Mast Cell Activation Syndrome: The Diagnosis Most Doctors Miss with Dr. Lawrence Afrin

[01:08] Dr. Linda Bluestein: Welcome back, every bendy body, to the Bendy Bodies Podcast. I'm your host, Dr. Linda Bluestein, the Hypermobility MD, a Mayo Clinic-trained expert in Ehlers-Danlos syndromes dedicated to helping you navigate connective tissue disorders and live your best life. Today, I'm so excited to be speaking with my friend and colleague, Dr. Lawrence Afrin. I first met Dr. Afrin many years ago when I was learning about Ehlers-Danlos syndromes and related conditions like mast cell activation syndrome. Dr. Afrin is an incredible educator and has helped me and so many of my colleagues learn about mast cell activation syndrome, how to recognize these conditions in our patients, and how to treat them to get better outcomes.
[01:46] Dr. Afrin is an internist and one of the world's leading experts on mast cell disease. He is widely known for his clinical and research work on mast cell activation syndrome and has authored or co-authored over 100 peer-reviewed scientific publications. Dr. Afrin is also the author of Never Bet Against Occam, a landmark book that has helped thousands of patients and clinicians better understand complex multisystem disease driven by mast cell dysfunction. His work has been especially influential in communities affected by Ehlers-Danlos syndromes, hypermobility spectrum disorders, dysautonomia, and other overlapping conditions.
[02:22] I am so excited because Dr. Afrin is such a leader in this space, and we need so many more people aware of mast cell activation syndrome and able to treat it. As always, this information is for educational purposes only and is not a substitute for personalized medical advice. Stick around until the very end so you don't miss any of our special hypermobility hacks. Here we go.
[02:46] Okay, well, I am so excited to be here with my dear friend — I hope it's okay that I consider you a dear friend — Larry Afrin, Dr. Larry Afrin, an incredible expert in mast cell activation syndrome and all mast cell disorders. How are you doing today?

[03:04] Dr. Lawrence Afrin: Oh, doing fine. Glad I was able to get to this on time. My last patient ran way over and I just managed to wrap up in time for this appointment.

[03:18] Dr. Linda Bluestein: Well, I'm so glad that you're here. I know from some of our mutual patients that you do such incredible in-depth evaluations and describe all of the processes that are going on and develop their treatment plans. So I can only imagine how it is running your clinic on a day-to-day basis.
So I want to start with laying some of the groundwork because I feel like people hear the term mast cell activation syndrome, they might hear mast cell activation disorders, mastocytosis, hereditary alpha tryptasemia — they hear these terms. And I feel like it would be helpful to just start with a high-level overview of what the difference is between those terms. I know we could probably talk about this for a really long time, but if you could just give us a lay of the land, that would be helpful.

[04:08] Dr. Lawrence Afrin: I think it's fair to say that the totality of the mast cell disorders field is now being put under the umbrella term of MCAD — mast cell activation disorders or diseases — under the relatively new understanding that what's first and foremost about almost all mast cell disorders is inappropriate activation of these dysfunctional mast cells, inappropriate production and release of the mast cell mediators. That's what's causing 99-plus percent of all the symptoms in just about everybody who has mast cell disease, even those with mastocytosis.
[05:03] Now, under that umbrella term, the lion's share by far is mast cell activation syndrome, MCAS, in which there's inappropriate activation of the mast cells with little to none of inappropriate proliferation of the mast cells.
[05:30] There is a tiny portion under the MCAD umbrella that is the quite rare disease of mastocytosis — in both its more common cutaneous form, which you tend to see in younger folks, and the less common systemic form, which you tend to see in older folks. Mastocytosis is essentially a malignancy of the mast cell, in which there is a gross overproliferation, a cancerous overproliferation of mast cells. And that bulk of mast cells that can build up in various tissues in the body can cause some symptoms itself. But still, the great majority of the symptoms seen even in patients who have mastocytosis — it's not from the bulk of the mast cells, it's from the inappropriate activation of those malignant mast cells. Fortunately, when I mention malignancy, most people who have mastocytosis have a pretty indolent malignancy. They tend to have a relatively normal lifespan, but there are some less common forms of mastocytosis that behave like classic aggressive cancers and really will cut a patient's life short.
[08:47] Hereditary alpha tryptasemia, HAT, is a relatively new term emerging in just the last decade, coming from a new understanding that about 5% of the human population has inherited from one parent or another — sometimes both — one or more extra copies of the gene, the TPSAB1 gene, for making the portion of the tryptase mediator molecule called alpha-tryptase. And when you have extra copies of the gene that you've inherited, that means that every cell in your body has the extra copies for the duration of your existence. And that means that every mast cell is sort of genetically programmed to overproduce a little bit of extra tryptase. The more extra copies of the gene you have, the little bit more extra tryptase that you produce.
[13:41] Most people who have HAT only have one extra copy, and so they only have a slightly elevated level of tryptase floating around in their blood serum their entire life. And as best as anybody has figured out so far, these modest elevations in tryptase don't seem to have any clinical impact. Now, to be fair, there are an awful lot of people who have detectable HAT and they have a lot of symptoms, a lot of MCAS-consistent symptoms. But it's not the extra copy of TPSAB1, it's not the hereditary alpha tryptasemia, that's causing the activation of their mast cells to cause all their symptoms. Those patients have HAT that is probably not causing any problems at all, but they also have MCAS that's driving most or all of the symptoms they've long been having.

[13:58] Dr. Linda Bluestein: Interesting. So I know that you can test for hereditary alpha tryptasemia — for the extra copy. Is that a test that you think is helpful to do or not helpful to do?

Dr. Lawrence Afrin: Well, given that it's pretty standard in the diagnostic assessment for MCAS to include testing for the tryptase level, if we do find a modestly elevated tryptase level in somebody who's suspected of having MCAS, then until you do the additional genetic testing for HAT, you don't know whether that elevated tryptase level is an honest-to-goodness marker of mast cell activation — the MCAS that's causing the patient's symptoms — or whether it's a completely insignificant marker for HAT.
So if you find a modest elevation in tryptase, then you kind of have to go on and do the genetic testing for HAT. And if you do have one or more extra copies of the TPSAB1 gene, then those elevated tryptase levels are expected from that inherited genetic anomaly, and you can't use those elevated tryptase levels as clear markers of a mast cell activation syndrome diagnosis.
But if you do this genetic testing and somewhat surprisingly you don't see extra copies of the gene, then at that point you can say that the elevated tryptase level you found in that patient must be coming from actual activation of the mast cell. So at that point, that elevated tryptase level could serve as one of the pieces of laboratory evidence supporting a diagnosis of MCAS. Does that make sense?

Dr. Linda Bluestein: Yeah, I think so. I think the whole HAT thing has gotten really confusing because I know when Dr. Lyons first published about hereditary alpha tryptasemia and published his NIH work, it was thought that maybe this is the explanation behind the triad of MCAS, hypermobile EDS, and POTS. But in the meantime, there have been other published studies that have shown that there are people who are asymptomatic and have hereditary alpha tryptasemia, who have extra copies.

Dr. Lawrence Afrin: Look, I'll hold out the possibility that in the very rare patients who have HAT but have a lot of extra copies of the gene — and are therefore constantly making excessive tryptase at a more significant level, not the modest levels we see in people who have just one or two extra copies of the gene — maybe the chronic effects of such a significantly higher level of tryptase really can bring about some clinical effects in them.
But the great majority of these patients only have one or at most two extra copies of the gene. And the elevations in the tryptase level that result from that are so modest that it's really hard to see that those elevations are causing any problems at all. And actually nobody has yet identified in the literature that such modest elevations clearly do cause any problems at all. I've come to view the elevated tryptase levels in the common HAT patients who have just one or two extra copies of the gene as kind of a red herring. It's an abnormality, but not every abnormality is a problem. Some abnormalities are findings, but they're not really problems. And I think most people who have HAT — which again is about 5% of the human population, not a trivial fraction — HAT is probably a finding in them, not really a problem.

Dr. Linda Bluestein: And we're definitely going to talk more about tryptase later because that is obviously a whole topic unto itself when we're talking about the diagnosis of MCAS. So let's talk now about the clinical picture and clinical presentation of MCAS, which you and I both know is extremely variable. And if people think about when they do know something about MCAS, they might think of the allergic-type phenomena like skin rashes, hives, flushing, respiratory issues, et cetera. But of course, we know that there can be lots of other symptoms that can occur. What are the symptoms that you want clinicians and patients to be most aware of, that would make them pause and think, could this person have MCAS? Or, somebody's really miserable with all these things, maybe MCAS is the thing that ties this all together.

[14:49] Dr. Lawrence Afrin: I think the best way to answer that is twofold. Number one, the symptoms of MCAS, unsurprisingly, are going to be consequent to the known effects of the mast cell mediators — the very potent mast cell mediators that just happen to be getting inappropriately produced and released by the patient's dysfunctional mast cells. Now, many of those mediators produced by the mast cell have effects that you would categorize as inflammatory effects. Many other mediators drive effects you'd categorize as allergic-type effects. Other mediators are integrally involved in guiding growth and development in all tissues in the body. So yes, MCAS can easily drive a huge variety of abnormalities in growth and development — thank goodness, most commonly benign, but occasionally even malignant.
[16:00] So, the first part of the answer to your question is: given that these cells are everywhere in the body and that they produce such an enormous repertoire — a menagerie, a potpourri, if you will — of mediators, and so many of the mediators have inflammatory-type effects, I think we're entering a new era in medicine where we have to learn that in any patient who has chronic multisystem inflammation, it becomes reasonable to include MCAS in the differential diagnosis. That's not saying that everybody who has inflammation has MCAS at the root of it. It's just saying these are the patients in whom it's reasonable to start thinking about whether MCAS might be what's actually at the root of the inflammation in that patient.
[17:10] And particularly if the patient has not only chronic multisystem inflammatory issues, but also allergic-type issues and tissue growth and development issues, you start to wonder more and more about whether it might be MCAS as opposed to other disorders that might be able to accomplish some of those problems, but maybe not all of them. Because in the end, it's going to be more likely there's just one root answer for most or all of the problems in the patient, rather than the patient being so unlucky that they've coincidentally acquired multiple independent problems that are each driving different symptoms.
[17:42] So many doctors are quite familiar with the situation where they see patient after patient after patient where the problem list has a lot of problems on it. And many of those problems are "-itis, -itis, -itis, -itis" — inflammation, inflammation, inflammation, inflammation. And honestly, is the patient so unlucky as to have acquired so many different inflammatory problems, all of them developing independently? No, they likely have one underlying disease that can drive such a wide range of inflammatory issues in different systems in the body.
[18:35] So any patient a doctor is seeing who has these chronic multisystem inflammatory conditions — and obviously the specific symptoms of inflammation can be quite different depending on what system in the body you're talking about, so inflammation in the respiratory tract manifests very differently than inflammation in the gastrointestinal tract — I know we're trained to focus on one chief complaint for each visit, but with this disease, you have to try to back out and look at the big picture. And if you see chronic multisystem inflammation, plus or minus allergic issues, plus or minus tissue growth and development issues — what we call dystrophisms — then it's at least worth thinking about MCAS.
[19:29] Now, the one area in the body where it's often much more difficult to recognize that the symptoms actually are inflammatory — in large part because we're not even taught that such symptoms are or can be inflammatory, even though they can — this relates to the anatomy of this disease. Where are the mast cells in the body? In truth, they're everywhere, but they're actually very sparsely distributed in most tissues. You could do a random biopsy of most tissues in the body and be hard-pressed to find even a single mast cell in most biopsies. Where the mast cells are dominantly sited is at the environmental interfaces: the skin and the rest of the integument, the respiratory tract from top to bottom, the GI tract from top to bottom, the genitourinary tract from top to bottom. So they're at the environmental interfaces, and directly abutting all vessels and all neurons, both peripheral and central.
[20:25] And so it is very common for mast cell patients to have a whole variety of neuronal issues — not only peripheral neuronal issues like tingling and numbness from time to time, but also an awful lot of central neuronal issues. And I learned a long time ago, it really doesn't matter whether you characterize any one of those specific issues as a neurologic issue, a cognitive issue, a psychiatric issue, or a dysautonomic issue. They're all coming about because one set of neurons or another up here is not working in a normal fashion — but it's not because there's anything fundamentally wrong with the neurons, not in a mast cell patient anyway. It's because the neurons, which are normal neurons, are reacting to the constant assault, to one degree or another, of these very potent inflammatory mediators that are constantly emerging from the literally adjacent dysfunctional mast cells. And then it's entirely a matter of which mediators are impacting on which neurons as to which particular neuronal issues the individual patient is going to suffer at any particular point in time.
[21:50] So not only should doctors be thinking about MCAS when they see the symptoms that they have been classically taught as inflammatory symptoms, but also when they see patients with these neuronal issues — that's another area where they might need to start thinking about the possibility that maybe there's a mast cell activation syndrome here.

[22:22] Dr. Linda Bluestein: And I'm glad that you said symptoms consistent with inflammation, because it doesn't mean that the CRP is necessarily elevated or the ESR is necessarily elevated — those are very often normal.

[22:34] Dr. Lawrence Afrin: Yeah. CRP and ESR are not particularly sensitive or specific markers of inflammation. When you find an elevated CRP or ESR, yeah, there probably is some degree of inflammation, but it doesn't even begin to tell you what the source of the inflammation is. And there's no question there are lots and lots of mast cell patients — and other patients with other chronic inflammatory disorders — in whom the CRP and/or the ESR are just steadfastly normal.

[23:07] Dr. Linda Bluestein: A few years ago, I met Dr. Janet Settle, one of our colleagues here in Colorado, at the mast cell conference and had some fascinating conversations with her at that time. I had her on the podcast recently and we talked about the role of mast cells in mental health. Do you have any thoughts on that?

[23:24] Dr. Lawrence Afrin: Well, as I was mentioning just a moment ago, the range of neuronal problems — central neuronal problems — that mast cell disease can drive includes not only neurologic and cognitive and dysautonomic problems, but also psychiatric problems. There's a huge range of psychiatric disorders. I'm not saying that every psychiatric disorder is a case of MCAS — that'd be silly. But nevertheless, we do know that MCAS is a very prevalent disease, so it's likely that some non-trivial proportion of the patients out there who have various psychiatric disorders probably do have those disorders rooted in a yet unrecognized MCAS.
[24:12] There are some patterns to this. We more commonly see anxiety and mood-type disorders with MCAS compared to some of the other broad categories of psychiatric disorders. But there's no question that all of the other types of psychiatric disorders can be seen in some patients with MCAS.

[24:39] Dr. Linda Bluestein: And speaking of the wonderful MCAS conferences that you have hosted — you hosted one in New York and you asked me to do a presentation on pain and MCAS. I told you I wasn't sure if I was the right person to do that presentation, but you talked me into it. Well, in the process of preparing for that presentation, I learned so much about mast cells and pain processing that I didn't know and understand before. I used to think that of my EDS patients, only a tiny percentage would have MCAS. But after I prepared for that presentation, I ended up starting to treat a lot more of my EDS patients as if they had MCAS somewhere on the spectrum, and started getting better results.
[25:20] And I know that you published a paper in 2021 — "Some Cases of Hypermobile Ehlers-Danlos Syndrome May Be Rooted in Mast Cell Activation Syndrome." I've shared that paper over and over and over again. I've discussed it multiple times on this podcast. Now I feel like some other scientists and clinicians are starting to say, huh, hypermobile EDS may actually be a neuroimmune condition, might involve the complement system. Maybe — there's something Dr. Chip Norris said recently — maybe something in the immune system is chewing up connective tissue. Maybe people with hypermobile EDS, at least some of them who have the hypermobile EDS phenotype, are actually born with healthy collagen, but the mast cell mediators destroy it. You published that paper a few years ago. What are your thoughts about that now?

[26:10] Dr. Lawrence Afrin: Yeah, I don't know that my thoughts have changed a whole lot. I think it's been fascinating following the work that's been emerging from the Norris lab in Charleston at the Medical University of South Carolina, MUSC — my old haunt.
[26:26] But I still think — first of all, let's be clear that EDS is a very broad range of disorders and there are roughly a dozen different types of EDS. Most of them we long ago nailed down with one or two particular inborn inherited mutations in one connective tissue protein or another that drives one or another of these different variants of EDS. But the most common subtype of EDS by far, the hypermobile EDS — hEDS, or what previously was called type 3 EDS — lots of research groups have been diligently searching for, gosh, it's got to be 40 years now, for any inborn congenital mutation in any of the connective tissue proteins, the genes for those proteins, that could account for hypermobile EDS. And not a single mutation has been found yet that occurs in any significant proportion of these patients.
[27:42] Furthermore, it's become evident in the last 10 to 15 years that when you take the full history from these hypermobile EDS patients, an awful lot of them have not only their hEDS-consistent connective tissue problems, but also an awful lot of other health anomalies that would be difficult to impossible to attribute to a connective tissue problem of any sort. And in those many, many patients, you then start wondering: might there be some other underlying disorder that can drive not only the connective tissue phenotype that we clinically label as hypermobile EDS, but also drive all of these other generally inflammatory and allergic-type issues that are being seen in these patients?
[28:44] And because the range of mediators that the mast cell expresses can drive inflammatory and allergic issues and dystrophic issues, and given that the mast cells are everywhere in the body, honestly, who would be surprised if there are at least certain variants of these mutated dysfunctional mast cells at the root of MCAS that output various growth-influencing, connective tissue growth-influencing mediators in abnormal patterns that ultimately wind up producing connective tissue that we superficially label as hypermobile EDS-type tissue? I mean, that's well within the range of possibilities of what MCAS can do.
[29:47] Now, has anybody found the smoking gun yet — the proof that MCAS is underlying hypermobile EDS in any fraction, small or large, of the hypermobile EDS population? No, nobody's found the fire yet, but there's an increasing amount of smoke in this area that's exploring the associations. And you mentioned the Norris group in Charleston — they recently published a large global survey of hypermobile EDS patients and found a very high percentage of those patients had MCAS-consistent symptoms. So it sure makes you wonder.

[30:41] Dr. Linda Bluestein: Yeah, for sure. So I know a couple of papers that they published not too long ago. One — they looked at a little over 2,000 people and identified three different clusters of people, one of whom had really, really high rates of mast cell activation syndrome. The others had a lot of mast cell activation syndrome, but this one particular cluster had extremely high rates. And then another paper that they published recently looked at proteins and found a number of different proteins that were either extremely high or extremely low in people with hypermobile EDS, and these proteins were related to the complement system and other immune functions. So they're doing some excellent work.

[31:22] Dr. Lawrence Afrin: Yeah. What I would really like to see done — and I'm not aware yet of any research group that's pursuing this — would be the following experiment, so to speak.
[31:42] First, just to set the groundwork: we know from the research in the MCAS arena that what's actually driving MCAS in most patients who have the disease is an assortment — a very different assortment from one patient to the next — of mutations in various genes inside their dysfunctional mast cells, various genes that are of importance in regulating the behaviors of the mast cells. But these mutations that are driving most cases of MCAS are not inherited mutations. Instead, in a model kind of similar to what you see with cancer, they are acquired mutations, typically starting to get acquired fairly early in life. And as a mast cell patient goes through life, from time to time there's potential for them to acquire additional mutations, which just drives the disease to repeatedly escalate to a higher baseline.
[33:16] Now, to be clear, it's a very different assortment of mutations in a different assortment of regulatory genes from one patient to the next. And we know from the research that these mutations usually are not inherited — they're usually acquired, usually starting pretty early. In most cases of MCAS, the mutations are not driving cancer of the mast cell, except for the rare cases of mastocytosis. Instead, the mutations in most cases of MCAS are driving inappropriate activation of the mast cell, inappropriate production and release of the various mast cell mediators.
[34:06] These mutations get acquired at various stages in the patient's life. And it's common in mast cell patients that from time to time they can acquire, fairly suddenly, additional mutations. This usually happens shortly following a major stressor, either physical or psychological. And these major stressors have the potential for inducing additional mutations that then drive the disease to escalate to a whole new worsened baseline level of misbehavior of the dysfunctional mast cells.
[34:43] So this is what we think is driving the disease in most patients. But because these are acquired mutations — not inherited — if they were inherited, the mutations would be present in every cell in the patient's body for the patient's entire existence. That's not the case here. These mutations by and large are acquired mutations and they're only in the mast cells, which are a tiny population of cells in the human body.
[35:15] So doing a genetic sequencing study in the hypermobile EDS population where you take a sampling of their connective tissue, or a sampling of a big bunch of their white blood cells — which are nucleated and have all the person's DNA — and you go looking for these mutations that are just in the mast cells, there are so few mast cells there that those sequencing experiments probably will not find anything.
[35:47] So what would be really interesting would be to take a cohort of hypermobile EDS patients — maybe 20 or 30, a small study just to start. This would be relatively inexpensive to do with modern technology. You would not only evaluate those patients by standard current techniques to see whether they have MCAS, but even more importantly, take a blood sample from those patients. And because there are so few mast cells in the blood, it would probably have to be a slightly larger blood sample than normal. The researchers would first extract from the blood sample just the mast cells — not the whole set of white blood cells, in which the normal white blood cells would grossly outnumber the mast cells, let alone the subpopulation of mast cells that are actually mutated and dysfunctional. There are techniques for doing that. And then take that isolated population of mast cells and put it through one or another of our presently available sequencing technologies to see what sorts of mutations can be found.
[37:28] Because if it's, say, 10 or 20% of the mast cell population that bears these acquired mutations, you're not going to find those mutations if you sequence the whole white blood cell population, because there are so few mast cells to begin with in the whole blood. But if you cone down the sample, so to speak, and you do the sequencing just in a population of mast cells, then the sequencing techniques presently available probably would be able to pick up mutations even though they're not in all the mast cells — because again, it's not an inherited disease. But as long as the mutations are in probably 5, 10, or 20% of the mast cells, the sequencing probably would pick them up.
[38:22] And then at that point, if you're able to say, look, we looked at 30 hypermobile EDS patients and in 25 of them — or even 20 or 15 of them — we were able to find acquired mutations in the mast cells, that's some compelling evidence that probably these mutations, which are driving the MCAS, are probably also driving the hypermobile EDS.
[39:01] But where it gets even more interesting is if you then look at the sets of mutations found in the mast cells of different hypermobile EDS patients and see particular acquired mutations appearing over and over again — maybe not in all of them, but in a fraction of them. That's obviously not a coincidence. Then you start to wonder: maybe it's the specific impacts of that particular mutation on the behavior of the mast cell that ultimately drives the inappropriate mediator expression that winds up producing the hypermobile EDS phenotype.
[40:08] Lots of people have done lots of genetic studies in hypermobile EDS patients, but they've only looked for inherited mutations. Nobody has looked for mutations that are confined to just one particular type of cell. And for sure, nobody has looked for them in the mast cells, this very tiny cell population in the human body. But from what I've been seeing clinically, boy, it sure is suspicious that there are some mutations that can happen to these mast cells that probably seem likely to be able to drive hypermobile EDS. And by similar analogy, probably other mutations that drive misbehaviors of the mast cells in other directions, driving other symptoms that we commonly see in MCAS.
[41:07] And so it's the genetic dissection of this disease where I think we're going to get the greatest leaps forward in understanding not only the biology of what's going on, but once you understand the biology, then you can start much more rationally coming up with treatments that ought to be effective for one variant or another, once you understand what's really happening at a molecular, mediator, and genetic level in these patients. It's just that so far nobody is doing these genetic analyses looking specifically at isolated populations of mast cells. And until you isolate the mast cells, doing genetic studies of the whole white blood cell population, you're not going to find these mutations — they're just too few scattered among the vastly greater numbers of other normal white blood cells.

[42:15] Dr. Linda Bluestein: Well, maybe somebody listening to this — I am in contact with Dr. Norris and Dr. Gensimer, and I know that you probably are as well. So hopefully either they will have heard this conversation, or somebody will say, hey, have you thought about doing this particular study? I mean, it would also explain why — like you said — a particular stressor, whether it's an infection or a concussion, or, you know, it could be psychological, it could be physical, why that often sets off hypermobile EDS. COVID especially, in these patients. They might be relatively functional, doing quite well, not having a lot of problems. And then they get something like that and it really starts to cause a cascade of symptoms.

[42:56] Dr. Lawrence Afrin: Yeah, for some people it's something that comes on a little bit later in life, though still most commonly in the formative years. But these acquired mutations that can drive MCAS can sometimes be present almost right from birth.
[43:17] I have mentioned these ideas to various EDS research groups in the past, and so far they haven't seemed inclined to do genetic testing in any cell populations other than the whole white blood cell, looking for the inherited, inborn, congenital, germline mutations. Nobody is yet looking for the mutations specifically in the mast cells. Somebody will probably win a Nobel Prize — or some prize — from doing that, and they'll deserve it for sure.

[43:56] Dr. Linda Bluestein: For sure they would deserve it, because MCAS affects such a large percentage of people, which is going to be the thing we're going to talk about first when we come back. We're going to talk about tryptase and what people can do if they're seeing clinicians who think that tryptase is the end-all and be-all for making the MCAS diagnosis. We're going to take a quick break, and when we come back, we are going to tackle that topic. We'll be right back.

[45:50] Dr. Linda Bluestein: Okay, I am back with Dr. Lawrence Afrin and we are talking about mast cell activation syndrome. And I know the burning question that everybody has is: what do I do when I am seeing doctors who think that tryptase is the end-all and be-all for making an MCAS diagnosis? They say if I don't have an elevated tryptase, I cannot have MCAS. What would you say about that?

[46:15] Dr. Lawrence Afrin: Well, I would say that it would be nice if such doctors were to be open to learning that this is a very biologically complex disease. The mast cells can misbehave in many, many different ways. And tryptase is certainly not the be-all and end-all of this disease.
[46:43] In fact, I'd say the large majority of patients who have long been clinically behaving as if they have MCAS, and then we find elevated levels of mast cell mediators in them other than tryptase, and then we diagnose them with MCAS, we treat them with mast cell-targeting treatments, and they get better — it's obvious that they have MCAS. And it would be nice if doctors who think that tryptase is the be-all and end-all of this were to be open to the notion that the biology in this cell is extraordinarily complex. We know these cells are producing and releasing, at various times and various circumstances, more than 1,200 different mediators. So why on earth would anybody rationally think that if you don't have an elevated level of one particular mediator, you can't have a significant abnormality of these cells? Obviously, there's tremendous potential for abnormalities in mast cell function in fashions that don't involve tryptase.
[47:55] And if patients sense an opening with their doctor and they want to try to help the doctor learn more about this broader view of MCAS, there certainly are papers in the literature that patients can consider providing to or pointing their doctors toward, to learn about these broader perspectives. But I'm also aware that many doctors, for all sorts of reasons, are just kind of set in their ways. They learned one particular way of thinking about a disease and they're just not going to budge. There's no sense in arguing with those doctors. You can't fix that. All you can do is courteously excuse yourself and go find another doctor who's more willing to learn.
[48:51] The fact is, we're 19 years now since — it's 2026 now — we're 19 years since publication of the first case reports of this disease. And to this day, this is still not mentioned in any medical school textbooks. It's in few to no graduate training program curricula. So the medical students, the residents, the subspecialty fellows — they're graduating to this day, going out into practice for the next 30 or 40 years, having never heard of this disease.
[49:22] I mean, yeah, there are a few exceptions out there, but I can guarantee you the vast majority of the very few doctors around the world who have even heard of this disease, let alone have actually acquired any real familiarity with it — it's not because they were trained or taught about this. It's because they stumbled across it, or they were at a medical conference and wandered into the wrong meeting room but it sounded interesting so they stayed for the rest of the talk. Or maybe they inherited a patient from another doctor and they were reading the records and it said MCAS. They said, MCAS, what the heck is that? And so they did some reading.
[50:05] This is how the vast majority of the very few doctors around the globe who have yet developed any awareness of this disease are coming to acquire that awareness. And some of them, the particular paths they're taking to acquire that awareness, it's exposing them to this one particular viewpoint that says if you don't have recurrent anaphylaxis and you don't have elevations in the tryptase level to a certain degree, then forget it, you can't have a mast cell disorder.
[50:50] And then there's this other group of doctors — and full disclosure, I'm one of the ringleaders — that looks at this disease from a much broader perspective. These cells are putting out more than 1,200 mediators and they've got more than 300 different types of receptors sitting on their cell surfaces. Obviously, the potential for these cells to manifest all sorts of inflammatory, allergic, dystrophic, and other types of chaos all throughout the body is just phenomenal. This is not to say that every patient who has chronic mysterious illness of these types has MCAS at the root of it. We're just trying to say that we know from the preliminary epidemiologic research that this is a very prevalent disease — roughly 17 to 20% of the general population.
[51:45] And what that number means is that in truth, every doctor — and I do mean every doctor — is seeing these patients all day long, every day, their whole career. They just couldn't previously recognize these patients for what's truly at the root of their assortments of inflammatory and other problems, because number one, they had never been taught that such a disease exists. And number two — virtually as important — the biological nature of the disease, this enormous complexity of the underlying biology, essentially guarantees that the disease is going to clinically present in very, very different fashions in different affected patients.
[52:39] Yes, there may be, at a very high level, some aspects of the disease that are shared among different subpopulations of patients who have MCAS, like the subpopulation who has hypermobile EDS. But the totality of what this disease is doing in the individual patient is a good bit different from the totality of what it's doing in the next patient, and the next, and the next.
[53:04] And this notion that there could be so much heterogeneity, so much variability from one patient to the next for a given disease — this is something we've not seen before with just about any other disease we've ever known about. I mean, what is diagnosis but an art in pattern recognition? I don't care if you're a doctor or a car mechanic. You go to school for X number of years, you learn all the diseases of the car or the human body. You learn the one or two specific patterns that each disease presents with, and then you graduate, you go into practice, a car comes in the shop or a patient comes in the clinic. You take a history, you do a physical exam, you may run a test or two. You put those data points together, you match them up against your learned database of the different patterns. You've been taught that each known disease presents with just one or two specific patterns, and that's how you make a diagnosis.
[54:09] But now there comes along — and I say that facetiously, because no, it's not a new disease, it's just a newly recognized disease — this so-called new disease MCAS, that by its fundamental biological nature is not going to present in just one or two particular patterns. It's going to present in 100, in 1,000 different patterns. So pity the poor doctor who's got to learn how to clinically recognize chronically ill patient A, who comes in the clinic looking and acting and feeling quite differently than chronically ill patient B, who's quite different than C, D, E, F, and G. And yet under the hood, so to speak, they all just have different variants of MCAS.
[54:56] I'm not saying it's impossible to learn, but the details are quite different from one patient to another. So it's hard for doctors who have not been taught about this to recognize that such superficially different-appearing patients actually all have just different variants of the same root issue.
[55:17] I was actually very encouraged to see just earlier this year, back in May, that the very first formal teaching of this to a freshman medical student class actually took place at the University of California at Irvine, UCI. They got a good lecture on MCAS, followed up with a panel of national experts, so the students were able to ask the experts various questions about the disease.
[55:51] And it's going to be interesting to see what happens with these freshman students — who I guess are now sophomores — as they finish their classroom training and start getting into clinical training and get supervised by higher-level students and residents and fellows and attending physicians who are grading them. It's going to be interesting to see what happens when these students start to recognize that a good number of the patients they're seeing in the clinic or the hospital might have MCAS, but this is a disease that the higher-level people on the team have no familiarity with. If these lower-level students start bringing up this notion of, "hey, maybe this patient has MCAS, maybe that patient" — if they do it too often, the higher-level people might think the student's an idiot. So it's going to be interesting to see how the educational dynamics of this work out over the next many years. Ultimately, of course, the students become the teachers, but that's a generational change. It's going to be a long time until the average doctor comes out of training already knowing about this disease and being familiar with it. I wouldn't be surprised if it's another quarter century, half century before the average doctor knows at least something about this coming out of training.

[57:35] Dr. Linda Bluestein: And I would say that for most of us — I know this is true for me — when I first learned about MCAS, I thought it was interesting, but it wasn't until I started actually recognizing what I thought was maybe MCAS in my patients and treating them as if they had MCAS and getting success, that I started to really believe it. And you helped me a lot with that. I called you multiple times, and you were so kind to step away from the patient you were seeing and come out and talk to me for a few minutes and say, "well, have you tried this? Have you tried this?" But I think most of us who take this broader view of MCAS presentations — it's because we became so convinced after we started treating and we started seeing success.

[58:24] Dr. Lawrence Afrin: You bring up a really important point, and I've seen this over and over and over again with physicians who I've been privileged to help come to understand this disease better.
[58:37] You think about it — most physicians go through roughly 7 to 10 years of training altogether. And in that decade, you get literally one minute of teaching about mast cell biology and disease. And that makes all the sense in the world when you realize that the only mast cell disease we've known about for the last century — other than the very prevalent allergy, and that's no dissing of the allergists, but relatively straightforward, keyword relatively, to take care of — the only other mast cell disease we've known about for the last century has been this unbelievably rare disease of mastocytosis. And it's so rare, most doctors will never see a case of it in their decade of training or three or four decades of practice. So if it's that rare a disease, why would you spend more than one minute out of ten years learning about the biology of the mast cell and the disease of mastocytosis? It doesn't make any sense.
[59:45] And therefore, in that one minute, they learn that the mast cell produces like two mediators. There's histamine, which we've been studying for 80 years and have a pretty good idea of what it does in the human body. And tryptase, which we've been studying for nearly 75 years now — and we still don't have the foggiest idea what the principal role of tryptase is in the human body. We understand some of its minor roles, but we still don't know what its principal role is. And that just underscores how challenging this research is.
[1:00:17] So in 10 years, we're taught the mast cell produces two mediators, and we're taught that it has one receptor by which it interacts with other cells and tissues in the environment — the IgE receptor, which is how mast cells get wrapped up in allergy. That's what we're taught.
[1:00:36] So sure, when that's all you've known for a decade of training and one, two, or three decades of practice, and then somebody comes to you and tries to tell you: "I know you went through a great half-million-dollar, 10-year-long medical education with the best professors in the world, and I understand you've never seen a case of mastocytosis, but wait — you've been missing something. There's this other mast cell disease that's incredibly prevalent and it behaves in a zillion different ways because the mast cells are putting out not two mediators, but 1,200 different mediators. And they've got not one receptor, but hundreds of different receptors for interacting with different elements of the body."
[1:01:31] You can understand that the average doctor, based on how they were trained and thinking this is a very narrow-scope disease, when you try to explain what in truth is the extremely broad scope of MCAS to them, their initial reaction is almost reflexive: "That's not possible." And they just shut down. But every once in a while, when you go to explain this to somebody, you get somebody who's actually willing to take an extra couple of minutes to really think about it. And boy, I've seen so many light-bulb moments in so many doctors.
[1:02:22] There's this one webpage out there that provides a beautiful listing of most of the mast cell mediators. Very commonly when I'm trying to explain this disease to a doctor who's new to it, I show them this webpage and I say, "Look, you were told these cells put out two mediators. Here's the list of mediators that these cells are actually known to produce — not by the doctors, who don't get taught this, but by the biologists, who have long known this." And I just start scrolling, scrolling, scrolling, scrolling, scrolling. And after like a minute of scrolling, we're down to the Cs. Haven't even gotten to the Ds yet.
[1:03:12] And much of the time when I have the opportunity to share this with a doctor who hasn't previously been aware of the disease, I look at the doctor's face as I'm doing the scrolling. You can see their jaw dropping further and further and further. And they just look at me and say, "I had no idea." And I say, "Yes, that's the point. That's the problem. None of us were taught this."
[1:05:53] Now, I'm not blaming the doctors. They're doing the best they can with what they were taught. But there's this old joke that the medical school dean greets the incoming class of freshmen and tells them half of everything we're going to teach you in the next four years is wrong — we just don't know which half. And it's funny because it's true.
A good example: tryptase. I can show you the title of an article in the 1987 issue of the New England Journal of Medicine, one of the most prestigious medical journals in the world, that said tryptase is a marker of mast cell activation in mastocytosis. Well, fast forward a quarter century and new research emerged showing that actually tryptase is a pretty miserable marker of mast cell activation. What tryptase is a good marker of is the number of mast cells you've got in your body. So if you have a grossly cancerous overproliferation of mast cells — in other words, if you have mastocytosis — then pretty reliably the tryptase level is going to be way elevated. But if the mast cell disease you have is mostly activation, with little to none of the inappropriate proliferation of the mast cells, then the tryptase level is going to be elevated little to none — usually none in MCAS.
But it took a long time to figure that out. So one or two generations of doctors were taught that tryptase is the marker of mast cell activation. And now you have to go unteaching that. This is not easy.
So I'm not blaming the doctors, but it would be nice if more of them were open to this. I guess the other real complicating factor is that we're taught in that one minute that it's allergy, it's the rare mast cell disease of mastocytosis handled by the hematologist-oncologist, and that's it — that's all there is. So most doctors go through their decade of training and they're given no reason whatsoever to think that a mast cell disorder could have any involvement in their own domains of medicine, whether it's GI or cardiology, endocrinology, psychiatry, or connective tissue diseases.
[1:06:54] And yet once you start diving into the biology of this and you realize these cells are everywhere in the body and putting out this huge menagerie of mediators that are potently influencing very important processes going on all throughout the body, then you realize, oh my goodness, this disease is heavily intersecting with every domain in medicine — all the different medical subspecialties, all the different surgical subspecialties, psychiatry, OB-GYN. Then it's just a matter of getting the doctors to a point where they're being taught this basic biology and they start to learn they're going to have to start thinking about the possibility that mast cell disease might be what's at the root of the problems being seen in a hefty fraction of their patients. We'll see.

[1:08:01] Dr. Linda Bluestein: Yeah. And speaking of treatments, in terms of more recent things that have been found to be therapeutically beneficial, the glucagon-like peptide agonists — the GLP-1 drugs — are something that I know I've been prescribing after reading the paper that you published and hearing people talking about using them in mast cell activation syndrome patients. And I've found them to be very often quite beneficial at stabilizing mast cells. What is your current thinking on that?

[1:08:36] Dr. Lawrence Afrin: I think it's become very apparent in just the last couple of years — and even more so in just the last year — that these drugs can be significantly helpful in a lot of MCAS patients. That's not to say that they're going to be helpful in all mast cell patients, and it's not to say they should be tried willy-nilly. There are some significant risks with them, and a trial of a mast cell patient on these drugs needs to be managed with a lot of care to avoid potentially quite significant troubles. But if things are handled properly, yeah, these drugs really can be significantly helpful in a lot of patients.
[1:09:24] It's turning out that what these drugs fundamentally are is a whole new class of anti-inflammatory drugs. The problems and symptoms that these drugs are settling down are fundamentally inflammatory problems for the most part. You know that these drugs were originally FDA approved for diabetes and obesity. Well, the diabetes and obesity researchers began figuring out a quarter century ago that type 2 diabetes and obesity are chronic inflammatory diseases. They've not been able to figure out yet where the inflammation is coming from, although there is some interesting emerging data suggesting that mast cells have something to do with the inflammation in many diabetic and obese patients. I will not be surprised if MCAS is found to be the root of hefty fractions of the diabetic and obese populations.
[1:10:27] But these drugs, in simmering down diabetes and obesity, are fundamentally anti-inflammatory drugs. And therefore it probably isn't a huge surprise that they would have at least some utility in at least some other chronic inflammatory diseases like MCAS. And even though these drugs are not yet being prospectively studied in patients who specifically have MCAS, there are many studies now going on looking at the utility of these drugs in a wide range of other chronic inflammatory diseases. And what's particularly interesting about those studies is that most of those diseases — nobody has yet figured out what's causing the inflammation. And yet I can tell you from my experience that it's easily possible that MCAS of one variant or another might be what's at the root of some sizable fraction of the population of patients bearing one inflammatory disease or another. So it's possible that many of these studies are actually investigating the utility of these drugs in specific subpopulations of MCAS patients who all bear this one particular type of inflammation or another. Time will tell, but interesting times ahead, that's for sure.

[1:12:23] Dr. Linda Bluestein: And do you think that's the biggest development in the MCAS space, or is there something else that has been a big development?

[1:12:30] Dr. Lawrence Afrin: I think there are lots of developments going on, but in terms of new drugs coming on the scene that have a lot of potential for helping, yeah, the GLP-1 receptor agonists probably take the crown for drugs that have come along recently and had the biggest effect.
[1:12:55] It's been interesting to see, too, that not only are these drugs helping symptoms that you would classically recognize as inflammatory, but I've been impressed — and I've heard it from many colleagues who've seen very similar experiences with their patients — that an awful lot of central neuronal problems, neurologic problems, cognitive problems, psychiatric problems, and dysautonomic problems are actually getting significantly improved by these GLP-1 drugs. My suspicion — nothing proven yet — is that it's because these drugs are engaging with GLP-1 receptors, and we know these receptors are on the mast cells, and these drugs can help simmer down the activation of cells that bear these receptors. So if you have various neuronal disorders that are actually rooted in MCAS, who's going to be surprised if you apply a drug that can help simmer down mast cells and the neuronal issues simmer down as well?
[1:14:17] You were talking earlier about our acquaintance in the world of psychiatry, Dr. Janet Settle. I think there's a decent chance that she and all her fellow psychiatrists — I would not be surprised at all if at some point in the next 5 to 10 years the GLP-1 receptor agonists come to be used by psychiatrists on a regular basis to help address psychiatric issues of one sort or another. But it probably will be more so for the psychiatric disorders we more commonly see MCAS drive, like the anxiety and mood disorders I was talking about before. We may see less use of those drugs for other types of psychiatric disorders that seem to be less commonly driven by mast cell disease.

[1:15:15] Dr. Linda Bluestein: And it was actually my second patient that I ever had since starting my practice who had been diagnosed with psychiatric-type seizures. And they could not figure anything out to help this patient. And I thought, well, maybe it's a mast cell problem. So I treated it like it was a mast cell problem, thinking I didn't know what else to do. Her mom was like, "Can you help?" And I was like, "I don't know, but I'll try." And she came back 30 days later for her follow-up appointment and said she had not had a single episode. And I just about fell out of my chair. But that was—

[1:15:51] Dr. Lawrence Afrin: That was good for you for suspecting it and believing what the patient was saying and trying to treat it.
[1:16:04] In general, I think that when possible — and I understand there are lots of situations where it may not be possible, not only here in the US but even more so in other countries where you just don't have easy access to the diagnostic testing for MCAS — but when possible, I've found it's usually best to pursue the testing so you can really objectively nail down the diagnosis. Because again, this will be different 50 years from now when every doctor is aware of this disease and they just come out of training already knowing how the disease behaves. But until we get to that point, it's still going to be a long time where many patients who have MCAS are going to have to convince their local doctors that they've got this disease that the doctor has never heard of before, or at least doesn't have much familiarity with.
[1:17:09] And it's really important for the doctor to be convinced, because when the doctor's not convinced, that's when it becomes all too easy for the doctor to start making treatment decisions in the MCAS patient that are not going to be in the patient's best interest. Dangerous. There's an occasional doctor who might be convinced by hearing that the patient went to see some experts and the experts said that the patient had MCAS. But you and I both know that for most doctors, it's not opinions that are going to sway them — it's hard, cold data. It's the laboratory evidence that's really going to convince them.
[1:17:52] Again, I understand the challenges, but when possible, it's usually best to nail down the evidence. It just makes it easier for the patients to convince their local doctors, and it helps them avoid well-intentioned but nevertheless wrong-headed treatment decision-making. Because the way doctors go about treating a patient for a given symptom or a given problem can often be substantially influenced by the fact that the patient has a mast cell disorder. The doctor may treat a given problem one way when the patient doesn't have a mast cell disorder, and may treat that same problem in a very different fashion when the patient clearly has a mast cell problem. But we have to convince the local doctors, and that takes testing.

[1:18:51] Dr. Linda Bluestein: And maybe that's a good place for us to end on. What do you think — if a clinician is listening right now and they're thinking, okay, I'm convinced that this could be something that some of my complex patients have, what tests should I order and how should I order them so that I have the highest chances of getting helpful results?

[1:19:17] Dr. Lawrence Afrin: That's a great question. We probably don't have the time here for me to go into all the details of the specific tests to order. Again, it's a highly biologically complex disease with incredible variability and heterogeneity. So nobody should go expecting that it's just one mast cell mediator that's going to be reliably overproduced in most mast cell patients and not overproduced in most people who don't have mast cell disease. It's nowhere near that simple.
[1:19:52] There's quite the menagerie of mast cell mediators beyond tryptase that are typically checked in this testing. I think my best suggestion would be for the interested healthcare professional to read any of the papers on this subject. Perhaps the best one would be the paper from 2020 — if I'm remembering right — that described the so-called Consensus-2 approach to diagnosing mast cell activation syndrome. If you go to, for example, pubmed.gov and you search for "Consensus-2" and "mast cell activation," I'm sure you'll very quickly get to that paper. It's openly available. It does describe in there the approach to diagnosis, and there are references in there to earlier papers that actually go into even more detail about the particulars of diagnosis. That's probably the best way to start learning about this.

[1:21:19] Dr. Linda Bluestein: That's a great suggestion, and I can definitely link that in the show notes because I'm also a co-author on that paper, so I definitely have easy access to it. So we'll link that. And I can get from you afterwards the mediator webpage, because I want to link that as well.
[1:21:40] So, very last thing. As you know, we usually end every episode with what I call a hypermobility hack, but you don't have to have a hypermobility hack. Do you happen to have an MCAS hack, which would probably also benefit most people with hypermobility?

[1:21:57] Dr. Lawrence Afrin: Yeah, honestly, the best MCAS hack I can think of is that when the doctor — and I don't care what type of doctor — sees a patient who has a sizable assortment of fundamentally inflammatory, plus or minus allergic, plus or minus dystrophic problems, that's the patient in whom it's reasonable to at least start considering whether maybe what's underlying a large extent, maybe even all of the illness that's usually been long going on in the patient, is this disease that you had never previously heard of, never previously been given any reason to think could possibly be a mast cell disorder. And yet yes, this is exactly the population of patients in whom it's reasonable to think about MCAS.
[1:23:19] And it turns out there are a lot of these sorts of patients. I understand you were taught that mast cell disease is a very rare disease, and that is true for mastocytosis. But now we all have to learn there's this other mast cell disease, MCAS, and it's not rare. It's incredibly prevalent. It's just challenging because it shows up in so many different ways at the superficial clinical level.
[1:23:53] But as long as you're willing to think about the possibility that MCAS might be what's going on here, that initial spark of recognition — that's what can then lead you forward. You may not be the doctor who's actually going to do the evaluation. You may suggest to the patient, "Hey, maybe this is what's going on, but I don't have any expertise in this, so you ought to go try to find some other doctor who's more familiar with it, who you can consult with to get the testing done and all that." But if that initial spark never happens, how is the diagnosis ever going to get figured out?
[1:24:36] And that's the saddest part of all. Because the fact is, most of these patients seem to have a normal lifespan — it's just that it's a life of misery, suffering all these different symptoms, until it comes to be accurately diagnosed. Which often takes many decades, if it ever happens. And then they come to get it effectively treated. And yeah, I'll be the first to acknowledge that treatment's not simple or easy, but we're blessed with already having a boatload of different treatments that have been found helpful in different mast cell patients. And the fact is that most MCAS patients do sooner or later piece together some cocktail of mast cell-targeted treatment that really does get them feeling significantly better than the pretreatment baseline the majority of the time.
[1:25:32] And given that they're probably going to live a normal lifespan, boy, the quality of life in the remainder of that lifespan is huge. So if you can find the diagnosis that then gets them to treatment that will get them a better quality of life for decades to come — that's huge even in the individual patient, let alone the implications when you start realizing, oh my goodness, this is in 20% of the population. And most of them at present, it is utterly unrecognized and probably will continue that way for a long time to come.
[1:26:14] So every doctor who sees these patients has an opportunity to maybe turn things around for this chronically, multisystemically inflamed patient. That's not really a hack — that's way too long to be a hack, but—

[1:26:34] Dr. Linda Bluestein: That's okay.

[1:26:37] Dr. Lawrence Afrin: It's my best suggestion, and I think it will bring about the greatest amount of benefit for not only the patients, but honestly, the doctors too. Boy, when so many of them are so close to burnout from having taken care of these very complicated patients for so many years and they can never find a unifying diagnosis that makes sense, they can't find effective treatment — and then they start learning about MCAS and they start pretty quickly seeing how dramatically the health of these patients can be turned around. It's been interesting to see how many of these doctors have told me in follow-up that this has brought the joy in medicine back into their lives. I've come to call it chicken soup for the doctor's soul.

[1:27:34] Dr. Linda Bluestein: Maybe that's the hack. That's the hack. I think that's true, because so often we feel frustrated because we don't have enough tools in our toolbox. But if we open our minds to this and think, well, this could be a possibility, it gives us something to do. It gives us things to try. It gives us things to test for. So I love that — chicken soup for the doctor's soul. I think that's great.
[1:27:52] So thank you so much for taking the time to talk with me today. I know that you are extremely busy and have a lot going on. I know that you're not on social media, which is fabulous. But is there someplace that people can find you?

[1:28:14] Dr. Lawrence Afrin: Yeah, at my practice — the AIM Center for Personalized Medicine in Purchase, New York. The URL is aimcenterpm.com.

[1:28:32] Dr. Linda Bluestein: Well, thank you again so very much for sharing this extremely important information, and most importantly for all that you do to educate me and the other people who want to learn about this condition and want to be able to help people who kind of struggle to get answers. You dedicate so much time — it's amazing, the group that you've started, the listserv, where so many of us post questions, de-identified of course, challenging cases and things like that. And you spend so much time helping us for free on your own time. So thank you so much for all of that.

[1:29:11] Dr. Lawrence Afrin: My pleasure. I enjoy solving puzzles. I think that's self-evident.

[1:29:18] Dr. Linda Bluestein: Yes, most definitely.
[1:30:21] Well, I'm so glad that I finally got to talk with Dr. Lawrence Afrin about mast cell activation syndrome. He has taught me and so many other clinicians so much about this incredibly complex condition that affects so many people. And I'm really excited that we finally had this conversation, because the more minds that we can open, the more people that will get help and get effective treatments. Because as we were both discussing, there are really so many things that can be tried, and it really is possible to improve quality of life once we recognize that mast cell activation syndrome is playing a role in a particular patient.
[1:31:01] Thank you so much for listening to this week's episode of the Bendy Bodies Podcast with the Hypermobility MD. I have lots of other resources including my newsletter, the Bendy Bulletin. Check that out on Substack at hypermobilitymd.substack.com. You can help us spread the word about connective tissue disorders and related conditions like mast cell activation syndrome by leaving a review and sharing the podcast. This really helps raise awareness about these complex and multidimensional conditions.
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