can identify triggers, sometimes they can’t. But very often, there is a trigger in their lives that they can identify with that changed the course of the rest of their lives. So I love this cartoon. I’m going to give credit to Jill Brooks. She’s a nutritionist and she’s also a cartoonist. And this is what a mast cell patient feels like. There are the triggers. There are so many triggers. There are a thousand symptoms. Am I multi-talented or what? It’s really, really rough. These patients are sick.


I want to shift gears a little bit, and I want to dive into the manifestations of mast cell activation syndrome. These are things that we see in our patients all the time. We’ll do a little audience participation too—that’s coming up. We just published this with Dr. Claudia Miller from the University of Texas, really looking at how mast activation syndrome may explain the cases of chemical intolerance. We know people who are sensitive to perfumes or smoke or gasoline or lots of things, but what we wanted to look at is whether that could be explained by MCAS. So what we did was give our patients a questionnaire, which I’m going to show you, called the QEESI. We correlated their scores on the questionnaire with their diagnostic criteria. So, if we diagnosed them with MCAS and they had a certain score on the QEESI, we saw that there was a high percentage of patients who had MCAS who also had high scores on the QEESI.


You could be chemically intolerant and not have MCAS—we think—and vice versa. You could have MCAS and not be chemically intolerant, but the correlation between the two was really, really mind-blowing for us. It’s what we suspected, but it was nice to find it.


I want to do the BREESI questionnaire with all of you. So the QEESI questionnaire is a 50-question intake. This is three questions. I want you to raise your hand—if you don’t mind—if you have any of these symptoms. So we’ll start with question one. Do you feel sick when you’re exposed to tobacco, smoke, certain fragrances, nail polish, gasoline, paint, paint thinners, cleaning supplies, new furniture, carpets? By sick, we mean headaches, difficulty thinking, difficulty breathing, weakness, dizziness, upset stomach. There are a few, right? Yes.


Question two: Are you unable to tolerate or do you have adverse or allergic reactions to drugs or medications like antibiotics, painkillers, contrast dye, birth control pills, implants, prostheses, etc.? Yes.


Number three: Are you unable to tolerate or do you have adverse reactions to foods such as dairy, wheat, corn, eggs, soy, caffeine, or alcohol? Okay, since quite a number of you had your hands up for those, I would recommend that you do this first and then think about doing it with your patients. Go to or TILT is toxicant-induced loss of tolerance. I’m going to explain; I’m going to show you a slide on that. They’ve done incredible work. Dr. Claudia Miller is the one that’s sort of leading them. She has put together the BREESI as a screening tool and the QEESI as a more comprehensive look. Then you can take that QEESI and if you have a high score, you might want to look further as to whether you have MCAS or your patients do.


This is an interesting symptom star that they put together [so] that once you have your QEESI score, you can sort of outline it. I think what’s really interesting to see—you see the green area? They actually recommend you take the QEESI test twice. First, you answer the questions before you got sick or before you noticed a change in your health, and then you answer them with how you’re feeling now. Then you can compare the scores. So we have patients who know that there was an event; they got Lyme disease, they were exposed to mold, whatever it is. Before that, they can score, they can be on the green, and it’s small, right? And then the symptoms expand dramatically after a particular trigger or exposure.


So this is toxicant-induced loss of tolerance, which we can’t say because we haven’t improved it in the literature yet, but this is what we’re seeing in clinical practice is that there’s usually this susceptibility. There’s some genetic susceptibility that I don’t think we’ve identified yet. But the susceptible person has an event, an exposure of some sort. In my practice, it could be mold, it could be a tick bite, it could be COVID—there’s a large array—it could be a heavy metal exposure. They lose their tolerance and they become a sensitive person.


The sensitive person doesn’t need as much of a trigger. It could be low-level exposure. This is an iceberg, right? They’re underneath; you don’t see it yet. Then there’s some bigger event trigger that then brings the symptoms up to the surface. Those are the patients that we see—they’ve presented. I would say this is exactly what we see in MCAS. These are the various triggers. I think many of them are obvious.


I thought what was really interesting about the work that they’ve done with the QEESI questionnaire [was that], because it’s a validated questionnaire, they found that the highest initiators for predicting chemical intolerance were actually implants—number one. Pesticides, combustion products, mold—and you see it go down. But implants are the number one predictor of whether they would develop chemical intolerance. That’s huge because we’re seeing a huge amount of implant illness.


The manifestations of mast cell activation disorder and syndrome are [in] every organ system and every symptom you can imagine. I’m not going to go through each one, but you’ll have those in the slides. But it is pronounced, right? It’s a lot. We’re going to dive into the nervous system a little bit more. We see that MAST cells and MCAS are related to these pain syndromes. We’ve seen it in migraines and endometriosis, vulvodynia, and fibromyalgia. There’s this link between those mediators that the mast cells are producing, the effects on the nerves, and then the production of pain.


We actually published on using mast cell targeted treatment targeting underlying pain syndromes for women. So things [such as] dyspareunia, vaginitis, dysfunctional uterine bleeding. We showed that treating the mast cells actually has a far-reaching effect on their symptoms—really relieving them. We had patients stop having abnormal uterine bleeding. We’ve had patients stop having dyspareunia. So this is a great article if you want to just look at our case series.


This was a good article. It was really presenting a hypothesis about COVID-19 and MCAS, and I think that this sets the stage for how I want to think about MCAS or how I want you to think about MCAS in your patients. We believe that MCAS may be one of the root causes of COVID, but we haven’t proven it yet. That’s why we need people like Bruce Patterson and others to do the research. We hope that we’ll be able to come closer to the answer.


I think what I want to make sure you understand is that this is the distinction between normal and abnormal. Everyone has normal mast cells. Some people have normal mast cells and dysfunctional mast cells. So in this case, they looked at: If you had a baseline, a healthy patient, a patient who did not know they had MCAS, and a patient who knew they had MCAS and [was] treated, what would happen?—what they were seeing with COVID patients. What they found was that the people who had untreated MCAS—they didn’t know they had it—had inappropriately activated mast cells even at baseline. They didn’t know it. They were the same as the diagnosed patients, except the diagnosed patients, because they were on treatment, had better control of their abnormal mast cells. Then they got COVID and what they found was that the healthy people, because they didn’t have abnormal mast cells, had a normal response to COVID and then recovered.


The patients who did not know they had MCAS had appropriate mast cells if they were normal, but the dysfunctional mast cells were inappropriately activated—overactivated—releasing cytokines. That’s the cytokine storm that everyone talks about. Then, after recovery, their mast cells do not return to normal as they would in a normal person—they continue to be activated. The patients who were controlled with MCAS, they found that at the end, they were more controlled through[out] the illness.


This is what we’re seeing in our patient population. We don’t see a lot of our patients getting long-haul COVID because they’ve been in my practice—they’ve been pretty well controlled. They’re not perfect. We have patients who are still very ill, but they have some things on board to help. Whereas the patients that I’m seeing who I haven’t been treating, who have post-COVID syndrome and are coming to see us because they’re suspicious that there’s something going on with their immune system, we’re finding that they probably had MCAS before. They didn’t know it, and now they’re still sick. So this is a big piece of the puzzle.


Thinking about COVID or any trigger on the mast cell, we just published this last month, I think, a case series of post-HPV—post-Gardasil vaccine—and the escalation of mast activation syndrome. So, sort of the same way to think of it, these were patients who we only saw after they were really sick. But when we took a really thorough history, what we found is that these patients probably had underlying MCAS untreated—maybe mild, not affecting them—then they had the vaccine. And for some of these patients, it wasn’t until the third in the series—some of those patients had effects after the first one—that they then developed POTS.


You’ve heard POTS mentioned a few times—postural orthostatic tachycardia syndrome—which is a dysautonomia. It’s an issue with the autonomic system. They developed POTS and then, over time, were finally diagnosed with MCAS because they came to us and we diagnosed them. But what we found was that, again, they had MCAS—probably couldn’t prove it—they had an event and then… Actually, our theory is that MCAS is the driver of POTS. It’s the mast cells in the nervous system, in the autonomic nervous system, that are then releasing their mediators, causing the nerves to react and then have an effect on the blood vessels, etc. It’s a complex process.


I think it’s important when we think about our patients that we always go back in time and understand what they were like before, what the trigger is, what they have now, and then, obviously, how do we treat it?


I want to spend a little bit of time on the diagnosis of MCAS because there’s a lot of misinformation. I equate this to the Lyme world—it’s a little bit of two sides to the story. Two sides here, right? So there’s a group [of] really pioneers in the MCAS world who have come out with what we’re sort of terming the consensus-1 criteria for how to diagnose MCAS, and they have very specific guidelines. They’re very similar to what I’ll talk about. My group is consensus-2. But the important point that I’m going to bring up is tryptase because I think the most common question that I get asked by practitioners when they reach out to me for help with patients is about the tryptase [levels]. They say: “Well, their tryptase isn’t elevated. So based on this criteria, they don’t have MCAS.” Again, this is one way of looking at tryptase. We challenge the view of the tryptase.


We published this a couple of years ago, I think it was 2020, where we presented another way to look at diagnosis not using tryptase. There are so many mediators that mast cells make that if we rely on tryptase only, we’re missing the boat. We know that they’re making a thousand chemicals or more. Our way of looking at it is having the ability to use all the different types of mediators that we can test for; there are lots [of them] that we can test for. If you have an elevation in these mediators and you have a clinical picture that’s suggestive of this and they have one of those three themes that I mentioned, allergic, inflammatory, or dystrophic, then that supports the diagnosis.


Heparin is probably the most specific mast cell mediator. It’s one that I have found to be the one piece of evidence that I can use to support the diagnosis. Very often, these patients have negative histamine levels, and you think: “Oh, how is this possible? How can they have MCAS and not have elevated histamine?” Well, it’s because that’s not one of the mediators their mast cells are making or we can’t capture it at the time.


Heparin is so specific. If you think about what heparin does, it’s a blood thinner. It’s being produced by abnormal mast cells—not normal; abnormal. Think about the things that could happen. So if the mast cells in the uterus are producing heparin, you’re going to have dysfunctional uterine bleeding or heavy periods. It may affect other bleeding issues or other clotting issues. So I love that it’s hard to test for; you have to have the right lab. I want to mention that because I think it’s far more important than tryptase. This is just for you; this will be in your slides, just the things that you want to test for diagnosis. Biopsy staining is always encouraged as well to look for mast cells.


I won’t belabor the point on tryptase, but basically, all mast cells have tryptase. So if you have mastocytosis and you have cancer of the mast cell, you’re going to have a lot of tryptase. But other than that, it’s very variable. So a very small percentage of our patients actually have a tryptase issue, and they might even have this hereditary problem—HaT.


I think about the diagnosis of MCAS. Consider it in patients who have failed to find any other evident disease that better explains their full range of findings. You’re going to look at the physical exam. They might have dermatographism—the scratch test produces a wheel. They may have other findings. They may be hypermobile. There are other associated diseases that we see. They may have POTS. And then you want laboratory data. It has to be consistent with chronic aberrant mast cell mediator expression.


You’d like to see a response to intervention. Usually, before I’m even waiting for anything to come back, I’m starting them on something because if they get better, that helps in thinking about it. We have a questionnaire that we give. We’re giving the QEESI questionnaire to everybody. I think it’s really important. It helps us understand them better.


I’m not going to go through every minute aspect of the treatment. I can probably spend two hours just talking about five drugs on this list, but I want to make a point. Since I mentioned earlier that mast cells are different—they’re heterogeneous, and they make different mediators—the treatment is going to be different in each patient and even between the different organs or different systems in their body. So you might find something that works for their mast cells in their respiratory tract, but that might not be the one that’s going to work in their GI tract or their nervous system. So it’s complicated. Everything has to be done one thing at a time.


I would say that probably the basic stuff that we use if we’re looking at pharmacologic—I’ll mention the non-pharmacologic too—we think about H1, antihistamines that block the H1 receptor. We think about H2. We trial and error each one. We even compound them. Again, these patients are sensitive, right? So they may be sensitive to an excipient in a pill. It could be the dye. I can’t believe that they use so much dye in so many of the pills on the market. But there are other ingredients: magnesium stearate, microcrystalline cellulose, and the list goes on.


Sometimes, if you have patients who are not responding, you have to look and say: “Is it the drug they’re not responding to? Or are they reacting to the drug? Or are they reacting to something else?” So it’s a lot of work. It takes time, and the patients have to start to learn to recognize things themselves.


We use leukotriene inhibitors because leukotriene is a mediator that mast cells make. We use a lot of low-dose naltrexone, which I know Dr. Horowitz mentioned before, I think. Aspirin could be good; it could be bad; it really depends on the patient. All of these things really are like that. We try to avoid steroids, but sometimes it’s inevitable. The mast cell stabilizers: cromolyn, ketotifen, and even hydroxyurea could be in that class. I don’t use that as much, but cromolyn and ketotifen are definitely a big part of the practice. But again, I can’t predict who’s going to react to what [or] in which way. So it’s frustrating. Patients want to get better yesterday; you have to work your way through it. Some respond to Xolair. That’s a monoclonal IG antibody. Imatinib, which is a mastocytosis chemotherapeutic agent, might have an effect as a tyrosine kinase inhibitor.


And then there are lots of non-pharmacologic treatments. Some of the stuff we’re doing simultaneously or we’re thinking about first, we’re setting the foundation of their health. We are thinking about their diet. We’re thinking about reducing inflammation. They may have issues with methylation, which is one of the ways histamine is metabolized. There are definitely pros and cons to the histamine diet. People ask me all the time: What is the diet? What should they do? We don’t have it on our website. We don’t promote it because everything has to be personalized and individualized. There are a number of other products and things that we use pretty routinely, but one thing at a time. Here are some references.


So again, even the monsters don’t understand why they designed this low-histamine diet. “It has to be inconvenient, confusing, and frustrating”—absolutely—if your patients ever ask you why there are five histamine diets online and they’re all different.


Now I want to look at the study that really looked at mast activation syndrome and neuroinflammation and immunity. So this was just a case review of my patients. We looked at eight patients. I believe I did the slide deck for the 2020 or 2021 IHS conference. These slides are actually a little bit old because I definitely have more than eight patients. But I looked at these patients between the ages of 5 and 25. We looked at patients who had been evaluated for persistent neuropsychiatric illness and who were unresponsive to traditional psychiatric medication. So these are the patients. They’ve been to the psychiatrist, they’ve been hospitalized, and nothing works.


We looked at mast cell activation syndrome. So we tested them for it. We also looked at autoimmune markers. We looked at antineuronal antibodies, we looked at other markers for inflammation. What we found was that all patients—again, a small number—had confirmed mast activation syndrome according to the consensus-2 criteria. All patients had at least one auto-antibody. Six out of eight of them had antineuronal antibodies. Then when we targeted the mast cell—mast cell targeted therapy—it led to significant improvement in their neuropsychiatric illness.


Since I have a little time, I’d like to run through a case that demonstrates this so that you understand how I approach patients like this. This is an 11-year-old boy who I saw for the first time in October of 2018. He had recurrent fevers, severe fatigue, leg pain, insomnia, and brain fog for a year.


I always go back to the history before birth, the health of the mother. He had some early stuff. He was delivered by c-section; he was breastfed for a year, but the mother really struggled with her diet. He was sensitive to everything she ate. Soy, eggs—she had eliminated everything. He had blood in his stool, so he had a milk protein allergy. But the history was that he was developmentally normal and actually met his milestones early. Now, in retrospect, there are some questions about his development. But at least physically, he was developing normally. He had a lot of problems early on in life. Introducing food, he developed seasonal allergies. Again, he’s become a sensitive kid. The mother describes that the socks have to be a certain way and the pants have to be sweats. He’s sensitive.


At age three, he developed recurrent ear infections and then needed the tympanostomy tubes placed. Then, somewhere shortly after that, he developed a cholesteatoma and then needed a really profound surgery for a very young child where they used implant material. They used titanium and synthetic materials to recreate the bones. Then he lost his hearing. He regained his hearing, thankfully, but then needed tubes placed again. When I met him in 2018, he still had the tubes. There was some history of a questionable bull’s-eye rash. He wasn’t diagnosed with it at the time. The parents believed that’s what it was in retrospect, but he was never treated. So again, I saw him at age 11. This was at age four. The symptoms started about a year before I saw him.


He had these random fevers. He was having more difficulty going to school. He couldn’t do his normal activities. Then he started getting sick a lot. He got parvovirus on top of what he was dealing with already. Then he had head trauma. You should be hearing the common theme here, and that is that there’s an event, and then there’s stabilization, and then there’s another event. And this is a big event, right? A TBI is major in a young child. The brain is developing. Inflammation—there are tons of mast cells in the brain, right? And he’s told he doesn’t have a concussion, but he probably did. Then he developed tinnitus that continued until I saw him and that really was the point at which his entire condition worsened. He was dealing with his symptoms on some level.


When I saw him, he actually also had a hearing aid because he had lost hearing in that ear that had regained it originally. He continued with fevers. He got the flu. The pediatrician said: “I don’t know what to do. Maybe it is Lyme, so I’ll put you on doxy[cycline].” Maybe it helped, maybe it didn’t; it wasn’t clear. His diet—he was really, really irritable and it was very hard to get good food into him.


The family history is interesting. I always like to look at the genetic piece. The mother says: “Oh yes, I’m sensitive and I have allergies. I’ve fainted a few times, and I’m really hypermobile and my knees pop.” We know that there’s an association between connective tissue issues and mast cell activation, so that’s where the flag goes off. The father also had some autoimmune issues: thyroid nodule, and white matter changes on his MRI—very non-specific. His sister had some gut issues at the time I saw him. I wasn’t seeing the sister. But then I’ve since started seeing the sister, who really probably is now worse than he was. So she had her turn, and now I have a bunch of triggering events that we’re trying to deal with.


When I met them, they were living in mold, but it wasn’t so apparent. I think they minimized it. They were going to move. In the beginning, you know, we always pay attention to mold, but they really didn’t think it was a big deal except that he was really in this moldy home all day because he was being homeschooled. The review of systems could go on and on. Every part of his poor body was suffering.


He was pale, he was lethargic, he had lymphadenopathy, he had mild dermatographism, and he was hypermobile but didn’t meet criteria for hEDS. His lab work was really, really interesting and concerning. This is going to be the take-home message: I thought this was the answer. I said, “This is it!” I told the parents, “We found it.” He’s PCR positive for Lyme. He has had exposure to Borrelia miyamotoi. He has had exposure to Bartonella henselae. Whether it’s active or not, I don’t know. But given the PCR for Lyme, it’s possible that these are all active. His initial MCAS testing was negative. So I thought, “All right. I know where we’re going with this.”


Because he was having a lot of neurologic symptoms and trouble concentrating, I did the Cunningham panel, which is an antineuronal antibody panel that looks at the antibodies that may be responsible for neuropsychiatric issues. Here’s an example of his Moleculera test: elevation of inflammatory markers, basically, so his brain is on fire; he has Lyme disease; he also had Strep A antibodies and ANA; low vitamin D; and dysbiosis.


So this is the type of patient that we see—so complex, right? I use this analogy all the time with my patients: You have an onion and you have the layers of the onion; you’ve got to peel each layer at a time; what I think may be the top layer of the onion may turn out not to be the case. I always start with the foundation. We’ve got to work on his diet as much as we can.


He’s a kid, he’s stubborn, and he’s sensitive. He’s sensitive to food textures and all that. But we’ve got to start working. We’ve got to cut some things out. He needs vitamin D because the number one thing that we can do for his immune system—mast cells have vitamin D receptors on their surface. Okay. I don’t know if he has MCAS, but vitamin D’s not going to hurt and he needs it, right? Then we’re going to monitor his levels. I’m working on his gut. I’m working on his inflammation.


I said to the parents that we’ve got to figure out what’s going on in the house, so we did mycotoxin testing, which was off the chart. They go back; they do the testing on this home. It was a rental home. They were renting basically with the intention of buying a house eventually, which they thought was going to be sooner rather than later. But in any case, the house was a mess. They’re actually now dealing with the landlord. And that’s a whole other thing. I feel bad for them. The house basically needs to be gutted. But they moved out, thankfully, and he really started to improve.


All the things we were doing were moving the needle a little bit. He noticed that he was a little bit different, but he was still very dysregulated and very difficult. He couldn’t get along with his siblings. He was having trouble in school with others. He was having these outbursts. So we said: “All right, you know what? Maybe we need to start treating the mold.” So I did some of the mold protocols: binders and other things. He started getting hives and allergic symptoms, which he hadn’t had before. So we kept trying different things.


He kept reacting to different things. We wound up with some homeopathy because the mother really was struggling with how he was doing, and she was so afraid of making him worse with everything that we had tried. Maybe it helped a little bit, right? So, we were always going back, like: “What are we missing? What are we missing?” He was maybe kind of stable for a little bit. Then he started having suicidal ideation and depression. This is an 11-year-old, right? The mother said, “Something is wrong.” The psychologist that he was seeing was doing this type of therapy with him. She said to me: “I’m sure this has been going on for longer. Yes, he’s had these triggering events, but I’m telling you that his nervous system is just different.” You know, maybe not neurotypical. That’s not bad; it just is.


Then the light bulb went off, and I said: “We’ve got to go back. We’ve got to go back and think about mast cell activation syndrome.” I know I did some testing and it was negative. “It’s okay, it happens; let’s do it again,” because the [patient] history was just starting to sound. He was reacting to everything. He wasn’t responding to treatments. I may have glanced over that really quickly, but I treated him with antibiotics too for the Lyme. We did various things—herbs and antibiotics. It was impossible to get him on anything. So we did the testing, and twice we were able to isolate an elevated histamine level. I could not find any other mediator in him, but I thought: “Well, I’ve got two. I’d like to confirm it twice.” I had the clinical picture.


“So let’s do this,” [I said]. I put him on a quercetin-bromelain-NAC combination—a chewable pill. He cut it into four pieces. He would chew a little bit. It took months to titrate him up. But he got to the point after a few months that if he skipped a dosage, he knew the difference. And actually, his family knew the difference, and they would see him starting to become a little bit dysregulated. [They’d ask him], “Did you take your quercetin?” So it was good. You know, we tried; it was good. It was not perfect, though. We tried all these other mast cell-targeted therapies. Again, [they were] not tolerated. We compounded; we did a lot of things.


Then I said to the mother: “Okay, you know what? We’re going to try cromolyn. Because what I’m seeing—and again, this is anecdotal—is that cromolyn, while it’s not absorbed into the body, basically, it stays in the GI tract, for some reason, there’s this effect it’s having on the mast cells in the gut that is having an effect on the mast cells in the nervous system. Well, I say “for some reason,” but it’s the gut-brain connection. So let’s treat the gut with cromolyn and let’s see what happens.


I titrate cromolyn really slowly. I know that the prescription can be written [as]—it’s a liquid for those of you who don’t know—one vial four times a day. I’ve seen patients who’ve come to me from other doctors and they said: “I couldn’t take cromolyn. My doctor told me to take it four times a day and it made me so sick.” You cannot start it four times a day. It does cause what we consider tachyphylaxis. It will make the mast cells more reactive; they degranulate further before it actually stabilizes them.


So we go super slow. I’ll have them take a vial [mixed] in water. I might tell them: “You know what, make it eight ounces. Measure it. And maybe you start with half an ounce or an ounce of that preparation. We’re going to go slow until your mast cells know what’s happening, and then we’ll go up.” And that’s what we did. He titrated up. All he was taking was one vial of this. It took a month or two to get up to that. It is, in the mother’s words, “a game changer.” He starts skiing. In fact, the reason I knew it was a game changer [was that] she sent me a video of him on the ski slopes. I wanted to cry. I mean, this kid could barely stand, could barely move when I saw him in the office. Now he’s skiing.


He went back to school. He’s happy; he’s playing; he’s making friends. He has no joint pain—[no] leg pain. This was really the thing that was most bothersome to him. One of the things we see rarely with cromolyn is constipation. We just cleaned up his diet a little bit and increased his water, and actually he was okay.


So these are my pearls. Please get a comprehensive history from birth. Think about all those triggers. Consider MCAS for patients whose earlier evaluations didn’t reveal a specific disease or diagnosis. The choice of intervention cannot be determined based on symptoms. They could be based on mediators. So if you had histamine, you could try going after the histamine. But there’s no way to know what’s really going to work other than some of the anecdotal stuff that I see.


There’s no way to predict response to a particular treatment. Really, it’s one thing at a time. And it could be one thing once a month, it could be one thing once a week—you really have to work with the patients very, very carefully. Given the profound effects mast cells have within both the innate and adaptive immune systems and their diffused distribution throughout the body, it’s not surprising that the literature and our growing clinical experience support MCAS as a potential driver for the development of autoantibodies with or without true autoimmune disease and a broad range of neuropsychiatric manifestations.


So again, this child did not have an autoimmune disease. He had autoimmune markers that we believe were driven by the underlying mast cell activation syndrome. So we’re really only at the tip of the iceberg, and I would argue that we’re at the bottom of the roller coaster because you can see how, from 1993 to 2020, all the different diseases and all the associated diseases we’re finding and we’re just going to keep going, unfortunately. So I’ll end here.


I do want to say one thing: I’m hosting, along with Dr. Larry Afrin, a mast cell conference—a mast cell Workshop—June 23rd through June 26th in Briarcliff Manor in Westchester County. It’s going to be three and a half days of really intense mast cell work. We’re going to be hearing about a wide variety of topics related to MCAS. There are going to be talks about things like craniocervical instability and connective tissue disorders, genetics, POTS. It’s going to be a very comprehensive look at MCAS as it manifests in various disorders. It’s a small group. We’re expecting about 60 people. We do have limited space available. We have a few slots available. If anybody’s interested, just come and talk to me.

Dr. Tania Dempsey: (1:00:46)

I think we have like 30 seconds for questions, but I’ll end there.

Audience member: (01:01:00)

Dr. Dempsey, do you think that children who manifest adverse reactions to Singulair could just be mast cell kids?

Dr. Tania Dempsey: (01:01:11)

Yes. I think it’s the excipients. Singulair is pink in a lot of the generics. I think the brand is pink. So there’s a dye in there and there are a lot of excipients. We’ve been entertaining the theory that there probably is something that that compound montelukast is doing that might be causing the depression in that set of patients, but it is probably doing it through the mast cell, I think. And then the other reactions that people are having to Singulair may be the excipients. The depression may be [due to] the excipients as well. It’s a good question.

Audience member: (01:01:52)

Any correlation between abnormal GGT levels and MCAS?

Dr. Tania Dempsey: (01:01:57)

With GGT, sometimes you see fatty liver with that, right? Are you talking about fatty liver or just… ? [crosstalk] General.

Audience member: (01:02:13)

[inaudible] they’ve got elevated [inaudible] 50 to 70 to 90 range, maybe fluctuate [inaudible] I’m curious if you have seen it with some of the research.

Dr. Tania Dempsey: (01:02:29)

Oh, oh yes. Elevated LFTs for no reason—very common. Elevated LFTs in response to some intervention we’ve done—very often. Things that you wouldn’t think. [For example,] you give them a herb or something really benign and their LFTs go up and you think: How is that possible? I would look at that as a mast cell reaction. But yes, it’s very common. There are so many mast cells in the GI tract and the liver. Yes, it’s a good question.

Audience member: (01:02:58)


Dr. Tania Dempsey: (01:03:27)

Yes, the bladder is also lined—I think about every organ is lined—with mast cells. There are going to be various triggers that could set it off. Why a person develops interstitial cystitis in the first place, we don’t always know. But the majority of the patients—I don’t know if I can say 100%, but I would say a majority—have underlying mast cell activation syndrome. They’ve had some event, some trigger. The mast cells in their bladder basically got the brunt of it for whatever reason. This is the other thing we don’t know: I don’t know why it affects somebody’s bladder, [or why] it affects somebody else’s GI tract or whatever. I try to diagnose it; if they have MCAS, we try to target it. So you can do more benign things like just trying the various H1 and H2 blockers—the variety of mast cell targeted treatments. We’ve had patients do installation into the bladder of things like cromolyn. They don’t do it on their own, obviously—working with a urologist. We’ve done things where we had to get the mast cell drug actually into the bladder to calm it down. We’ve seen that. Diet plays a role. There are so many factors. But yes, the mast cells are key there. I don’t know if I answered your question.

Dr. Tania Dempsey: (01:04:53)

Oh, I can’t see. Yes. Yes, go ahead.

Audience member: (01:05:04)


Dr. Tania Dempsey: (01:05:10)

Yes. So the mast cells. I’m sorry. [crosstalk] Oh, sorry. Yes. She asked about eosinophils and whether there’s an association between high eosinophils and MCAS and eosinophil cationic protein. Is that ECP? Is that right? [crossalk] So, mast cells, as I mentioned, talk to other cells in the immune system—B cells, and T cells. They also interact with the eosinophils. So yes, there’s a subset of patients where mast cell disease will cause increased numbers of eosinophils. They may get eosinophilic esophagitis, or they may have elevated levels of ECP. What’s really interesting is that eosinophilic esophagitis is treated—I don’t know if that was your question specifically, but if we talk about a disorder involving high eosinophils—[with] steroids, PPIs. It doesn’t really make a lot of sense to me.

Dr. Tania Dempsey: (01:06:14)

They don’t always take them off of gluten and they don’t always change their diet. But in my patient population, if they have EoE, we are going in, we’re changing their diet, we’re treating their mast cell disease. And if their biopsy showed high numbers of eosinophils, we tell the pathologist to go back and look at the mast cells, and then we can usually confirm that there are a lot of mast cells along with the eosinophils. So we treat that and actually they get better without the PPI that they always want to use for that.

Moderator: (01:06:52)

I am so sorry. We actually need to wrap up this session as we’ve got to move on to the next very exciting session. Thank you so much, Dr. Dempsey.

Dr. Tania Dempsey: (01:07:00)

I’ll be outside if anybody wants to talk.