Mast Cell Activation Syndrome: The Diagnosis Most Doctors Miss with Dr. Lawrence Afrin (Ep 181)

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Dr. Lawrence B. Afrin: [00:00:00] The fact is 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 view to no graduate training program curricula so that medical students, the residents, the subspecialty fellows, they're graduating to this day, going out into practice for the next 30, 40 years having never heard of this disease.

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 Syndrome 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 [00:01:00] 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.

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 Ccam, a landmark book that has helped thousands of patients and clinicians better understand complex multi-system disease driven by mast cell dysfunction.

His work has been especially influential in communities affected by Ehlers-Danlos Syndrome, hypermobility spectrum disorders, dysautonomia, and other overlapping conditions. I'm so excited because Dr. Afrin is [00:02:00] such a leader in this space, and we need so many more people aware of mast cell activation syndrome and be able to treat it.

As always, this information is for educational purposes only, and it's not a substitute for personalized medical advice. Stick around until the very end. So don't miss any of our special hypermobility hacks. Here we go.

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, um, Larry Afrin, Dr. Larry Afrin, and incredible expert in mast cell activation syndrome and all mast cell disorders. Um, how are you doing today? 

Dr. Lawrence B. Afrin: Oh, I'm doing fine. Um, glad I was able to get to this on time.

My last patient ran way over and I just managed to wrap up, uh, in time for this appointment. 

Dr. Linda Bluestein: Well, I'm so glad that you're here. I know from some of our mutual patients that we have that you do such incredible in-depth, [00:03:00] um, evaluations of your patients and, uh, describing all of the processes that are going on and developing their treatment plans.

So, uh, yeah, I can only imagine how, how it is running your clinic on a day-to-day basis. So I wanna start with laying some of the groundwork because I feel like, you know, people hear the term mast cell activation syndrome. They might hear mast cell activation disorders, mastocytosis, hereditary, alpha semia, like, you know, they hear these terms.

Right? And I feel like it would be helpful to just start with like a high level overview of what the differences between those terms. And I know we could probably talk about this for a really long time, but if you could just give us kind of a, a lay of the land that would be helpful. 

Dr. Lawrence B. Afrin: I think it's fair to say that the totality of the mast cell disorders field, we're now putting this under the umbrella term of MCAD, mast cell activation disorders or diseases under [00:04:00] the, uh, relatively new understanding, um, that, uh, 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 the mast cell mediators. Um, 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 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, uh, inappropriate [00:05:00] proliferation of the mast cells. Um, there is a tiny portion under the NCAT umbrella that is the quite rare disease of mastocytosis.

Um, in both, it's more common cutaneous form you tend to see in younger folks and the less common systemic form you tend to see in older folks. Um, mastocytosis is essentially a malignancy of the mast cell. In which there is a gross, uh, over proliferation, a cancerous over proliferation of mast cells and that bulk of mast cells that can build up in various issues in the body can cause, uh, some symptoms itself.

But still, the great majority of the symptoms that are being seen, even in patients who have mastocytosis, it's not from the bulk of the mast cells, it's from the [00:06:00] inappropriate activation of, uh, those malignant mast cells. Um, uh, fortunately when I mentioned malignancy, most people who have mastocytosis, it's a pretty, um, indolent malignancy.

They tend to have a relatively normal lifespan, but there are some, uh, less common forms of mastocytosis that behave like. Classic aggressive cancers and really will cut a patient's life. Short, hereditary alpha tryp emia, HATA relatively new term, uh, emerging in just the last decade, uh, coming from a new understanding that about 5% of the human population actually has inherited from one parent or another.

Sometimes both, uh, have inherited one or more extra copies of the gene, the tps AB one gene for making the portion of the [00:07:00] 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, uh, for the duration of your existence.

Um, and that means that every mast cell is going, is sort of genetically programmed to overdue a little bit of extra tryptase. And the more extra copies of the gene you have, then the little bit more extra tryptase that you manufacture. Most people who have hat, they only have one extra copy, and so they only have a slightly elevated level of, uh, tryptase floating around in their blood serum their entire life.

Um, and as best as anybody has figured out so far, these modest elevations in tryptase [00:08:00] don't seem to have any clinical impact. Um, so, um, now to be fair, there are an awful lot of people who have. Detectable HAT and they got a lot of symptoms, a lot of MCA consistent symptoms, but it's not the extra copy of TPS AB one, it's not the hereditary alpha tryp EMIA that's causing the activation of their mast cells to cause all their symptoms.

Those patients have a 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. 

Dr. Linda Bluestein: Interesting. So I know that you can test for the hereditary alpha Semia, um, you know, for the extra copy. Is that a test that you think is helpful to do or not helpful to do?

Dr. Lawrence B. Afrin: Well, given [00:09:00] that it's a pretty, it's pretty standard to include in the diagnostic assessment for MCAS to include testing for the tryptase level. Uh, you know, if we do find an elevated, uh, 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.

Uh, the, the, the MCAS, it's causing the patient symptoms or whether it's a completely uh. In significant marker for hat. And so if you find a modest elevation in tryptase, then you kind of have to go on and do the genetic testing for [00:10:00] hat. And if you, uh, do have an ex one or more extra copies of the TPS 81 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, um, uh, extra copies of the gene, then at that point you can say that that elevated tryptase level you found in that patient must.

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. [00:11:00] Does that make sense? 

Dr. Linda Bluestein: Yeah, I think so. I think the whole hat, thing's gotten really confusing because I know when Dr. Lyons first published about, about, uh, hereditary Alpha Tryp semia and published his NIH work, it was thought that, well, maybe this is the explanation behind the triad of MCAS, um, hypermobile EDS, right, and pots.

But in the meantime, there's been other published studies that are, that have shown that there are people who are asymptomatic and have her red Sherry Alpha have, have extra copies, right. 

Dr. Lawrence B. Afrin: Look, I'll hold out the possibility that in the very rare patients who have hats, but they've got a lot of extra copies of the gene and they are constantly making excess of tryptase at a more significant level, not not the modest levels we see in people who have just one or two extra copies of the gene.

Maybe the chronic [00:12:00] effects of such a significantly higher level of tryptase really can be bringing about some clinical effects in 'em. But the great majority of these have patients, they've only got one or at most, two extra copies of the gene and the elevations in the tryptase level that are a result of that are, are so modest that.

It's really hard to see that those elevations are causing any, 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. So I've looked at those modest elevations, uh, in the common hat, patients who have just, you know, one or two extra copies of the gene.

I've looked at the elevated, uh, tryptase levels in those patients. It's kind of a red herring. [00:13:00] Um, so it, it, it, it's an abnormality, but not every abnormality is a, is a problem. Some abnormalities, they're, they're findings, but. They're not really problems. Uh, and I think most people who have hats, which again is about 5% of the human population, uh, not, not, not a trivial fraction, um, but most of those people hat is, uh, probably a finding in them.

Not really a problem. 

Dr. Linda Bluestein: And we're definitely gonna talk more about tryptase later because that is obviously a, a, uh, whole topic onto itself when we're talking about diagnosis, um, of MCAS. So let's talk though now about the clinical picture and clinical presentation of MCAS, which you and I both know is extremely variable, right?

And if people think about when people do know something about MCAS, they might think of the allergic type phenomenon, like skin rashes, hives, flushing, respiratory [00:14:00] issues, et cetera. Um, 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 also to be most aware of that would make them pause and think, you know, could this person have MCAS?

Or, you know, somebody's really miserable with all these things. Maybe MCAS is the thing that ties this all together. 

Dr. Lawrence B. Afrin: I think the best way to answer that is twofold. Number one. The symptoms of MCAS, unsurprisingly are gonna be consequent to the known effects of the mast cell mediators, the very potent mast cell mediators that just happen to be getting inappropriately expressed, inappropriately produced, and released by the patient's dysfunctional mast cells.

Now, many of those mediators that are produced by the mast cell have effects [00:15:00] that kind of. Generically categorize as inflammatory effects many other mediators drive effects you'd kind of categorize as allergic type effects. Other mediators are integrally involved in guiding growth and development in all tissues in the body.

So yes, mcm, CAS can easily drive a huge variety of abnormalities and growth and development, thank goodness, most commonly benign, but occasionally even malignant. Um, so the first part of the answer to your question is given that these cells are everywhere in the body. That they produce such an enormous repertoire, a menagerie, a popery, if you will, of uh, mediators.

And so many of the mediators have [00:16:00] inflammatory type effects. I think we're entering a new era in medicine where we have to learn that in anybody, any patient who has. Chronic multisystem inflammation, that it becomes reasonable to include MCAS in the differential diagnosis, uh, the, the, the set of diagnoses that are reasonable to at least consider in that patient.

That's not saying that everybody who has inflammation has MAS at the root of it. It's just saying these are the patients in whom it's reasonable to start thinking about whether MAS might be what's actually at the root of the inflammation in that patient. 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 NCAS as opposed [00:17:00] to other disorders that might be able to accomplish some of those problems, but maybe not.

Of them because in the end it's gonna be more likely they're just one root answer for all the, uh, 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, which are each, you know, driving different symptoms.

So many doctors are quite familiar with the situation where they see patient after patient after patient, where the problem list for the patient has a lot of problems on the list, and many of those problems are itis. Itis itis. Uh, 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 [00:18:00] underlying, uh, disease. It actually can drive such a wide range of inflammatory issues in different systems in the body. So that's any patient a doctor is seeing who has these chronic multisystem, inflammatory conditions and, and obviously the, the specific symptoms of inflammation can be quite different.

Depending on what system in the body you're talking. So inflammation in the respiratory tract manifests very differently than inflammation in the gastrointestinal tract and so on and so forth. 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 multi-system inflammation plus minus allergic issues, plus minus, um, growth, tissue growth and development issues, what we call DYS TRMs, uh, [00:19:00] then it's at least worth thinking about MCAS now the one area in the body where it's often much more difficult to recognize that the symptoms actually are.

Inflammatory, uh, in large part because we're not even taught that such symptoms are or can be inflammatory even though they can. Uh, th this kind of relates to the anatomy of this disease. I mean, where are the mast cells in the body, in truth are everywhere, but they're dominantly, uh, they're actually very sparsely distributed in most tissues in the body.

You could do a random biopsy of most tissues in the body. You'd be hard pressed to find even a single mast cell in most biopsies. Where the mast cells are dominantly cited is at the environmental interfaces, so the skin and the rest of the integument, the respiratory tract from top to bottom, the GI tract from top to bottom, the genital urinary tract from top to bottom.

So there's the environmental interfaces [00:20:00] and directly abutting all vessels and all neurons, both peripheral and central. 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, uh, 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 or a cognitive issue or a psychiatric or dis autonom 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 ma cell patient anyway. It's because the neurons, they're normal neurons that are react. Sting to the constant assault to one degree or another of these [00:21:00] very potent inflammatory mediators that are constantly emerging to one degree or another from the literally adjacent.

Dysfunctional mast cells. And then at that point, it's entirely a matter of which mediators are impacting on which neurons as to which particular neuronal issues the individual patient is gonna suffer at any particular point in time. So, um, 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 also start thinking about the possibility that maybe there's, uh, a mast cell activation syndrome here.

Dr. Linda Bluestein: Mm-hmm. And I'm glad that you said symptoms consistent with inflammation, [00:22:00] because it doesn't mean that the CRP is necessarily elevated or the esrs necess, right. They, those are very often normal. 

Dr. Lawrence B. Afrin: Yeah, they, they 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.

It doesn't even begin to tell you what the source of the inflammation is, but 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. 

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. Um, do you have any thoughts on, on that? 

Dr. Lawrence B. Afrin: Well, [00:23:00] 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 dis problems, but also psychiatric problems.

There's a huge range of psychiatric disorders. I, I'm not saying that every psychiatric disorder is, is a case of MCAS, uh, that that'd be stupid, 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 probably a yet unrecognized MCAS.

I mean, there are some patterns of this. Uh, we more commonly see, uh, anxiety and mood type disorders with MCAS compared to some of the other [00:24:00] broad, uh, 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 Mc CAS.

Dr. Linda Bluestein: Speaking of the uh, 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 and I told you, well, I'm not sure if I'm the right person to do this presentation, but you talked me into doing it. Well, in the process of preparing to do that presentation, I learned so much about mast cells and pain processing so much that I didn't know and understand before.

And I used to think that of my EDS patients like this tiny little percentage will have MCAS. And after I prepared for that presentation, I ended up starting to treat a lot more of my EDS patients as if they had MCA somewhere on the spectrum and started getting better results. And I know that you published a paper in 2021.[00:25:00] 

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 that paper 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 neuro immune condition, might involve the complement system.

Um, maybe there's something, uh, Dr. Chip Norris said recently. You know, maybe something in the immune system is chewing up connective tissue. Um, that maybe people with hypermobile EDS, at least some of them that have the hypermobile EDS phenotype actually are born with, you know, healthy collagen, but the mast cell mediators destroy it.

Um, you published that paper a few years ago. What are your thoughts about that now? 

Dr. Lawrence B. 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, uh, from the Norton Lab in Charleston at the medical university. Uh, my old haunt, uh, the Medical University of South Carolina and [00:26:00] USC.

But I still think that, um. I mean, 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 though one or two particular inborn, you know, 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, H EDS, or heads, or what previously was called type three EDS, slots of research groups, have been diligently searching for, gosh, it's gotta be 40 years now for. Any mutation in any genetic inborn, congenital, uh, mutation in any of the connective tissue proteins, uh, the, the [00:27:00] 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.

And furthermore, it's become evident in the last, I don't know, 10, 15 years, that when you take the full history from these hypermobile EDS patients, an awful lot of them have not only their H EDS, consistent connective tissue problems, but also an awful lot of other health anomalies that. Difficult to, impossible to attribute to a connective tissue problem of any sort.

And in those many, many, many patients, you then start wondering, well, might there be [00:28:00] some other. Underlying disorder that can drive not only the connective tissue phenotype that we, you know, 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.

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, I mean, honestly, who would be surprised if there's at least certain variants of these mutated dysfunctional mast cells at the root of MCAS that output various growth?

Influencing, uh, connective tissue growth, influencing mediators [00:29:00] in abnormal patterns that ultimately wind up producing connective tissue that we superficially label as hypermobile EDS type tissue. I mean, that, that's well within the range of possibilities of what Mc a can do. Now, has anybody. Found the smoking gun.

Uh, 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, in this area that's exploring the associations. And you mentioned the Norris Group in Charleston and you know, they recently published a paper finding a, a very large study global survey of hypermobile EDS patients and [00:30:00] found very high, uh, percentage of the hypers patients had sort of MCA consistent, uh, symptoms in them.

So it sure makes you wonder. 

Dr. Linda Bluestein: Yeah, for for sure. They, so I know a couple of papers that they published, not. Too long ago, one, they looked at a little over 2000 people and they identified three different clusters of people, one of whom had really, really high rates of mast cell activation syndrome. And 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, uh, proteins and found a number of different proteins that were either, uh, extremely high or extremely low in people with hypermobile EDS. And these proteins related were related to a complement system and other immune, um, functions.

So they're, they're doing some excellent work. 

Dr. Lawrence B. Afrin: Yeah. What I would really like to see [00:31:00] done, and I'm not aware yet of any research group that's pursuing this. I, I, what I think would be the most fascinating, uh, experiment, so to speak, to, to run, would be to, uh, well, first of all, just to set the groundwork for this, we, 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.

Very different assortment from one patient to the next, but an assortment of mutations in various and sundry of the genes, uh, 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 veca, they are not inherited mutations.

Uh, and instead [00:32:00] in a model, kind of similar to what you see with cancer, they are acquired mutations, uh, typically starting to get acquired fairly early in life. But as a mast cell patient goes through life, then from time to time there's potential, uh, for them to acquire additional mutations. And that just drives the disease to repeatedly escalate to, um, higher and higher baseline.

Just to set some groundwork for this, we have to understand that, uh, what's been found in the research to be driving almost all cases of MCAS is various mutations in various genes inside the dysfunctional mast cells, various genes that are of importance in regulating the behaviors of the mast cells. Uh, now to be clear, these mutations that we know, and it's a very different assortment of mutations from, uh, in a different assortment of regulatory genes, uh, from one patient to [00:33:00] the next, but.

We know from the research, these mutations usually are not inherited. They're usually acquired, uh, usually starting pretty early. And this is a model very similar to cancer. Of course, cancer is disease, uh, of acquired mutations in one type of cell or another. But in this case, with MCAS, uh, the mutations are not driving, uh, cancer of the mast cell except for MAs, 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. And so these, uh, mutations get acquired at various stages in a patient's life. And it's common in mast cell patients that from time to time they can acquire, uh, fairly suddenly additional mutations.

And, uh, this. Usually happens shortly following a major [00:34:00] stressor, either physical or psychological. And these major stressors have potential for inducing additional, uh, mutations that then drives the disease to escalate to a whole new worsened baseline level of misbehavior of the dysfunctional mast cells.

So this is what we think is driving the disease in most patients. But because these are acquired mutation, not if they were inborn, if they were inherited mutations, 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 by and large, only in the mast cells, which is a tiny population of cells in the human body.

So doing a genetic, uh, sequencing study in the hypermobile EDS population where you take [00:35:00] a sampling of their connective tissue or you take a sampling of say, uh, a big bunch of their white blood cells that all have, uh, the, they're nucleated, they have all the DNA person and you go looking for these mutations that are just in the mast cells.

There are so few mast cells there that tho those sequencing experiments probably will not find anything. So what would be really interesting to do be to take a cohort of hypermobile EDS patients, maybe 20, 30 a, a small study just to start. Um, this would be relatively inexpensive to do with modern technology and.

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's so few mast cells in the [00:36:00] blood, it would probably have to be a little bit larger blood sample than a normal, uh, blood sample for normal blood testing.

And the researchers would first extract from the blood sample just the mast cells, not, not the whole set of white blood cells in which the normal white blood cells would kind of overpower, so to speak, grossly outnumber the mast cells, let alone the subpopulation of mast cells that are actually mutated and dysfunctional.

So first you would have to extract from the blood sample the mast cells, and there are techniques for doing. And then take that isolated population of mast cells, put that through one or another of very presently available sequencing technologies to see what sorts of [00:37:00] mutations can be found at that point.

'cause if it's, say, 10 or 20% of the mast cell population that bears these acquired mutations, you're not gonna 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, and you do the sequencing just in a population of mast cells, then the sequencing techniques, uh, presently available probably would be able to pick up, uh, 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 probably in five, 10, 20% of the mast cell, the sequencing probably would pick it up.

And then at that point, if you're able to [00:38:00] say that, 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 in this non-trivial fraction of this cohort. I mean, that's some compelling findings there that probably, uh, these mutations, which, which are driving the MCAS, that it's the MCA that's probably driving the hypermobile EDS, but where it gets even more interesting than that is that.

If you then find in looking at the sets of mutations that would be found in different hypermobile EDS patients, in in, in the mast cells, in the different hypermobile EDS patients, if there are particular acquired mutations [00:39:00] that you see over and over and over again may, maybe not in all of them, but nevertheless in a fraction of them, that's obviously not a coincidence, then you start to wonder, hmm, 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, uh, phenotype. Lots of people have done lots of genetic, uh, studies in hypermobile EDS patients, but they've only looked for inborn for inherited mutations. Nobody has looked for mutations that are confined to just one particular type of [00:40:00] cell or another.

And for sure nobody has looked for it in the mast cells. This very tiny cell population in the human body. Um, but from, at least from what I've been seeing, clinical experience. 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.

And so it's the genetic dissection of this disease where I think we're gonna get. The greatest leaps forward in understanding not only the biology of what's going on, but once you understand, uh, the biology, then you can start much more, uh, [00:41:00] rationally, um, coming up with, uh, treatments that ought to be effective for one variant or another.

Once you understand what's really happening at a molecular and a mediator level and, and the genetic level in these patients, just that so far, nobody is doing these genetic analyses, just looking specifically at isolated populations of mast cells. Uh, and until you isolate the mast cells, then doing genetic studies of the whole white blood cell population.

You're not gonna find these lieutenant, they're, they're just too few, um, scattered among all the normalcy of all of the other, the, the massively greater numbers of the other normal white blood cells. 

Dr. Linda Bluestein: Well, well maybe somebody listening to this who, I mean, I am in contact with Dr. Norris and Dr. Genser, and I know that, uh, you probably are as well.

So hopefully either they will have heard this [00:42:00] 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, you know, an infection or a concussion or, you know, like you said, it could be psychologic, could be physical.

Um, why that often sets off hypermobile EDS, uh, COVID, especially, um, in these patients, like they might be relatively functional, they're doing quite well, they're not having a lot of problems, and then they get something like that and it really, um, starts to cause a cascade of, of symptoms. 

Dr. Lawrence B. Afrin: For some people, it's something that comes on a little bit later in life, uh, though still most commonly in the formative years.

But then again, these acquired mutations that can drive MCAS can sometimes be present almost right from birth. Um, so, um, I actually have, uh, mentioned these ideas to various EDS research groups in the past and so [00:43:00] far they haven't seem inclined to do genetic testing in any cell populations other than the, the whole white blood cell looking for the inherited, the inborn, the congenital, the germline mutations.

Nobody is yet looking for the mutation specifically in the mast cells. Um. Somebody will probably win a Nobel Prize from doing that. Um, but, or some prize. Uh, and they'll deserve it 

Dr. Linda Bluestein: for for sure, for sure. They would deserve it. 'cause the, the MCAS affects such a large percentage of people, which is going to be the thing we're gonna talk about first when we come back.

We're gonna 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 gonna take a quick break and when we come back, we are going to tackle that topic. We'll be right back.

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Okay, I am back with Dr. Lawrence Afrin, and we are talking about mast cell activation syndrome, and I [00:45:00] 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? 

Dr. Lawrence B. 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 MAs cells can misbehave and. Many, many different ways, and tryptase is certainly not the be all and end all of this disease. 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 [00:46:00] cell mediators in them other than tryptase. And then we diagnose 'em with MAS, we treat them with mast cell targeting treatments and they get better. So it's obvious that they have MCAS and it would be nice if doctors who think that tryptase is the be all on end all of this.

Uh, were to be open to the notion that it's an extra, uh, the, the biology in this cell is extraordinarily complex. We know these cells are producing and releasing at various times, various circumstances. Uh, they're able to produce more than 1200 different mediators. So why on earth would anybody rationally think that if you don't have an elevated level of one particular mediator that.

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, uh, tryptase. [00:47:00] And if patients sense an opening with their doctor and they wanna try to help the doctor learn more about, um, this broader view of MCAS, there certainly are papers in the literature that patients can consider trying to provide to, or pointing their doctors to, to learn about these broader perspectives.

But I'm also aware that many doctors, for all sorts of reasons, uh, they're just. Kind of set in their ways and they're, they, they learn one particular way of thinking about a disease and they're just not going to budge. So there, 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.

The fact is, we're 19 years now since, uh, it's 2026 now. We're [00:48:00] 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, the medical students, the residents, the subspecialty fellows, they're graduating to this day, going out into practice for the next 30, 40 years, having never heard of this disease.

I mean, uh, there's 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, uh, let alone have actually acquired the even fewer. Who have yet acquired any real familiarity with this. It's not because they were trained or taught about this, it's because they stumbled across it or they were off at a medical conference and they stumbled into the wrong meeting room.

But it sounded like an interesting topic. So they sat in for the rest of the talk or, or [00:49:00] maybe they inherited a patient from another doctor and they were reading the records and it said MCAS. I said, MCAS, what the heck is that? And so they did some reading, and this is how the vast majority of the very few doctors around the globe who have yet developed any awareness of this disease at all, this is how they're coming to acquire that awareness.

Some of them, the particular paths they're taking to acquire that awareness, it's exposing them to this one particular, uh, viewpoint that says that if you don't have recurrent anaphylaxis and you don't have, um, elevations in the tryptase level to certain degrees, then forget it. You can't have a mast cell disorder.

Uh, or at least it's extremely unlikely you would have a mast cell disorder. And then there's this other, uh, group of doctors and full disclosure on [00:50:00] one of the ringleader that looks at this disease from a much broader perspective, says, look, these cells are putting out more than 1200 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. Uh, that just phenomenal potential. This is not to say that every patient who has chronic mysterious illness of these types, that it is m at the, 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%, the general population.

And what that number means is that in truth, every doctor, and I do mean every doctor, it is [00:51:00] seeing these patients. All day long, every day, their whole career. They, they just couldn't previously recognize these patients for what's truly at the root of their assortments of inflammatory and other problems.

'cause number one, they had never been taught that such a disease exists. And number two, and this is virtually as important, the, the biological nature of the disease, the, the, 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.

Yes, there may be at a very high level, there may be some aspects of the disease that are shared among different subpopulations of patients who have MCAS, like the subpopulation, who has hypermobile EDS, but. [00:52:00] 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, the next and the next, 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 and pattern recognition. I don't care if you're a doctor or a car mechanic. Uh, you go to school for x number of years, you learn all the diseases of the car or the human body.

Uh, 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 a shop or a patient comes in a 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 [00:53:00] against your learned database of the different patterns you, you've been taught that each known disease presents with just one or two specific patterns, and that's how you make a diagnosis and then you know how to treat the patient.

Now there comes along and I say that facetiously. 'cause no, it's not a new disease, it's just a newly recognized disease. So now there comes along, so to speak, this so-called new disease MCA, that by its fundamental biological nature, it's not gonna manifest, it's not gonna present in just one or two particular patterns.

It's gonna present in a hundred, in a thousand different patterns. So pity the poor doctor who's gotta learn how to clinically recognize a 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.

A, [00:54:00] I'm not saying it's impossible to learn, but yeah, the details are quite different from one patient or another. So, uh, it's hard for doctors who have not been taught about this to recognize that such superficially different appearing, uh, different appearing patients actually all have just different variants of the same root issue.

I thought I was very encouraged actually to see just earlier this year, back in May, that the very first formal teaching of this C is to, uh, a freshman medical student class actually took place at the University of California at Irvine, UCI. They, they got a good, a good lecture on MCAS and that was followed up with, uh, a panel of, of national experts.

So the students were able to ask, uh, the, the experts various questions about the disease. And, um, it's gonna be interesting to see what happens with these [00:55:00] freshman students who I guess now are sophomores as they finish their, um, classroom training and they start getting into clinical training and they start getting supervised by higher level students and residents and fellow and attending physicians who are grading them.

It's gonna 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. So 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.

[00:56:00] Um, so. It's gonna be interesting to see how the educational dynamics of this work out over the next many years. I mean, ultimately, of course, the students become the teachers, you know, but that's a generational change. Um, gonna be a long time until the average doctor comes out of training already knowing about this disease and being familiar with it.

Uh, I wouldn't be surprised if it's another quarter century, half century before the average doctor knows at least something about this coming outta training. 

Dr. Linda Bluestein: And I would say that for most of us, I know this is true for me, when I first learned about M-C-A-S-I, you know, 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. And that's when I started to really believe it. And [00:57:00] you helped me a lot with that. I called you multiple times and you were so kind to come out of the room of, with, you know, the patient that you were seeing and come out and talk to me for a few minutes and say, well, you know, have you tried this?

Have you tried this? Um, but I think most of us who take this broader view of MCAS presentations, I think that uh, it's because we became so convinced after we started treating people and we started seeing success. 

Dr. Lawrence B. Afrin: You, you bring up a really important point, and I, I've seen this over and over and over again with physicians, uh, who I've been, you know, privileged to be able to help them come to understand this disease better.

But, you know, you think about it, most physicians go through roughly seven 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 that the [00:58:00] teaching about mast cell disease would be so limited when you realize that the only mast cell disease we've known about for the last century, other than a very prevalent allergy, but that's, um, no, no dissing of the allergist, but relatively straightforward key keyword, relatively, relatively straightforward to take a care of allergy.

But the only other mast cell disease that 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 disease, why would you spend more than one minute?

Um, out of 10 years in learning about the biology of the mast cell and learning about the disease of mastocytosis, it doesn't make any sense. Therefore in that one minute they learn that the mast cell produces like two mediators. You know, there's [00:59:00] histamine, we've been studying for 80 years, got a pretty good idea of what that does in the human body.

And tryptase, we've been studying for nearly 75 years now. We still don't have the foggiest idea what the principle role of tryptase is in the human body. We understand what some of its minor roles are. I still don't know what its principle roles, and that just underscores how challenging this research is.

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, uh, other cells and tissues in the environment. And that's the IgE receptor, which is how mast cells get wrapped up in allergy. That's what we're taught, so sure. When that's all you've known for a decade of training and 1, 2, 3 decades of practice, and then somebody comes to you and tries to tell you.

Oh, wait a second. You know, I, I know you went through a great half million dollar, 10 year long medical [01:00:00] education, the best professors in the world, and I understand you've never seen a case of mastocytosis, but wait a second, you've been missing something here. 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 1200 different mediators, and they've got not one receptor, but hundreds of different receptors for interacting with different elements of the body.

And so. You can understand that the average doctor, based on how they were trained and thinking, this is a very narrow scope, that 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. [01:01:00] Turn off is that you're crazy.

That's not possible. 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 this. And boy, uh, I've seen so many light bulb moments in so many doctors. Uh, there, there's this one, uh, webpage out there that provides this beautiful, uh, listing of most of the mast cell mediators out there.

Very commonly, when I'm trying to explain this disease to a doctor who, who's new to it, I show them this webpage and I say, look, you were told these cells put out two mediators. So here's the list of mediators that these cells are actually known by. The biologists, not the doctors. They don't get taught this, but the biologists [01:02:00] have long known these cells are putting out all these mediators and.

I just start scrolling, scrolling, scrolling, scrolling, scrolling. And after like a minute of scrolling, we're down to the cs. Uh, haven't even gotten to the D'S yet. And much of the time when I have the opportunity to, to share this with a doctor who hasn't previously understood that, uh, been aware of the disease, I look at the doctor's face as I'm doing the scrolling and as the scrolling is going on, you can see their jaw dropping further and further and further.

And they, they just look at me and they say, I had no idea. I said, yes. That's, 

Dr. Linda Bluestein: that's 

Dr. Lawrence B. Afrin: the point. That's the problem. You know, none of us were taught this. Okay? So I'm not blaming the doctors. You know, they're doing the best they [01:03:00] can with what they were taught, but. You know, there's this old joke that the medical school dean greets the incoming class of freshmen and tells them half of everything we're gonna teach you in the next four years is wrong.

We just don't know which half. 

Dr. Linda Bluestein: Right. 

Dr. Lawrence B. Afrin: And it's funny because it's true. Uh, good example. Uh, Chitta, you know, I can show you the, uh, the title of the article in the 1987 issue, new England Journal of Medicine, one of the most prestigious, uh, medical journals in the world. And there was an article, uh, back in 1987 that said, tryptase is a marker of mast cell activation in mastocytosis.

Well fast forward a quarter century and it turns out new research emerged that showed that actually tryptase [01:04:00] is a pretty miserable marker of mast cell activation. What tryptase is a good marker of is the number of mast cells that you've got in your body. So if you have a grossly cancerous. Over proliferation of mast cells.

In other words, if you have mastocytosis, then pretty reliably the tryptase level is gonna be way elevated. But if the mast cell disease you have is a disease where it's mostly activation and there's little to none of the inappropriate proliferation of the mast cells, then the tryptase level is gonna be elevated little to none, usually none in MCA.

But it took a long time to figure that out. So, you know, one or two generations of doctors were taught that tryptase is the marker of mast cell activation, and now you have to go unteaching [01:05:00] that. Um, this is not easy. So I, I'm not blaming the doctors, but it would be nice if more of the doctors were open to this.

But I guess the other real. Confounding or complicating factor is that we're taught in that one minute that it's allergy. It's the rare mast cell disease of mastocytosis, which is handled by the hematologist oncologist, and that's it. That's all there is to it. So most doctors go through their decade of training and they're given no reason whatsoever to think that a mass cell disorder.

Could have any involvement in their own domains of medicine, whether it's GI or cardiology, endocrinology, psychiatry that we were talking about before, connective tissue diseases we're never given any reason to suspect that mast cell disorders could have any involvement. And yet, once you start [01:06:00] diving into the biology of this and you realize, uhuh, these cells are everywhere in the body and they're putting out this huge menagerie of mediators that are potently, uh, 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, uh, all the different medical subspecialties, uh, all the different surgical subspecialties, psychiatry, ob, GYN, um, 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 that they're gonna have to start thinking about the possibility that mast cell disease might be what's at the root of the problems that are being seen in [01:07:00] a hefty fraction of their patients.

We'll see. 

Dr. Linda Bluestein: Yeah. And speaking of, of teachings, um, in terms of more recent. Things that have been found to be therapeutically beneficial. The glucagon-like peptides, uh, agonist, the GLP one drugs are something that I know, uh, I've been prescribing after reading the paper that you published and hearing some people talking about using those in mast cell activation syndrome patients, and I've found them to be very often very beneficial at stabilizing mast cells.

Um, what is your current thinking on that? 

Dr. Lawrence B. Afrin: I think it's become, uh, very apparent in just the last couple of years and, uh, even more so in just the last year, that these drugs, uh, can be significantly helpful in a lot of MCA patients. And that's not to say that they're [01:08:00] gonna be helpful in all mast cell patients.

And it's not to say they should just be tried willy-nilly. There are some significant risks with them. And, uh, a trial of a mast cell patient on these drugs needs to be managed with a, 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.

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. Yeah. You know, uh, that, that these drugs were originally FDA approved for diabetes and obesity.

Well, the diabetes and the obesity researchers began figuring out a quarter century ago that diabetes, uh, at least type [01:09:00] two diabetes and, 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 ma cells have something to do with the inflammation in many diabetic and obese patients, I will not be surprised if MAS is found to be the root of hefty fractions of the diabetic and obese populations.

But you know. These drugs in simmering down diabetes, simmering down obesity, they 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 [01:10:00] diseases, uh, like MCAS. And even though, uh, these drugs are not yet being prospectively studied in any patients who specifically have MCAS, nevertheless, there are many studies now going on looking at utility of these drugs in a wide range of other, uh, chronic inflammatory diseases.

And what's particularly interesting about those studies is that most of those diseases, uh. Nobody has yet figured out what's causing the inflammation in those diseases. 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 or another.

Um, and so it's possible that many of these [01:11:00] studies actually are investigating the utility of these drugs in specific subpopulations of MCAS patients who all bear this one particular type of inflammation or this other particular type of inflammation. So time will tell, but interesting times ahead, that's for sure.

Dr. Linda Bluestein: And, and do you think that's the biggest development in the MCA space or is there something else that has been a big development? 

Dr. Lawrence B. Afrin: Um, I think there are lots of developments, uh, going on, but in terms of new drugs coming on the scene that have a lot of potential for helping, yeah. The GLP one receptor agonists, uh, probably take the crown and, uh.

To come along recently that have had the biggest effect. It's been [01:12:00] interesting to see too that not only are these drugs helping symptoms that again, you would classically recognize or label as inflammatory. Boy, I've been impressed and I've heard of it from many colleagues too, who've seen very similar experiences in many of their patients that an awful lot of central neuronal problems, uh, neurologic problems, cognitive problems, psychiatric problems, denomic problems are actually getting significantly improved by these GLP one drugs.

And it's my suspicion, again, nothing proven yet, but my suspicion is 'cause these drugs are engaging with GLP one receptors and we know these receptors are on the mast cells, and these drugs can help simmer down the activation of cells that are bearing these receptors. So if you have these various neuronal [01:13:00] disorders and.

Various cases of these neuronal disorders are actually rooted in MCAS. Then who's gonna be surprised if you apply a drug that can help simmer down mast cells? Who's gonna be surprised if the neuronal issues, uh, simmer down when you apply those drugs? You know, you were talking earlier about our, uh, acquaintance in the world of psychiatry, Dr.

Settle, Janet settle, and I think there's a decent chance that Dr. Settle and all the rest of her, uh, brethren, uh, psychiatrist. I, I would not be surprised at all if at some point in the next five, 10 years that the GLP one receptor agonists come to be used by psychiatrists on a regular basis to help address psychiatric issues of one sort to another.

But it probably will [01:14:00] be more so for the psychiatric disorders. We more commonly see MCAS drive, like the anxiety and the mood disorders that I was talking about, uh, 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.

Dr. Linda Bluestein: And it was actually my second patient that I ever had since starting my practice who had, uh, was diagnosed with like a psychiatric type seizures and they that. I could not figure anything out to help this patient. And I thought, well, maybe it's a mast cell problem. And so I treated it like it was a mast cell problem thinking, you know, I didn't know what else to do.

And the mom was like, can you help? And I was like, I, I don't know, but I'll try, you know? And, uh, she came back 30 days later for her follow-up appointment and she said, I have not had a single episode, and I just about fell outta my chair. But that was, that was the 

Dr. Lawrence B. Afrin: beginning. Oh, good for you. Yeah. Uh, [01:15:00] for suspecting it and believing what the patient was saying and, and trying to treat it.

You know, in general, I think that general, 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, uh, where you just don't have easy access to the diagnostic testing for MCA, but. When possible it's, I, I found it's usually best to pursue the testing.

Uh, so you can really objectively nail down the diagnosis. 'cause again, this'll be different, you know, 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. And it's very prevalent and they can recognize these patients at a moment's glance.

Um, but until we get to that point. It's still gonna be a [01:16:00] long time where many patients who have MCAS are gonna 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. And it's really important for the doctor to be convinced.

'cause when the doctor's not convinced, that's when it becomes all too easy for the doctor to start making treatment decisions in the MCM CA patient that are not gonna be in the patient's best interest. So you gotta convince the patient. And yeah, there's an occasional doctor who might be convinced by hearing the patient say that the patient went to see some experts and the expert said that the patient had MCAS, but you and I both know that.

For most doctors, it's not opinions that are gonna sway them. It's hard cold data. It, it's the laboratory evidence that's really gonna convince them. So, again, I understand the challenges, [01:17:00] um, uh, but. When possible, it's usually best to nail down the, uh, the evidence. It just makes it easier for the patients to convince their local doctors, and it just helps them avoid well intention, but nevertheless, wrongheaded treatment decision-making.

Uh, 'cause the, the way the 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 Dr. May go treating a given problem in one way when the patient doesn't have a mast cell disorder, and then may go treating that same problem in a very different fashion when the patient clearly has a mast cell problem.

But you, you have to convince the local doctors and that takes testing. 

Dr. Linda Bluestein: And, and maybe that's a good place for us to [01:18:00] end on. What do you think would be what, um, if, say, say there's a clinician listening right now and they're thinking, okay, I'm, I'm convinced that this could be something that, you know, some of my complex patients have, what tests should I order and, and how should I order them so that I have the highest chances of getting helpful results?

Dr. Lawrence B. Afrin: That's a great question. Um, we probably don't have the time here for me to go into all the details of the specific test to order. Again, it's a highly biologically complex disease, incredible variability, heterogeneity, so nobody should go expecting. It's just one mast cell mediator that's gonna be reliably overproduced in most mast cell patients and not, uh, overproduced in most people who don't have mast cell diseases.

Nowhere near that simple. So there's, uh, quite the menagerie of [01:19:00] 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, uh, the best one would be the paper back in 2020, if I'm remembering right, described the so-called consensus two, uh, approach to diagnosing mast cell activation syndrome.

So if you go to, for example, pubmed.gov and you search for Consensus two, and then mast or mast cell or mast cell activation, consensus two, [01:20:00] I'm sure you'll very quickly get to that. Paper and it, it, it's openly available. It does describe in there the approach to diagnosis and there also are references in there to earlier papers that actually go into even more detail, uh, about the, um, particulars of diagnosis.

Um, that, that's probably the best way to, to start learning about this. 

Dr. Linda Bluestein: That's a great suggestion and I can definitely link that in the show notes because, uh, I'm also a co-author on that paper, so definitely have easy, easy access to that paper. Of course. So, we'll, we'll link that and if, um, I can get from you afterwards the mediator webpage, 'cause I wanna link that as well.

Um, so very, very last thing. As you know, we usually end every episode with what I call a hypermobility hack, but, but you don't have to have a hypermobility hack. Do you happen to have an MCAS hack, which probably also would benefit most people with [01:21:00] hypermobility. 

Dr. Lawrence B. Afrin: Honestly, the best MCAS hack that I can think of to suggest is that when the doctor, and I don't care what type of doctor the doctor is, when the doctor sees a patient who's got a sizable assortment of fundamentally inflammatory plus minus allergic plus minus dystrophic problems, that's the patient in whom it's reasonable to at least start considering whether.

Maybe what's going on in this patient? What's underlying a large extent, maybe even all of the illness that's usually been long going on in the patient. Maybe [01:22:00] what's at the root of it is this disease that you had never previously heard of, never been, never previously been given any reason to think that this 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.

MA, uh, 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, and that is true for mastocytosis. But now we all have to learn there's this other man cell disease, MCAS. And it's not rare. It's incredibly prevalent. It's just that it's challenging 'cause it shows up in so many different ways at the superficial clinical level.

But as long as you're, you're willing [01:23:00] to think about the possibility that MCAS might be what's going on here, that, that initial spark. Of recognition. That's what can then lead you. You may not be the doctor who's actually gonna do the evaluation. You may, you know, 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 trying to find some other doctor who's more familiar with it, you can consult with to get the testing done and all that.

But if that initial spark never happens, h how is the diagnosis ever gonna get figured out? You know? And, and that's the saddest part of all, because the fact is most of these patients seem to have a normal lifespan. And 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 [01:24:00] 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, which 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 pre-treatment baseline the majority of the time. And given that they're gonna live, they're probably gonna live a normal lifespan.

Boy, the quality of life and the remainder of that lifespan is huge, you know? So if you can find a diagnosis that then gets them to treatment, that will get them a better quality of life for decades to come. Uh, that's huge. Even in the [01:25:00] 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.

So every doctor who sees these patients, and it's an opportunity to maybe turn things around for this chronically multi systemically inflamed patient. That's not really a hack. That's way too long to be a hack, but 

Dr. Linda Bluestein: that's okay. 

Dr. Lawrence B. Afrin: That's okay. It's, it's my, it, it's my, it's my best suggestion, uh, that I think will bring about the greatest amount of benefits for not only the patients, but honestly the doctors, uh, boy, when there's so many of them are so close to burnout from having taken care of these very complicated patients for so many years and they [01:26:00] can never find a diagnosis, 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, uh, the health of these patients can be turned around. And it's been interesting to see how many of these doctors told me in follow up that. This has brought the joy in medicine back into their lives.

I, I've come to call it, you know, chicken soup for the doctor's soul. 

Dr. Linda Bluestein: Maybe that's the heck, that's the heck. Um, I, I think that's, I think that's true because I think that so often we feel frustrated 'cause we don't have enough tools in our toolbox. But if we open our minds to this and if we 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, um, I, I, I love that Chicken soup for the doctor [01:27:00] soul. I think that's great. So thank you so much for taking the time to talk with me today. I know that you are extremely busy and you have a lot going on. I know that you're, that you're not on social media, which is, which is fabulous. Um, um, but is there someplace that people can find you?

Dr. Lawrence B. Afrin: At my practice, uh, the Aim, a IM, um, center for Personalized Medicine and Purchase, uh, New York. Uh, the, uh, URL is aim center pm.com. 

Dr. Linda Bluestein: Well, thank you again so very much for, uh, sharing this extremely important information and, and most importantly, for, 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 and, you know, kind of struggle to get answers.

You dedicate so much time. It's amazing, um, with the, the group that you've started [01:28:00] where, you know, the listserv, so many of us put questions on there, de-identified, of course, um, challenging cases and things like that. And you spent so much time helping, helping us for free on your own time. So thank you so much for all of that.

Dr. Lawrence B. Afrin: My pleasure. I enjoy solving puzzles. I think think that's self-evident. 

Dr. Linda Bluestein: Yes. Yes. Most evidently.

Well, I'm so glad that I finally got to talk with Dr. Lawrence Aron 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 [01:29:00] life once we recognize that Mast Cell activation syndrome is playing a role in a particular patient.

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@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 ensuring the podcast.

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