Episode 40 – Mast Cell Mayhem with Dr. Larry Afrin Dr-Larry-Afrin.mp3

00:01 Announcer: Welcome to the Standing Up to POTS podcast, otherwise known as the POTScast. This podcast is dedicated to educating and empowering the community about postural orthostatic tachycardia syndrome, commonly referred to as POTS. This invisible illness impacts millions and we are committed to explaining the basics, raising awareness, exploring the research, and empowering patients to not only survive, but thrive. This is the Standing Up to POTS podcast.

00:29 Jill (Host): Hello fellow POTS patients and wonderful people who care about POTS patients. I'm Jill Brook, your horizontal host and today we have an episode of the POTS practitioners. I am so excited for my conversation today because it's with a clinician and researcher who has hugely improved the world understanding of mast cell activation syndrome. He is truly a major hero of mine for all he's done to help patients like me and to help more doctors learn and appreciate all the many things that mast cell activation syndrome can do. Dr. Larry Afrin is a specialist in hematology, oncology, and mast cell diseases. He was valedictorian of his class with a computer science degree from Clemson University. Then he earned his medical degree from University of South Carolina. He has held numerous senior positions at various hospitals and academic institutions. He has won numerous recognitions for his educational and research efforts. Since 2017, he has worked at the center that he co-created specifically to focus on complex mast cell disease patients. Dr. Afrin has published over 85 peer reviewed medical journal articles and honestly, I kept losing count after that. He has delivered hundreds of invited presentations and lectures throughout the world. He has served on the editorial boards of numerous hematology, oncology, and informatics journals. And he has also served on numerous national committees and boards. He is the author of the first book about MCAS published in 2016 called Never Bet Against Occam, and he is a mentor to many other physicians and researchers who are now learning about MCAS and trying to help patients. Most recently, he was among the very first to notice and publish about the possible role of mast cells in COVID and long COVID, and there's so much more, but I want to let him talk. So I'll shut up now. Dr. Afrin, thank you so much for being here today. I know how busy you are.

02:41 Dr. Afrin (Guest): Thanks, Jill. I appreciate the opportunity.

02:44 Jill (Host): You have probably seen more MCAS patients than any other doctor on the planet. You have published on it more than just about anyone else. You specialize in it when some doctors actively avoid seeing MCAS patients. Can I ask what makes mast cell activation so interesting or important to you?

03:08 Dr. Afrin (Guest): I'm just attracted by the opportunity to help so many people who I guess have been having difficulty finding help elsewhere. I've been very fortunate to get to a point where I can sometimes recognize the presence of a disease and a patient disease that's likely explaining what's long going on in the patient, patient who previously had great difficulties in identifying any explanations, and often had thought they might never understand what's going awry, and I'd never be able to identify any opportunities to get better. And if I see an opportunity to help, well, yeah, that's why doctors go into medicine.

04:06 Jill (Host): Well, in the patient world, I certainly hear lots of stories just like what you're talking about - people who have crazy things going on with them and they thought they would never improve. And then they learn that mast cells can account for it, and that there's actually a way to treat or control a lot of that, and I think your book, Never Bet Against Occam, is kind of about that, right? I know that a lot of patients when they read your book, they think, "Oh my gosh, that is describing me." I'm wondering if you can explain the meaning behind the title of your book, Never Bet Against Occam, 'cause I think it has a little bit to do with kind of what you just were talking about a minute ago. Do you mind sharing?

04:59 Dr. Afrin (Guest): Sure. There is a basic principle or tenet in science. It's not just in medicine, but kind of a basic rule by which our universe operates, that all other things being equal, the simplest explanation is the most likely explanation. It doesn't say that the most widely known explanation is the most likely explanation. It doesn't say the most popular explanation is the most likely explanation. It says the simplest explanation is most likely. So, your listeners are probably familiar with many folks who have developed long lists of medical problems. Many doctors in particular are well familiar with patients who come to see them with astonishingly long problem list - 10, 20, 40, 50 distinct medical problems. And typically, the doctors who consult on these patients, they tend to focus on one problem or a small handful of problems and tend to those problems that they're comfortable in dealing with and they just assume that the other problems are independent issues and they'll just have to leave it to somebody else to deal with it. But at some point, as the problem list grows in length, you have to start asking yourself what's more likely. I mean, is this patient who has so many problems really so unlucky, just so uniquely unlucky as to have coincidentally acquired so many different problems, all of them developing independently of one another? Or is it more likely there's just one thing going on, one process that actually is biologically capable of causing either directly or indirectly, but ultimately one process capable of causing most or all of what's long been going on in the patient? And up until fairly recently in these patients who now we're coming to understand have a mast cell activation syndrome, up until we began recognizing that such a disease exists, we really didn't know of any biological processes that could account for all of what's going on in these patients. The symptoms and the findings in a typical mast cell activation patient, often initially and superficially, appear strange, odd, bizarre, curious, weird, inexplicable to many people, including physicians, whose, you know roughly 10 years of training, has given them one minute of teaching about mast cell biology and disease, teaching them that, yes, there do exist these things called mast cells, but we're not really told where they reside in the body. And we're told mast cells produce two mediators - two of these signaling chemicals, tryptase and histamine. We have a fairly good idea what histamine does in the body. We have fairly little idea what tryptase does in the body. And that's after decades of research. And we are taught that there is really only a couple of areas of disease that mast cells are involved in. We're taught that they're involved in allergy, particularly anaphylaxis, and we are taught that there is this rare mast cell disorder, essentially a cancer of the mast cell called mastocytosis. Now fortunately, in most people who have that rare disease, it's a very slowly progressing cancer that really does not impact on the longevity of the patient's life, so that's good. But nevertheless, those patients often can have many symptoms that are often actually somewhat bewildering. And the symptoms that go well beyond, you know, allergies and anaphylaxis, and it's hard to make sense of what's going on in this disease when you look at these cells and think of them as nothing but producers of two things, tryptase and histamine, and it's easy to understand how if that's all you know that these cells do, there can't really be much capacity in these cells to cause much trouble by producing, you know, inappropriate amounts of histamine or tryptase. And the fundamental deficiency here is that what the biologists have been learning for many decades now is that mast cells actually produce not just a couple of mediators, but actually more than 1000 mediators, and each of which has a huge range of effects all throughout the body. And once you start understanding that that's the reality of the biology here and that the particular symptoms that are seen in any given patient with the mast cell disorder are entirely consequent to the particular pattern in that patient of inappropriate mediator production and release by the patient's dysfunctional mast cells has different mediators, which naturally have different effects, but if you have inappropriate amounts of those mediators being released by different mast cells and different parts of the body, different mast cell patients are going to have different symptoms and different findings. And the initial weirdness of all this starts to make a whole lot more sense once you start better understanding the frankly pretty complex biology of these cells. But doctors today have not really been taught about any of this. So, once you start understanding this biology exists, then you start realizing there really is a way that the human body can go awry, just one root process - misbehavior of the mast cells in one pattern or another, that actually can lead to such a vast array of otherwise inexplicable symptoms and findings in these patients. And so, when patients present to a doctor and they have such a large assortment of problems, then it's probably better to presume, I mean, again, this is Occam's razor, probably smarter to bet with Occam that there's likely one root explanation for everything that's going on. Even if you don't yet know what that explanation is, still, it's more likely that there's one explanation rather than betting against Occam and assuming that all of these different problems in the patient have come about independently of one another. We have to be a little careful with this. Yes, mast cell disease can account for most or even all what's going on in most patients who are proven to have a mast cell disorder, but at the same time the doctor who's attending to a mast cell patient, and even the patients themselves always need to keep in mind, that just because they have developed one problem - a mast cell activation disorder of one type or another, whether the rare mastocytosis or the far more common mast cell activation syndrome, but just because they've developed that mast cell problem doesn't necessarily mean they can't develop other problems. So anytime new problems arise in a mast cell patient, both the patient and the doctor have to be careful to put the brakes on themselves and not instantly assume that the new problem is necessarily due to the mast cell disease. In the end, if you can't identify other causes of a new problem and if the new problem is something that mast cell activation can account for then, then probably most likely again goes back to Occam, Occam's razor. It's most likely there's just one thing going on that's accounting for all that's being seen in the patient. That was a really long answer to a simple question.

14:42 Jill (Host): No, that is a fantastic answer and I think that you are such a generous physician and you tend to, I think, listen to your patients and believe your patients that you didn't mention the other hypothesis that can account for a lot of different symptoms, and that is that the patient is crazy, or a hypochondriac, and I think that is maybe the Occam's explanation that some physicians go to, but that's why people like me are so grateful for your book and for your work, because even if we didn't have mast cell treatments that were effective, and we do, and that's fantastic, it's worth so much to me just to have an alternate explanation than I’m crazy.

15:29 Dr. Afrin (Guest): Well, to be fair to the doctors, I mean, there is a psychiatric disorder, goes by various names, the somatization, psychosomatic disorder, conversion disorder and so on and so forth, where due to some primary problem in brain circuitry somewhere, patients literally do imagine that they are enduring some particular or symptom. Well, we know that exists, but it's a pretty rare phenomenon, actually. But unfortunately, when a busy doctor who only has a very brief amount of time that he in truth can afford to spend on thinking about what might be going on in the individual patient, and he looks at this array of symptoms and findings and he hasn't been taught about any disease that can physically explain all of the symptoms the patient has been reporting. It's a little easy to understand how as a kind of a fall-back diagnosis, the doctor might just say, "Well, you're dreaming it up. I don't know why and I'm not a psychiatrist. I don't know how to how to deal with this, but I don't have any other explanation." And unfortunately, that's again, it doesn't really jive with what Occam's Razor teaches us, because again, rare things happen rarely, and psychosomatism is rare. So, it's more likely that what's going on in the patient with you know, 50 problems that don't seem to jive, it's more likely there is one thing going on. It's just one thing the doctor doesn't know about. And therefore, in truth, probably the better way for the doctor to approach such a patient is to say, "Look, I just don't know of any disease that can well account for most or all of what's going on, and you know there's a, there's a possibility that you might have this rare psychiatric phenomenon of psychosomatism. But it's a pretty rare thing." And furthermore, in patients - puzzling patients - who not only have a lot of strange symptoms, but on top of that they've actually got laboratory findings that the physician also cannot explain, well at that point, it gets even harder to understand how a psychiatric disorder could actually drive the various physical systems in the body to manifest various abnormalities on different lab tests. So again, in that situation, it's just more likely there's something going on that the doctor just doesn't know about. So looking back on medical education these many years, I I won't tell you how many years I'm out of school, but if there's one thing I wish I could have been more emphasized in the education I got, it would have been teaching the doctor to just be more more humble, more willing to acknowledge the limits on the doctor's knowledge. One generation has been teaching the next, which has been teaching the next, and so on and so forth. This is a rare disease and now all of a sudden we have to say, "Wait a second. That's not right at all. Actually, this is a very common disease. It's just that the form of the disease that's very common is something you never learned about before, and so when you were taught mast cell diseases or rare disease, now that part of your teaching was wrong. Turns out, if you were told mastocytosis is a rare disease, yeah, that part is right. But if you were told that mastocytosis is the be all and end all of mast cell disease, and therefore if you just establish in your head an equivalency between mastocytosis and mast cell disease, that's where you take the wrong turn."

20:14 Jill (Host): Is it correct that some German research suggests that up to 17% of the population could have the right genetics to develop mast cell activation syndrome?

20:26 Dr. Afrin (Guest): You know, despite all the smart doctors in the history of medicine, it's really only been in, oh, roughly, the last 15 years or so that a few doctors around the world have been coming to recognize the existence of this other mast cell disease that we're now calling mast cell activation syndrome, or MCAS. So, that's not a whole lot of time for much research to have been done, and in truth very little research has been done, and I think it's only fair to characterize all the research that has been done so far as preliminary. But with all those caveats stated, the little bit of epidemiologic research that's been done in the MCAS arena so far indeed does appear to be suggesting this disease is very prevalent. You're right that Dr. Gerhard Molderings and his colleagues, mostly at the University of Bonn in Germany, did a study a number of years ago, suggesting that about 17% of the general German population likely has MCAS. I actually saw another small study here in the US just last year that suggested it was actually about 20%. And I'm aware there are some investigators in the mast cell arena who continue to think that MCAS is a pretty rare disease, not much more common than the rare disease of mastocytosis. But, what can I say? I respectfully disagree with those perspectives. And one possibility is that some doctors who are still thinking the disease, that that the MCAS is rare just may not yet be all that willing yet to accept the vast range of problems that the disease can can cause. Listen, let let's acknowledge again, this is an extraordinarily complex area of biology and medicine. I don't think it's possible to find another disease that's more biologically complex than this disease. So the truth of the matter is everybody is at an embryonic state in developing their understanding of this. We're going to be working on this for decades, if not centuries to come. Nevertheless, I've learned the hard way that if both the patient and the doctor, both of them, can put forth sufficient patience and persistence and some degree of method to their madness in trying to get to a point of diagnosis and then identify helpful treatment, you know with patient's persistence and method, in most cases we actually do manage to nail down the diagnosis and actually find some cocktail of mast cell targeted treatments which will get the individual MCAS patient to a significantly better state than they previously had long been enduring.

23:58 Jill (Host): And that's a really hopeful message. I always am happy when I see you mention that. But you had mentioned research and that's one thing where I'm very interested in any potential links between MCAS and POTS because this audience and the nonprofit that hosts this podcast, we all are involved in funding research that can help POTS patients. And there I know are some of your colleagues think that one of the biggest causes of POTS might be MCAS. Now, I have heard others of their colleagues say that maybe it's a chicken and the egg - maybe POTS contributes to MCAS. Do you have any thoughts? I know there's not really any existing research or proof, but are there any possible links between MCAS and POTS that make sense for why - I think it's about 30 to 40% of POTS patients are diagnosed with MCAS in some studies. Any ideas there about the connection?

25:02 Dr. Afrin (Guest): Yeah, there actually are some intriguing possible linkages in the little that is presently known about the biology in these areas. I guess part of it, you have to understand some anatomy, and you also have to understand some biology. If you're going to try to figure out how the mast cells could bring about POTS among the many, many many, many other problems that mast cell disease can bring about. And you first have to understand, well where are the mast cells in the human body? And in truth they're virtually everywhere. They're in every vascularized tissue in the body, and that's just about every tissue in the body. But in most tissues in the body, they're pretty sparsely distributed. You could actually go doing a random biopsy in most tissues in the body and examine that biopsy under the microscope, using all the best techniques you've got for identifying mast cells in that specimen. And in most tissues in the body, a random biopsy would not show you a single mast cell. So very sparsely distributed in most tissues. Where the mast cells are dominantly sighted is at the environmental interfaces - so the skin, the respiratory tract, the gastrointestinal tract, and the genitourinary tract, so the environmental interfaces - and in the walls of all vessels and nerves in the body. And this is, if you think about it, given that the mast cell has a crucial role in the immune system in the body's defense systems. So this is where you want them to be - principally located so they can best serve their principal role in the body, and the first line of defense against assaults and insults upon the body. I mean, the other parts of the immune system - they, they do react to assaults upon the body too, but not nearly as quickly as the mast cells do. For example, lymphocytes often take hours to activate upon becoming aware of an assault. Neutrophils take minutes to activate. The mast cell can activate in sub-second time. It's kind of the frontline defender. It's what's going to most rapidly sense any assaults on the body. So, you'll want it in all of these particular places I listed - the environmental interfaces and the walls of all the vessels and the nerves. So, that's an important piece of anatomical knowledge there to know that if you go doing biopsies in those tissues, oh yeah, you'll easily see mast cells in those tissues. So beyond the anatomy, you got to understand a little bit of the biology here. Again, this relates to the mediators that the mast cell puts out, and again these cells put out more than 1000 mediators and many of them do have inflammatory roles. This is why the universal constant clinical feature of mast cell disease is chronic, multisystem inflammation. But there are plenty of other mediators that have lots of other effects which wouldn't necessarily, you know, by default, go thinking of as inflammatory effects. And these other mediators include some mediators that actually have the ability to influence the state of blood vessels and also influence the activity level of muscle cells and the activity level of neurons. So, imagine that you've got some mast cells, in particular, some dysfunctional mast cells that are prone to, every now and then, just go releasing various and sundry of their mediators for no good reason. And imagine you've got a number of these dysfunctional mast cells in the walls of, say, an artery - very important for supplying blood to some major organ in the body, like the heart or the brain - and imagine if these dysfunctional mast cells were to suddenly inappropriately release into the tissues surrounding the mast cell. And again, we're imagining mast cells that are in the wall of the blood vessel, and imagine they suddenly release a large load of a mediator that happens to have the ability to intensively constrict the blood vessel. Well, what's going to happen? The blood vessel is going to constrict, and the amount of blood flow through that vessel is going to be greatly reduced, perhaps even entirely choked off. And if that happens, just as an example, in an artery that feeds blood to the heart, say one of the coronary arteries, what's going to result? A heart attack, you know. The same thing that would happen if there had developed a cholesterol blockage inside the artery, right? But it's a totally different mechanism by which the blood flow to the heart gets choked off.

31:27 Jill (Host): And could different mediators do the opposite and dilate that blood vessel too much?

31:32 Dr. Afrin (Guest): Now you're thinking like a mast cell biologist. And yes, there are mediators that can intensively dilate a blood vessel. So what would happen if, say, mast cells in the carotid artery that's feeding blood to the brain were to suddenly release vasodilatory mediators that would dilate the carotid artery? What would happen with the pressure of the blood going through that artery? That would dramatically drop, and if the pressure drops then the amount of blood being delivered to the brain very quickly abruptly drops and you have the lightheadedness, the the dizziness, the the weakness, the near blackout that we sometimes call presyncope. Sometimes you even just totally black out. But these mediators that get released, many of them, including the ones that bring about the most dramatic effects in the body, like squeezing the blood vessels or dilating the blood vessels, they have very short lifespans in the body, once they get released from the mast cell. So, for example, some of these mediators that constrict or dilate the arteries and sometimes the veins as well, they will disappear. They'll be metabolized by various chemical systems in the body within a minute or so of being released from the mast cell. Let's go back to the situation of vasoconstriction. So, the coronary artery constricts due to misbehaving mast cells in the wall of the coronary artery, and blood flow gets cut off. The patient starts developing a heart attack, develops chest pain, goes to the emergency room. The EKG is put on the patient and the blood is drawn looking for the chemical signs of a heart attack. And right there within two minutes, the emergency room doctor is saying that's on the EKG tracing that, "Oh my goodness, the patient really is having a heart attack," and then the the word comes back from the laboratory 5 minutes later that the blood sample - Yep, there's a clear chemical sign of a heart attack there. Well, the ER doctor knows that a heart attack is coming about because say, coronary artery has become obstructed. So what do you do about that? Well, you have to open the artery, so you'll rush the patient to the catheterization laboratory where, fortunately, cardiologists and interventional radiologists are waiting to immediately put a catheter in the patient's femoral artery and they snake it up into the coronary arteries, and they inject dye to highlight the contours of the coronary arteries to try to identify which coronary artery has been obstructed. And it takes time, of course, to get the patient to the cath lab and to start the catheterization process. And at the point the dye is squirted into the artery, the cardiologist is then flabbergasted to see that there are no blockages whatsoever. My goodness, how could it be that just 15 minutes ago the EKG and the blood work was clearly showing that there was a heart attack and there had to have been an obstructed coronary artery, and yet there is no obstructive coronary artery. So, what's happening is that in the, you know, the the 15 minutes it took to get the patient from the ER to the cath lab, all those mediators have been pouring out of the mast cells in the walls of the coronary artery to constrict the artery shut, those mediators are gone and the artery has relaxed. Blood is flowing again. Unfortunately, blood is now flowing again to heart tissue that died for lack of blood flow. So the patient is still had a heart attack, but there is no obstruction any longer in the artery. So this is a phenomenon that cardiologists have come to know as allergic angina or vasospastic angina or Kounis syndrome. And it can happen, of course, not only with coronary arteries, but fundamentally any artery anywhere in the body. So, if it happens in a cerebral artery, no surprise that that patient would develop a stroke, but then when the scanning is quickly done in the ER to find which blood vessel has become occluded to lead to the stroke, once again, the radiologist is and the neurologist is there, they're flabbergasted to find that there is no obstruction. So, in the same fashion that, you know, this type of mast cell dysfunction can constrict the blood vessel, yes, there are other mediators that can lead to dramatic dilations of blood vessels, and this can drop the blood pressure briefly. But you can imagine that by the time the patient gets to any doctor and undergoes any testing, those mediators that were causing the dilation are long gone and so testing of all sorts on mast cell patients, which typically occurs many minutes often hours, sometimes days or weeks beyond the point at which they had a sudden strange event. Testing is normal, and it's just one more reason why the doctor who is not familiar with mast cell disease says, "Oh, you're normal. You're healthy, there's nothing wrong with you. You're imagining it all." Now, there was a real event and it's just a matter of coming to understand what processes could have actually driven that event and then disappeared so mysteriously. So whether it's these vasoconstrictive or vasodilatory mediators that are directly causing the vessels to constrict or to dilate, or perhaps what's going on is that these dysfunctional mast cells in the walls of the vessels or the walls of the nerves, and remember that there are many nerves in the body that terminate in the walls of the blood vessels, 'cause the nerves help control as well the state of muscular contraction and relaxation of the blood vessels. So maybe these mast cell mediators that are inappropriately coming out of the mast cells, maybe these mediators are directly driving contraction or relaxation of of the muscles in the walls of the blood vessels, or maybe these mediators are actually impacting the functioning of the neurons that are also in those areas and driving those neurons to then send various impulses to the muscles in the walls and the vessels that again will either cause constriction or dilation. All of this biology needs to be worked out, but bottom line is that is there anatomy in biology that makes it possible for misbehaving mast cells to drive POTS? Yes. You know, another theory that's been emerging in the last few years regarding potential causes of POTS is that it's various autoantibodies that are targeted against perhaps the endothelial cells in the blood vessels that make up the walls of the blood vessels. Or maybe it's autoantibodies against the muscles that accomplish the construction and the dilation of the blood vessels. Maybe it's autoantibodies against the nerves that provide the impulses to the muscles in the walls of the vessels that lead to ultimately the dilation of the blood vessels, the acute dilation of the blood vessels that leads to a drop in blood pressure, and therefore the symptoms that we see in POTS and the abnormalities and blood pressure and pulse responses that we can easily see in patients who have POTS. And especially given that another one of the many, many, many, many effects that mast cell disease can have on the various systems in the body is to actually drive the immune system - the antibody producing part of the immune system - to start spuriously producing all sorts of antibodies that the immune system has no legitimate business producing. This is another way in which mast cell disease might be involved in the development of POTS. That said, there's also a little kink or hiccup with the explanation that it's autoantibodies that might be principally driving POTS, in at least some portion of the POTS population and let me make that clear, too. POTS, like MCAS, is a very complex disease and it's almost certain that there are multiple different mechanisms that are driving what we clinically call POTS, what we clinically recognized as POTS, different mechanisms in different patients. But, with regard to whatever portion of the POTS patient population in whom you think the problem is being driven by autoantibodies, I think one of the difficulties with that explanation - and maybe it's just that we don't yet understand enough about the biology of all this - but one of the gaps in that explanation there is that if you have these autoantibodies, I mean the way that antibodies are made in the body, they're produced by, you know, a particular part of the immune system. And once a given antibody has been produced, it actually has a half-life in the body of about three weeks. So if the immune system is producing enough antibodies, and usually when the immune system starts at normally producing a given antibody, it just persistently produces that antibody, and if those antibodies are going to stick around for weeks on end, and yes, the individual antibody eventually gets metabolised and broken down. But meanwhile, the immune system is just making more and more of those abnormal autoantibodies. So why would it be that the folks who have POTS, they have episodes of POTS, why wouldn't it be that they're always having troubles with constricting their blood vessels? Why are they not always having inappropriate dilation of the blood vessels that leads to the low blood pressure that leads to the high heart rate and all the symptoms that they have from those. And yet, in most people who have POTS, they're well aware it fortunately is not a 24 by 7 problem. It's an episodic problem.

44:17 Jill (Host) That's a great point.

44:19 Dr. Afrin (Guest): That doesn't fit all that well, if you're imagining that there is an auto antibody floating around in the body, and it's got a pretty stable level in the body across the course of weeks, if not months or years. Then why is the clinical behavior of the disease not being seen in a more stable fashion? Why is it episodic? The episodic behavior of POTS frankly fits a whole lot better with these spastic flares, these spastic degranulations of the mast cells, these dysfunctional mast cells that they get triggered and there's a huge array of things that can trigger mast cells to activate and to release their mediators, but it's a very rapid process and it's an episodic pulsatile process. And that's the process that fits a whole lot better with the clinical behavior in POTS. Now, it doesn't mean that the autoantibody hypothesis is wrong. It may be that there's just some other complex piece of the biology here that’s connecting the stable production of an autoantibody with the episodic behavior of the mast cell. Maybe to get these sudden dilations of the of the arteries, you have to have a combination of an autoantibody against a neuron or against a muscle cell or an endothelial cell, and that you have to have some complex interaction between the stable presence of that autoantibody together with God knows which mediators that are acutely flooding out of an inappropriately activated, dysfunctional mast cell. Who knows? I mean, I don't doubt that in time, the research will be done which will figure out at a molecular level the biology of what's going on in each different type of POTS patient. But from what I can see of the research landscape, we're still a good ways off from figuring that out. Listen, you and I both hope that research gets done in the next year or two, but nobody should be surprised if it's another few decades before we finally put all the molecular pieces in place in this vastly complex jigsaw puzzle.

47:15 Jill (Host): Well, I know that you are pulling your weight and you are actively involved in tons of research and we sure appreciate all of that. And I try to help out with statistics here and there on projects where I can hopefully speed things. And I do hope that more and more POTS patients and POTS organizations get interested in funding research on MCAA, and I think that some of the researchers are starting to do more of the intersection between the two. And I know I can't keep you much longer. I'm so grateful for the time that you've spent, but your book - I really feel like your book, I just want to encourage all of our listeners to read it, because if they are enjoying hearing about the mechanisms by which mast cells can cause so many of these different problems, that's really what your book is about, right, is explaining a lot of these possible connections?

48:15 Dr. Afrin (Guest): It's showing how there's an explanation for all of the odd initially inexplicable behaviors that are seen in these patients. There is an explanation, and in fact all of the different explanations, the further different behaviors, it actually all traces back to misbehavior in one pattern or another of the mast cell. Now, we have to be careful, too - let me let me give the caution too - that even though mast cell disease can cause a huge array of problems, there are other diseases too, which through their own unique molecular mechanisms can also cause a vast range of problems in the body. So I'm - please don't go thinking that I'm asserting that every chronically mysteriously multisystemically ill patient necessarily has MCAS at the root of their troubles. That would be silly to say. But life is too complex for everybody with multifaceted mystery is to ultimately have it rooted in just one problem - mast cell disease. So I'm not saying that that. But at the same time, I think we do need to start acknowledging that we might have thought mast cell disease was a rare disease before, but no, it's just mastocytosis that’s rare, and actually MCAS is quite common. And so it's turning out that a hefty proportion of the many patients out there who had chronic, mysterious, multisystem illnesses probably do have one variant of MCAS or another at the root of their troubles. And I think this sooner the doctors can begin learning about this, and that actually gets back to the medical education systems, then this sooner we're going to be able to start helping all of the many patients. I mean, think about it. If it's really as prevalent as the preliminary research is saying - 17 to 20% of the general population - the fact is that there are hundreds of millions of these patients out there, and it's just that the vast majority of them have not yet been recognized as having MCAS at the root of their troubles, and, you know, that's unfortunate, but hopefully as education advances, then we'll be able to increasingly recognize these patients and find the treatments that will help them.

51:14 Jill (Host): Well, Dr. Afrin, thank you so very much for all your research, your compassion, your tireless work to help more doctors learn about MCAS. I'm always amazed at how patient and thorough and generous you are with your time and your knowledge to patients and doctors. So, thanks a million, and can we convince you to please never retire?

51:38 Dr. Afrin (Guest): If only that were possible. I’m as human as anybody else, so we'll see how long I can keep it up. Well, we'll see what happens. I'll keep doing what I can for as long as I can.

51:50 Jill (Host): Well, we are so full of gratitude for all you've done and all you continue to do. So, OK listeners, as always, this is not medical, dental, spiritual, fashion, menu, or relationship advice. Consult your physician about what's right for you. Please consider subscribing because it helps us get found by more people like you. But most of all, thank you for listening. Know that you are not alone. And please join us again soon.

52:19 Announcer: You can find us wherever you get your podcasts or on our website, www.standinguptopots.org/podcast And I would add, if you have any ideas or topics you'd like to suggest, send them in. You can also engage with us on social media at the handle @standinguptopots. Thanks for listening and we hope you join us. This show is a production of Standing Up to POTS. © 2022 Standing Up to POTS. All rights reserved.

[Transcriber’s note: If you would like a copy of this transcript or the transcript for any other episode of the POTScast, please send an email to volunteer@standinguptopots.org]