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That's highly individualized. Every healthcare professional has been seeing these patients left and right all day long, every day, their whole career. They just couldn't previously recognize them for what they are. One chronically ill patient comes into the doctor's office looking and acting and feeling quite different from the next chronically unwell patient who looks and acts and feels completely different than the next and the next and the next. And yet under the hood, so to speak, they all just have different variants of the same root issue. A Mast Cell Activation Syndrome.

Welcome back everybody, and I am super excited to have Dr. Lawrence Afron today. He is one of the premier mast cell experts in the world and so I'm going to introduce him and we're going to get down to all things mast cell and mast cell related Dr. Afrin earned his BS in Computer Science from Clemson University in 1984, went on to earn his medical degree at the Medical University of South Carolina in 1988, where he also pursued an internal medicine residency and hematology, oncology and clinical and research fellow. He was on the faculty at Musc from 1995 till 2014, where he's been active in medical education, information technology education, a whole bunch of different things, practice as well as hematology, oncology and medical informatics. Since the mid-2000s, his clinical work has been increasingly focusing on hematology, especially mast cell disease, which is something we see a bunch of. He's also directed the Emmett USC's mild proliferative neoplasia clinical trials. Since 2014-17, his interests have increased in mast cells. At the University of Minnesota, he's also been developing a NE dependent institute which is in New York City, doing research education with mast cell disease. Again, lots of mast cell things. He is one of the premier educators in this and he's spoken widely in the area. His focus and extensive publications include some of the most highly accessed articles on mast cell activation syndrome and he actually has a popular book which I had the pleasure of reading a couple years ago. Never Bet against Occam. It's the tome on all things mast cell. It's a little deep, but it is the Bible, so to speak, of mast cell things. And he's currently on the board for various organizations including the mysocyt. So Dr. Afrin, I'm super excited to have you today and talk all things mast cell with you.

My pleasure. Just a clarification, I'm actually no longer on the board of the Mastocytosis Society. I was, but I'm involved with some other organizations at this time, yes.

So I got introduced to mast cell diseases probably eight or nine years ago. And when I first got introduced, it seemed kind of abstract. I'm kind of. This is kind of weird. What is this kind of thing? And I've kind of realized that depending on what literature you look at, maybe 19, 20% of people in our country are dealing with this thing. So, Dr. Affin, could you just introduce us to mast cells? What is this thing that many people have not heard of that actually is quite common? What's behind it, and what does a typical patient look like?

That last part of it is probably the toughest part of all. I can much more easily tell you what a mast cell is in general. It's a type of white blood cell. Actually, you have fairly few of them relative to how many of the other types of white blood cells you get. And this is why when you get a report back from the laboratory on the blood counts, the breakdown of the different types of white blood cells, you see listings of other types of white blood cells like neutrophils and lymphocytes and monocytes and eosinophils and basophils. But you never see mast cells on those reports because there are so few of them. But they are there. They are in pretty much every nook and cranny, every tissue. They serve an important role. They're kind of the first line sentinel against assaults or insults upon the body. Plenty of other systems in the body that can recognize assaults upon the body and react to that. But there's no other part of the immune system that reacts, that senses and reacts to insults upon the body faster than the mast cell. And when the mast cell senses they're sitting there in all tissues, just quietly most of the time, just sensing the environment around them. And as long as things are fine, then they do pretty much nothing. But the moment they sense something awry going on in the surrounding environment or tissues, they instantly jump into action, producing and releasing various there many hundreds of different types of very potent signaling molecules that we generically call mediators. And as these mediators leave the mast cell and diffuse out into the nearby tissues, sometimes even get into circulation. These molecules, these mediators, come to engage with other cells. And once a mast cell mediator engages with the corresponding receptor on one of these other cells, the other cells then immediately begin adjusting their functioning in whatever fashion is appropriate for helping the body resist and recover from whatever the original insult was. It's an extraordinarily complex system that has evolved over literally half a billion years. This has actually been worked out in the research. And so other white blood cells evolved over time that became better at handling various specialized roles in the immune system. But we still got our mast cells. They still remember all their original tricks. They're kind of the ultimate jacks of all trades and responding to insults of any type. They actually were the original host defense cells that emerged as multicellular life began emerging. I mean, you had to have a defense system, and the mast cells, or at least their forebears, actually were the original host defense system. So that's what they're doing. And as long as they sit in the tissues sensing properly and under appropriate circumstances, putting out the right mediators in the right amounts, right times, right places, right durations, then everything's fine. We have an enormous ability to tolerate a lot of insults upon the body and to get better from all that. But sometimes the mast cells go awry and they start producing and releasing various mediators at times and over durations and in situations and in various places in the body where they should not be releasing these mediators. It's just that the other cells and tissues that receiving ends of these mediators, they don't know that they're getting the wrong signals at those times. They're just biologically programmed to react in a particular way when a particular mediator comes at the other cell. And so the situation you get in mast cell activation syndrome is you had all these different cells and tissues and organs and systems in the body that are reacting in various ways that be reacting, and to degrees, they should not be reacting. At times and over durations, they should not be reacting. And those inappropriate reactions, when it's an appropriate reaction, that helps us, it helps us resist and recover from an insult. We get better from that. But when these are inappropriate reactions, that doesn't help anything. In fact, we just feel sick when various tissues and organs are activating in various fashions where they should not be reacting, and we just feel sick in different ways. The general themes of this many of the mast cell mediators drive effects that we would classify as inflammatory effects. The specific symptoms of inflammation can be different depending on what part of the body you're talking about. But in general, pain and redness and swelling and so many of the mediators are driving inflammatory effects. Some of the mediators are driving effects that we would classify as allergic. And you can easily envision what those symptoms are like. And believe it or not, there are a lot of mediators the mast cell puts out that are integrally involved in guiding growth and development in every tissue in the body. So you typically don't see any acute effects from acute releases of those mediators. But if those growth guiding or growth influencing mediators are getting inappropriately released from dysfunctional mast cells on an ongoing chronic basis, you can see how over time you can actually wind up developing any of a huge array of anomalies in growth and development, just depending on which particular growth influencing mediators are being chronically inappropriately released by these dysfunctional mast cells. Fortunately, most of these growth anomalies are benign and clinically insignificant. But sometimes it is significant and occasionally it actually is malignant. And that has to be dealt with as you would deal with a malignancy. So that's the kind of long and short of what mast cells do in general. And what can happen when you got a bunch of dysfunctional mast cells in somebody's body.

Yeah, so one thing you mentioned was the growth. And I'm wondering, because there's been this back and forth talk within the community that maybe the mast cells are a primary cause of hypermobility, which is a part of this thing called the Pentad super syndrome, which is this group of five things. The way I think about it, if you see one, look for all of them. So if you see gut issues, which can be IBS and other things, look for the other ones. If someone has an autoimmune issue, look for these other things. If someone has hypermobility, again, mast cell activation syndrome, and then POTS and dysautonomia, these are the five things in the, in the Pentad super syndrome. Does this growth thing play? Is that part of the hypermobility connection? Or could you.

Yeah, nobody has any proof of that yet. Let me be clear about that right from the outset. Nevertheless, if you look at the biology of mast cell disease, the various effects that various mediators can have on other cells and tissues, and you look at the anatomy of this disease, I mean, where are the mast cells in the body? In truth or everywhere, but in most tissues in the body, pretty sparsely distributed. Where they're dominantly found is that the environmental interfaces, the skin, the respiratory tract, the G from stem to stern, and the genitourinary tract. So they're at the environmental interfaces and directly abutting all vessels and all neurons. That's where they're dominantly cited. And once you understand the biology, the specific effects of these hundreds of different mediators, you begin to realize it would not be much of a stretch at all to imagine one particular pattern of inappropriate chronic mast cell activation that could drive the connective tissue anomalies that we recognize as the hypermobile spectrum disorders, including hypermobile ehlers danlos syndrome. And it's also possible that mast cell disease could drive postural orthostatic tachycardia syndrome and could drive another type of growth anomaly. One of the most common types of growth anomalies in mast cell disease Are inappropriate cyst development. So it's easily possible mcas might be underlying polycystic ovarian syndrome, pcos, and it just goes on and on. The number of things that mast cell disease might well underlie, and based on what I've seen in my clinical across thousands of mast cell patients the last 16 years, I think I can be forgiven for strongly suspecting that it is mast cell disease, these five associated things. But my own suspicion is that it's probably the mast cell disease. It's really at the root of this, Rather than just another phenomenon that's riding along, coincidentally, with the other. And the reason I've come to think this, if you look at some of the earliest research in this area, going back, gosh, 17 years now, some very clever researchers in Germany, Gerhard Molderings and colleagues at the University of Bonn, began discovering early that if you do some very sensitive genetic analyses inside the dysfunctional mast cells, you actually can find mutations in a wide variety of mast cell regulatory genes Inside these dysfunctional mast cells. And let me be clear, these are not inherited mutations. An inherited mutation, an inborn or germline mutation. You would find those mutations in every cell in the body from conception through death. But that's not what's going on here. These mutations, by and large, are acquired, and they're acquired in a fashion where they're showing up mostly or even exclusively just in the mast cells. And so this appears to be the root issue. And we're still trying to learn why these mutations develop in the first place. Why is this 20% of humanity susceptible to developing these mutations? But with those mutations having been found, it seems much more likely that it's this chronic, inappropriate activation of the mast cells in various patterns. This is probably what's driving downstream these other issues that we talk about in the pentad, as well as scores and scores and scores of other issues you can see in mcas as well.

So would you say that the environmental trigger is driving these mutations? Like, whatever the truth, like if it's a mold or a chemical or whatever the trigger is, or is it the inflammation that drives the.

We're not. We're not really sure yet. There are some Folks who I think not unreasonably have suspicions that various, that exposures to various modern chemicals, things our bodies have never seen before in millions of years of evolution, and our bodies aren't quite sure what to do with these chemicals and how to respond to them. So there is some concern that these modern chemical exposures may be involved. But honestly that research is way early and in its, I don't even think infancy is the right word. Maybe in its embryonic state come back in, I don't know, 50 or 100 years, maybe we'll understand a lot better what's actually driving this.

Gotcha. One of the things that I struggle with is some of these statistic numbers like 23% of the population in the United States has a gene for SIRS or mold related illness. Some of the literature I look at hypermobility, up to 20% of people have it. This 19% from Dr. Moldering's research. And I'm hearing the same number basically and so many different things and just makes me wonder like my struggle is the patient I'm seeing in the clinic because I deal with a lot of complex mold, Lyme, mast cell, hypermobile pots. Just the question with that person in front of me, what started it for you? And I found it varies with the patient. Some people they've had an allergic predisposition for years, some people it was a moldy building. And what are your thoughts as far as like which of the, which came first, the chicken or the egg or use or is this a spontaneous kind of thing and have to be, has to be individualized, right?

Well, there's no question it's highly individualized. You asked me back at the beginning to tell you what one of these patients looks like in general, but that's one of the hardest things because honestly, if this is 20% or anywhere close to that, then every doctor, every healthcare professional, and I do mean every health care professional, has been seeing these patients left and right all day long, every day, their whole career. They just couldn't previously recognize them for what they are because number one, they were never taught that such a disease exists. Number and number two, the heterogeneity of this disease is at such an extreme level, at every level, the mutational level, the mediator production or expression level, the clinical symptom level, that one chronically ill patient comes into the doctor's office looking and acting and feeling quite different from the next chronically unwell patient who looks and acts and feels completely different than the next and the next and the next and yet under the hood, so to speak, they all just have different variants of the same root issue, a mast cell activation syndrome that's just rooted in a different set of mutations, acquired mutations, not in all of their mast cells, but in just a portion of their mast cells. But it's of mutations in different patients. And this leads to different clinical presentations because they're superficially appearing so differently from one another. It's very hard to see the commonalities among these patients and understand that they're just different variants of the same root problem. I'm not saying you can't learn how to recognize this. I'm just saying it's not easy to learn how to recognize this and the natural history of this. What we've been learning is that, honestly, in the vast majority of these patients, you can pretty easily trace at least some of their symptoms back to at least adolescence and quite commonly back to childhood, occasionally even infancy. But it's usually a relatively mild problem early on, over time. I mean, this is the natural history that it's always waxing and waning to some degree, but it tends to wax and wane about a baseline that's pretty stable for long periods of time. But then from time to time, throughout a mast cell patient's life, the disease can fairly suddenly, significantly escalate in the baseline level of misbehavior of the dysfunctional mast cells. But when these escalations emerge, and I use that word, escalation to distinguish from just a flare of the disease, when these escalations emerge, they tend to shortly follow anywhere from a few days to at most a few months, shortly follow a major stressor, either a major physical stressor or a major psychological or emotional stressor. And what we think is going on here is that we know that when the body is subject to various major stressors, there's a whole variety of different major cytokine storms that flood out into the body depending on what the stressor was. And it's beginning to become apparent that folks who have mcas, they've got a fundamentally fairly fragile genome. See, ordinarily we got trillions of cells in our body, and they're undergoing trillions of DNA replication events every day. And there inevitably are going to be millions of mutations that develop every day. But fortunately, we evolve, we necessarily evolved millions and millions of years ago. Some very robust mechanisms for very quickly detecting these mutations when they develop and then either fixing them, or they're a type of mutation that can't be fixed, then the cell that developed that mutation gets eliminated. Okay. So that these mutations don't persist and we don't all devolve into balls of cancer even before we make it out of the womb. So it's beginning to appear that folks with mast cell disease probably have a relatively fragile genome, because these mutation detection and repair mechanisms probably are not. They are probably mutated themselves and are probably not operating as robustly as normal. So that when you have these cytokine storms, these floods of these very potent mediators, they come to have very complex interactions with different elements of the genome, and this induces additional mutations. Okay. But some of these mutations are going to persist because they're not being quickly detected and eliminated. And when you have a new mutation develop in a gene inside a stem cell, because that's where all the blood cells are coming from, from the stem cells in the marrow. So when a mutation develops in a stem cell and it happens to be in a gene that is of importance in the regulation of mast cell behavior, then you can see how all of the mast cell progeny of that mutated stem cell will bear the same mutation. And then those mast cells, not all mast cells, coming from the other normal stem cells, they're going to be fine. But the mutated mast cells that are the progeny of the mutated stem cell, they're going to start misbehaving in whatever fashion is dictated by that particular mutation. But over time, as you come to be subject to more of these major stressors, then more mutations develop, and the mast cells, step by step, kind of ratchet up their way baseline. They probably accumulate additional mutations, and they, stepwise, escalate their baseline level of misbehavior, depending on which mutations are developing in those cells.

Gotcha.

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So I want to shift focus just a little bit here to what this actually looks like in people. And I asked you that question because this is one of the great imitators, like it used to be tuberculosis back in the 1800s and it was HIV for a while.

But the, the best that I've been able to describe this so far is that it's a chronic multi system illness of general themes that kind of follow along the lines of what the effects are of the majority of the mast cell media eaters. So the general themes in this disease are inflammation. That's the universal constant. All mast cell patients have chronic multisystem inflammation in one fashion or another, one system or another, to one degree or another. They've all got chronic multisystem inflammation. Possible it might be at a very mild level. So mild patient may not even need to see the doctor, but nevertheless it's there. Maybe they take care of it with just occasional over the counter treatments, but nevertheless it's there. So chronic multisystem inflammation is the universal constant here. Then there's a plus minus on the second broad theme here. That's the allergic phenomenon. And I say plus minus because there are a lot of mast cell patients who actually do not have a speck of allergy. And then at the opposite end of that enormous spectrum, there are those mast cell patients, thank goodness, relatively few of them, who unfortunately are suffering 24 by 7 anaphylaxis, if you can even imagine such misery. And then everybody else with MCAS is somewhere in between those polar opposite ends of the allergy spectrum. So plus minus allerg is the second major theme, the third major theme, and this is the hardest of all to clinically recognize because these effects develop at the slowest pace. And this is the plus minus, abnormalities in growth and development and potentially any tissues in the body, what we medically call dystrophisms. Listen, mammalian brains are great at quickly recognizing acute changes. So inflammation, allergic phenomena, I mean, those are symptoms that hit you pretty quickly and the patient recognizes them, the doctor recognizes them pretty quickly. But the growth and development anomalies, they come out pretty slowly. And as I said, many of them are benign and not even clinically significant. So many times it's just under the water line and nobody even recognizes or pays attention to it. And yet still it's not normal to have those. There's got to be A reason why those growths are happening. And mast cell disease actually can drive that. Now, to be fair, there are an awful lot of other mediators too, that can drive an awful lot of other symptoms than just inflammatory and allergic and dystrophic symptoms. But these are the dominant. So inflammation, allergy, and dystrophisms, those are the dominant themes. So if you see a patient who's got a problem List of 57 different things on it, and at least half of them are itis, itis, itis, itis, itis, inflammation, inflammation, inflammation, inflammation, and oh, they got a bunch of allergies, including some really weird ones that really don't make any sense. And then maybe they do have at least a few tissue growth issues. If they're coming to you like that, with a ridiculous problem list like that, you got to stop and ask yourself, what's more likely? Is this patient really so uniquely unlucky as to have coincidentally acquired so many different problems, all them developing independently of one another, or is it more likely they got one thing going on that really is biologically capable of driving, either directly or indirectly, most or all of these problems? And the answer, of course, this is Occam's razor, that it's much more likely that there's one thing going on driving all that. It's just unfortunate that the one thing that's likely driving it all is something that is so biologically complex that our learned profession didn't even start to recognize the existence of this disease until the first case reports were published about 17 years ago. This is not a new disease, it's just a newly recognized disease. And if ever there were an 800 pound invisible elephant or an 8000 pound invisible elephant in, in the medical profession's waiting room, it's this disease. Because again, every doctor has been seeing these patients. They just haven't been able to recognize it.

When I first started seeing these patients, these multi system, multi symptom patients, which is the exact way we describe chronic inflammatory response in our mold patients, which is so, so interesting. Like, first thing I asked myself was, this can't be. Like, there's no way. Like, I'm seeing this all the time. Let me do some labs, like, and all of a sudden it's like, wait a second, this can't be happening. Because how come I'm the only person seeing it? It took me almost a year of patient after patient after patient to get to the point. I guess this really is a thing and become comfortable in my skin. This is after residency training, working, being in practice for 15 years that I. And I hit this thing. I had this realization and it took me another year to get comfortable with. This is actually a thing. It's just not being seen by other doctors.

Being seen, just not recognized.

Yeah, that's. That's better said. Quick question for you. I want to ask you an unrelated related question. Alpha gal. That is something that I here in Virginia see a lot of. And when I talk with my patients that are hunters and this guy came out to my house the other day, he was putting like a little hitch on a car. He's like, all his hunting buddies have alpha gal and they don't eat meat anymore. They don't go to the doctors and worry about it because they figured it out on their own. And I'm kind of curious. One, is Alpha gal crazy common? And two, is there an association with it and mast cell stuff because of the whole anaphylaxis kind of thing?

Alpha gal is turning out to be somewhat common. But I think you have to keep a couple of other things in mind. First of all, please understand that mast cells are everywhere in the body. They have potential to interact with every system in the body. Doesn't mean they will cause troubles in every system in the body, but there's potential to, and that includes the immune system. And one of the most common impacts of mast cell disease upon the immune system is to start driving the antibody producing part of the immune system, the so called humoral immune system, into this wicked sort of overdrive. You can almost think of it like an inflammatory effect upon the immune system itself. And the immune system starts making all sorts of antibodies that it has no legitimate business producing. Because in truth, you have not suffered the infection that these antibodies appear to be targeted against or you don't have the autoimmune disease that these antibodies appear to be associated with. And in truth, the great majority of this aberrant antibody production under the influence of mast cell disease, these antibodies actually are not being specifically manufactured by the immune system to target any particular target antigen. And in fact, they are just entirely randomly generated. But if you generate enough randomly targeted antibodies, some of them just by chance are going to come to resemble the real antibodies you would really get in a real infectious or autoimmune disease. Now, the immunologists have known for decades that the immune system can do this. They call these antibodies mimicking antibodies. And these mimicking antibodies resemble the real antibodies closely enough that they actually wind up registering positive on the tests that we have for detecting these antibodies. But they're not quite the same antibodies and they cannot actually cause any problems at all. Unless of course, some well intentioned clinician who's desperately trying to help a mysteriously unwell patient. He runs one of these antibody tests, he gets back positive result. And even though he knows in his heart it often doesn't look like the patient has the disease, the infectious or autoimmune disease that's associated with that positive antibody result, nevertheless he can't find anything else that's wrong with the patient. So he makes a diagnosis of the associated disease and he starts treating the patient for a disease that in truth, the patient doesn't really have. So, so you gotta be really careful in interpreting the results of any antibody testing in the setting of mast cell disease. It turns out there are differences in the patterns, in the isotype switching patterns and the titers of antibody production between differences in the patterns that you see with the mimicking antibodies versus the real on target antibodies. So I mean, it'd be great if we had a laboratory test that could distinguish a mimicking antibody from a real antibody, but we don't so often what you have to do, especially if you see in the patient a clinical situation, there's just not really aligning all that well with the positive antibody testing. You're saying, you gotta say, wait a second, maybe what's happening here is a mimicking antibody and then you repeat that, you follow that antibody level over time and you, you map out a pattern over time and you can often distinguish the patterns you see with mimicking antibodies versus real antibodies. I published a paper on this last year, you can find it in the literature. Some of these patients who have detectable alpha GAL antibodies, yeah, they have a real alpha GAL problem that was brought on by a tick bite. And you know the pathology about how that happened. But it's also possible that some of these patients, the positive antibody finding may just be a mimicking antibody. So that's one thing I wanted to say about that. The other thing I want to note regarding the meat allergy that is associated with alpha GAL syndrome, there are a number of patients with mast cell disease of them who have difficulties tolerating one sort of, of meat or another. And it's, it's often red meat, but it's actually not an alpha GAL based problem. And you have to keep in mind that these animals, they are incorporating into their muscle tissue that gets harvested for our food, they are incorporating trace amounts of the molecules that are actually in their feeds. And let's talk about cattle, specifically beef in particular, you probably know that most cattle everywhere in the world that are raised for food purposes, they are fed corn. And because corn puts weight on the animal far faster than any other feed and ranchers are paid at the slaughterhouse for one thing and one thing only, and that's the weight weight of the animal. So most cattle are fed corn and some of the corn proteins and other antigens in corn actually do come through into the cattle tissue, the beef tissue. And there are some mast cell patients who are terribly reactive to various antigens, various corn based antigens. So in some of those patients who mast cell patients who just cannot tolerate regular beef products, I have them go try grass fed beef and it, it gets complicated because there are some mast cell patients, they tolerate grass fed beef from one ranch just fine, but not from another ranch because the different ranches have different types of grasses and mast cel be differentially reactive to, they might react to this grass but not that grass. And it gets even worse than that in terms of the complexity because it turns out that by the current agricultural laws you're allowed to label your beef as grass fed beef, even if in the last couple of weeks of the animal's life you have switched it to corn feed in order to pack on as much more weight as possible. And so there are some patients who will react to any type of grass fed corn finished beef, no matter what ranch it's coming from. But in those patients, if you then switch them to grass fed grass finished beef, then they do fine. I mean, I've been in medicine a long time. I've learned about a lot of different complex chronic multi system diseases, but I don't think I've ever come across any other disease that's anywhere close in its level of its degree of biological complexity as this disease is. Alpha Gal is a real thing, but it may not be the explanation of what's going on for beef reactivity in some mast cell patients.

Appreciate it. Well, doctor off, if people want to learn more about you, more about what you're doing, where would you send them to learn more about mast cell about what you're doing? Do you have a reference or anything like that besides your boom of your.

Book, I can just recommend they read and try to read any of the open access reviews in the literature. And they can certainly read the book and hey, I'll appreciate the additional nickel I get each copy. Nobody writes and publishes a book to make money. It's simply love of the subject. Otherwise I haven't really had the time to go putting together websites and Whatnot. I have heard there are a number of forums out there on the Internet for patients. Some of them, I've heard, have acquired thousands and even tens of thousands of patience in them. And although you always gotta take with a grain of salt anything you get off the Internet, nevertheless, when you got that many people in a group, there's probably some non trivial bit of useful knowledge in that group. So maybe social media can help some of these folks. But reading the authoritative literature, the peer reviewed medical literature is probably the single best source. I know that's something that for many patients is kind of a little bit hard to understand. But even if you can't understand everything that's in an article, you may still be able to understand a good part of what's in an article. So that's usually the most authoritative source.

Well, great. I want to thank you so much for your time today. I wish we had more time to talk. Got a list of questions here, maybe talk. We'll, we'll catch up with some other time. But I super appreciate your time and your effort and all you're doing to educate people. I'm in a group with you and it's been super amazing just to see and learn from that group. So take care and thanks a lot for your time.

My pleasure. Bye.