- Symptoms of mast cell activation, history of Mast cell Activation syndrome
- Understanding the Biology, mast cells
- Understanding mast cell testing Tryptase & Histamines
Eric Gordon, M.D.
Good afternoon. This is another edition of Mycotoxins and Chronic Illness and today we have a treat. It’s a chance to discuss with Dr. Larry Afrin, all things mast cell. Dr. Afrin, is a hematologist oncologist, he went to the University of South Carolina for his training but what he has done, what makes Dr. Afrin, I think a very special physician is that he was a hematologist oncologist, but he never stopped thinking that something else could be happening with his patients. When things didn’t make sense, he didn’t decide that the patient was, you know, anxious and depressed or confused, or more importantly had 10 different unrelated illnesses. And Dr. Afrin wrote the book, “Never Bet Against Occam” which I think everyone should read, especially anyone with a chronic illness. I can tell you, I had some idea that mast cells were a problem because I had a patient who actually had some mild mastocytosis, but until I read Dr. Afrins book, I didn’t see all the connections. You know, I was still looking for rashes and maybe a little GERD. So, over the years, Dr. Afrin has taught the doctors, but most importantly as we’re gonna see, he’s taught the patients because it’s hard to get doctors to think about new things. So, Dr. Afrin, can you just briefly, ’cause I think it’s really important for people to understand, you know, how you actually got into this? I mean, what made you say, oh, maybe this lowly mast cell is doing something else than just causing allergies and a rare cancer.
Lawrence Afrin, M.D
How did I get into this? Well, that probably starts with chapter one of the book and chapter two and three but to summarize, I was confronted in early 2008, by a patient with a curious hematologic abnormality that had been diagnosed by another hematologist in a particular way. And she had received quite a bit of standard treatment for that diagnosis at the hands of that other doctor but she wasn’t getting any better. In fact, she was only getting worse and she came to suspect something was being missed and so she went looking about for another opinion and long story short landed in my clinic and it was immediately apparent to me that she didn’t have the diagnosis that she had been given ’cause I know that disease and her illness wasn’t behaving anything like how that disease is supposed to behave.
So then the question became, well, what do you have that can not only bring about the features that led to that kind of superficial appearance that she might have that other diagnosis, but also have the 573 other problems that had been developing in her in which her other doctors had either been discounting or ignoring. And it took nearly a year to work it out and in the end, all I knew to label it as, ’cause the term mast cell activation syndrome had not really emerged at that point, but so I wound up calling it an atypical mastocytosis and with treatment, which is a whole nother story in itself, she actually came back in just a month and was remarkably better. And have I actually continued doing very well for about a dozen years now. But from all that I had learned in trying to figure out what was going on in her, I began to realize that a number of the other mystery patients that I had seen over the years of my career to that point, that at least some of them might also harbor this atypical mastocytosis, just manifesting in very different fashions.
And the more I began looking for it now that I had learned how to see it, the more I began looking for it the more I began finding it. And the more I began finding it, the more I began treating it and lo and behold, these poor people who had been unwell in so many different ways for years, often decades, sometimes even almost our entire lives, and obviously quite often come to be dismissed as a psychosomatic and the like, even if they had been sick for decades. Once we made the right diagnosis and started applying the treatments that are appropriate for that diagnosis it was amazing how much better they got and with patient after patient after patient, actually, it was only about, gosh, the second and third patient and by that point, the term mast cell activation syndrome was just coming into the literature and I began realizing, yeah, that fits this much better.
‘Cause this absolutely was not mastocytosis by any of the criteria that we know that disease by, but it absolutely was a mast cell activation syndrome. And I began realizing that in polar contrast to the rarity of mastocytosis, MCAS actually is exceedingly common. The challenges are, it’s just the biology of it is such that it’s guaranteed to present with an extraordinary heterogeneity that can make it very difficult to recognize it at the superficial level because superficially one patient can look very differently from the next and the next. But eventually you learn that there are patterns to it, and eventually you learn how to recognize them, but I’ll be the first to admit it, it’s challenging.
Eric Gordon, M.D.
Yeah. Well, you know, there’s two things. One thing we’re gonna get to, we’re gonna talk a little bit about maybe not the depth of the biology, but just how important it is to realize the different manifestations of a histamine or not just histamine obviously, or other chemicals that mast cells can release in different tissues. So we’re gonna definitely dive a little bit into that. But one of the things I like to make clear to the people listening, is this how doctors think, ’cause I think, you know, I know, I don’t think I know, that has been the great frustration of many patients and they’re often angry with physicians and I always like them to have a little compassion, is that there are very few doctors, very few people go into medicine wanting to ignore people.
It’s just kind of how we’re taught in the concept of, you know, especially now that they’ve constrained the time limits where people are seeing people for seven minutes or 10 minutes, it is very much like a very old Groucho Marx joke that only people my age and probably your people’s parents and grandparents remember, but you’d say the magic word and the duck would drop down and you’d get a hundred dollars. Well, that’s how people practice medicine. You say the magic phrase, the symptom, you know, that fits a diagnosis, and that’s what you got. Now, the fact that you’ve got all these other symptoms that don’t fit the diagnosis in five or 10 minutes is ignored because it’s noise and here’s your diagnosis and here’s your prescription and what a good boy I am, and next.
So anyway, that’s what’s happened to medicine, but it’s not because doctors inherently don’t want to help you, it’s just that we have trained them in this model of like, you know, X equals your diagnosis and people are much more complex than that. You know, it works again for my favorite story is broken legs. You know, you get the x-ray, you see the thing it’s clear cut, we know what to do. But with chronic illness, and especially when you are involved in illness that is being magnified by a cell that I’m gonna let you talk about that is everywhere, it’s lots of places in your body, it can begin to cover the possible symptoms that can lead you to this diagnosis.
So on that note, let’s talk a little, I mean, and I just wanna say, I really think the… I know you like to do a lot of testing because you feel like, you know, you are the expert and it’s really important that you prove the point, but other than the testing, I like people to think about, and we’ll talk about that a bit, is the protein symptoms, symptomatology that this illness can cause. I mean, can we just run through really quickly, maybe just head to toe, you know, like where are your big hit? I know you can’t do everything but you know.
Lawrence Afrin, M.D
Running through head to toe, all the possible symptoms will probably take the rest of the hour.
Eric Gordon, M.D.
I’m sure. But I mean, just hit some of, maybe the high points.
Lawrence Afrin, M.D
It’s probably best to look at it from what the general themes are. The universal constant… First of all, let me backup just a little bit about biology. It’s very important to understand the doctors go through their roughly 10 years of training and in all that training, all that time, they by and large get taught that the mast cell and they really aren’t even taught where the mast cells are in the body, but they’re taught that the mast cell produces two mediators, tryptase and histamine. And that’s the be all and end all of it. And that’s really all the time there is to teach them about what the mast cell does because out of 10 years of training, one minute is spent on teaching about the biology and the diseases of the mast cell.
And that makes sense when you understand that the only disease of the mast cell that previously recognized was the very rare disease of mastocytosis that most doctors after 10 years of training, they’ll go out into practice for the next 30, 40 years and most doctors will never see a case of it. So if it’s such a rare disease, I can understand why the medical schools wouldn’t invest more time in teaching the students about the biology and the diseases. So when a cell is thought to produce only a couple of outputs, a couple of mediators, anybody could be forgiven for a failure to be able to imagine that any significant range of troubles could come about from disorders of that cell. But here’s the thing, the actual known biology of the mast cell, turns out that the mast cell is known now to produce and release more than a thousand mediators.
Eric Gordon, M.D.
And will come up.
Lawrence Afrin, M.D
Each of which has a huge range of effects throughout the body, direct effects, indirect effects, local effects, remote effects, acute effects, delayed effects, chronic effects. And the mast cell also is now, you know, it used to be that the only receptor we were taught in our training about mast cell is that the mast cell is a receptor for the IgE class of antibodies. And that’s true but turns out that the mast cell actually is now known to have more than 250 different receptors. So that’s an extraordinary range or scope within which the mast cell has potential to interact with other cells and organs and systems in the body in an extraordinary number of fashions.
So when you look at such a broad array of mediator output, and you try to understand in spite of all the different things, different specific effects that each mediator’s having, if you try to divine what are the themes of what’s going on? Actually three specific themes do emerge. The first theme, and this is the universal constant of mast cell activation disease. All mast cell activation features this in one fashion or another, to one degree or another, and that’s inflammation. Chronic multi-system inflammation. Each of those words is important. The chronic, because it’s there all the time. Yes, from time to time there are flares to heightened levels of inflammation, sometimes even the disease can sort of transform in a fashion and escalate permanently to a whole new baseline level of chronic inflammation, but it’s inflammation.
And you know that the manners, the specific manners, in which inflammation manifests in different areas of the body leads to very different symptoms depending on which organ, which tissue, which system is inflamed. And this is a large part of the heterogeneity, the superficial heterogeneity of the disease. So chronic is important. Multi-system is important. Every system in the body has potential to be affected by this disease. That doesn’t mean that every system will be affected, but every system has potential to be affected. And the fact is there are no mast cell patients who are being affected in just one system in their body. All mast cell patients are being affected by at least a few systems. And then inflammation.
Well, yeah, that is the universal concept of this. But then beyond all the different ways that inflammation can manifest in the body, there are a couple of other themes, but they’re not constants. So I like to say, plus minus allergic type. So it’s chronic multi-system inflammation, plus minus allergic type phenomena which can range anywhere from simple allergies to flagrant anaphylaxis, to angioherias and angioedemas and so on and so forth. And I say, plus minus because there are plenty of mast cell activation patients who honestly do not have a speck of allergic type issues to them. And then at the opposite end of that vast spectrum, there are those unfortunate souls, thankfully not too many of them who are literally in 24 by seven anaphylaxis, if you can even imagine such misery.
And everybody else with mast cell activation is somewhere between those polar opposite ends of the allergy spectrum. And then there’s another plus minus. Plus minus abnormalities in growth and development, in potentially any tissue in the body. And how does that come about? It’s because a number of the mast cell mediators actually are integrally involved in guiding growth and development processes in all the different tissues in the body. So you can imagine that if you had chronic abnormal output of these growth influencing mediators, then depending on which mediators are being expressed inappropriately in which amounts, at which times, and over which durations and at which points in the body, you can imagine a vast array of abnormalities in growth and development.
What we really call diastrophism. There’s a vast array of diastrophism that can emerge. And again, depending on the tissue that you’re talking about, the symptoms just can be vastly different from one organ to the next, the next. So those are the general themes of this. So if you see a patient who’s, you know, got a problem list of 57 different diagnoses, and you just take 15 seconds to step back and look at the big picture of what’s going on. And if you see that item after item, after item, after item on the problem list is, itis, itis, itis, itis, inflammation, inflammation, inflammation, inflammation, you have to stop and ask yourself at some point, whether it’s 20 diagnoses on the problem list or 40 or, or 60, you have to stop and ask yourself, what’s more likely? Is this patient so uniquely unlucky as to have coincidentally acquired so many different diseases, all of them developing independently of one another, or do they have one thing going on that is actually biologically capable of causing directly or indirectly most or all, probably all, of what’s long been afflicting them? And the obvious answer in the universe we live in is that it’s more likely they’ve got just one thing going on and the question all along has been, what disease is, is there a disease that is actually capable of causing all those different problems?
And now in just the last dozen years or so we’re beginning, just beginning, to understand, yes, there really is a disease that can cause such a vast array of generally inflammatory and allergic and dystrophic-like problems. Now, let me make it clear that I’m not saying that every chronically, multisystemic, mysteriously unwell person necessarily has a mast cell activation syndrome at the root of their are many problems, what I’m saying is we’re now understanding that mast cell activation syndrome in contrast to the rare disease of mastocytosis, mast cell activation syndrome or MCAS is a very prevalent illness.
And so when the doctor now sees a patient with these general themes about them, it becomes very reasonable to consider MCAS in the differential diagnosis, at which point the doctor needs to vet that diagnostic possibility just like he’s gonna vet the other diagnostic possibilities in the differential diagnosis. And when in the end it turns out that it really is a mast cell activation syndrome that can better account for all of what’s been going on in the patient and if you can find, ideally if you can find at least some laboratory evidence demonstrating mast cell activation, then at that point, likely a mast cell activation syndrome is the principle, the root diagnosis in that patient, and you can then set about trying to treat the patient accordingly.
Eric Gordon, M.D.
Well, I love how you laid that out. I mean, from my worldview, I look at, you know, mast cells as another one of those regulators of the terrain, you know, and yeah, there are people who, how do you say it? It’s sometimes, you know, many people have minimal hints that their mast cells are a little quick to fire. You know, there’s people who have had allergies since they were kids. I mean, those are the easy ones, you know? But then when they get older, they develop either exposure to other toxins or illnesses, then we lose regulation of the system and the mast cells start to make noise all over. And depending on the individual, that’s the point because we see people with, a handful that I’ve seen, with severe, for instance, the CCI, the Craniocervical Instability with terrible mast cells.
I mean, the mast cell is, and it’s a circle. The mast cell is supposed to be what the histamine and other chemical released is what’s tenderizing their ligaments. So that’s what makes it worse. And when you can control their mast cells, the other symptoms may often improve quite a bit. But also when the few, the handful that have had surgery, and stable ’cause they were so severe, they need it. I mean, it’s not something you would do unless you were like, you know, bedbound life didn’t exist, but the mast cell stuff disappears, sometimes disappears, but dissipates remarkably because you know, the beauty of the body is that we’re all one big soup. And when you keep your brain brainstem inflamed, it sends signal on, or but irritated, it signals danger to the whole body and your mast cell, and that’s what I’d love to hear you, from my understanding, is like one of the more primitive immune cells that we have and it’s gonna be set off.
So, you know, so again, there can be circles and if you can, so many people, if you control the mast cell, the symptoms go away and the body kind of restores homeostasis but sometimes we have to, you know, and I said, and we’ve had this discussion over the years, and I think you’re now agreeing that, you know, occasionally there are chronic infections that can also be triggers, because that’s been our experience. Is that in the old days when we had, a lot of the old days, lots of times when we have people that we think have a chronic infection, but we can’t treat them because as soon as we treat them, they would flare and people often call those herxes. I always thought that was a foolish name for these things, but still, and it’s really mast cells in most of them.
And if you treat the mast cells, a whole lot of stuff gets better, you know? So that’s just me, but you know, again, I think it’s like where you cut the circle, but you get to see the people who have the mast cell, when you fix the mast cell the system definitely returns to more normal. So, can you just give us a little story about mast cells? We’re gonna come back to some of the symptoms. I know we never got to them but we’ll circle back. But I just really wanna hear just a little bit of, you know, mast cells where they come from and where they generally live in the body.
Lawrence Afrin, M.D
You actually set up the answer to this question quite well with your use, just a couple of minutes ago of the word primitive. There is no more primitive defense cell in the human body than the mast cell. This has actually been worked out by the paleo geneticists, who knew there were such people? But the ancestral lineages of the different types of cells in the body have largely been worked out. And it turns out that back around the time that eukaryotic organisms or multicellular organisms were first arising, it actually was the mast cell or an ancestral version of the mast cell that was the host defense system in the earliest eukaryotic organisms that began arising somewhere 500 or 750 million years ago. And for tens of millions of years, they were the only defense cells that eukaryotic organisms had and they obviously had to keep the multicellular organism alive in the face of an astonishing array of threats and stressors.
So the mast cells necessarily, from an evolutionary perspective, acquired an extraordinary array of defense mechanisms. Not just defense mechanisms but sensing mechanisms to be able to sense threats in the environment and then defense mechanisms to respond and to help the multicellular organism resist and recover from the threats visited upon the multicellular organism. Well, over time other host defense cells with more specialized defense mechanisms began appearing on the scene like the other types of granula sites, the neutrophils, the eosinophils, the basophils, the monocytes, the macrophages, the lymphocytes, plasma cells and so on and so forth. And each of those defense cells clearly does a better job than the mast cell does at the specific range of tasks that that cell has evolved to address.
But the mast cell is still there and it still remembers all of its old tricks. And as long as it keeps all of its defense mechanisms properly controlled, you know, with a normal set of genes in the mast cells that regulate the functioning of the mast cell, then all of those extraordinarily potent mediators, the weapons the mass cell has developed over time to be able to deploy in different situations as needed, all of those weapons stay largely bottled up inside the mast cell. They don’t cause any trouble. The central problem that the mast cell activation syndrome patient has, is that the weapons, the mediators are now being deployed. They’re being released inappropriately.
Now, why is that happening? Well, in occasional cases, it seems like it may be an autoimmune disorder. There are a couple of specific autoantibodies we learned about that really do have the potential to attack and in the process of attacking the mast cell, they activate the mast cell. But this is a relatively uncommon, relatively rare phenomenon. What the research today has shown though, is that in the vast majority of MCAS patients, these patients unfortunately are acquiring mutations in various mast cell regulatory genes which lead to inappropriate release of the mast cell mediators, not only at a baseline level, what we call constitutive mediator release, but also inappropriate releases of mediators in a reactive fashion so that when the mast cell is presented with a specific threat, you know, there ordinarily should be a specific set of mediators released in a particular pattern to deal most effectively with that threat.
But these mutations lead the mast cell to both constituently behave abnormally and to reactively behave abnormally. And it’s when you get the release of these mediators in fashions that are not normal, fashions that don’t contribute to resisting and recovering from insults to the body. Well, that’s when you run into problems because the receptors and all these other cells in the body that these released mediators are targeting, these receptors are present on a vast array of other types of cells all throughout the body. And these other cells, of course, they don’t know that they are being presented with mediators in an inappropriate fashion. All the cells they’re just biologically programmed to react in a certain fashion when a particular mediator comes–
Eric Gordon, M.D.
Let me just, mediators are just our way of saying chemical signals. And so in this case, the thousand or so chemicals.
Lawrence Afrin, M.D
Right, so when these signals come to dock with these other cells, the other cells start reacting. And if it’s in a situation where these other cells should not be reacting, then that doesn’t contribute to health. That doesn’t help you recover from anything. It just actually makes you sick in one fashion or another when various cells are starting to do things that they’re not supposed to be doing at that time. So the next part of your question, you know, where are the mass cells in the body? In truth they’re everywhere. They are present in every vascularized tissue in the body, which is to say just about every tissue in the body. But it’s very clear that there are a couple of particular areas where they’re dominantly cited.
See, most tissues in the body they’re very sparsely distributed. You would be hard put if you were to do a random biopsy in most tissues, you’d be hard pressed to find even a single mast cell. But where the mast cells are dominantly found, number one, at the environmental interfaces. So the skin, the respiratory tract, the GI tract and the genitourinary, the GU tract. Which is kind of where you want your primary sentinel against threats to the body. That’s where you’d want your primary sentinel to be positioned, to be able to most quickly detect assault upon the body.
So, number one, there are environmental interfaces in good numbers. And the other place where we dominantly find them is in the walls of all vessels in the body. The blood vessels, the lymphatic vessels. So this is where they dominantly are in. Therefore, it’s no surprise that, you know, the dominant symptoms, and this gets to the third part of your question, where are the specific symptoms that are typically seen here? It follows from biology, you know, where are the mast cells? Well, they’re at the environmental interfaces and in the walls of the vessels and what are the dominant themes of the effects of these mediators? Well, I said inflammation is the dominant theme. So we see, for example, in the skin.
We see plenty of rashes and we see something called dermatographism where if you scratch the skin lightly, you’ll see a very quick red flaring in the skin in the track of the scratch. And it lasts an unusually long period of time in somebody who has mast cell activation syndrome. Well, why is the skin turning red there? Well, it’s because there’s an infusion of extra red blood cells into the area. Well, how can there be an additional amount of red blood cells infusing into that area? Well, it’s because the blood vessels in that area have dilated to be able to accommodate more blood flowing into that area. So again, it goes back to the biology of where are the mast cells?
They’re at the environmental interfaces like the skin and in the walls of all vessels. And you better believe there are some mast cell mediators that can potently dilate blood vessels, as well as other mast cell mediators that can actually can potently constrict blood vessels. So that’s the skin in the respiratory tract. We have all the symptoms of inflammation in the respiratory tract, the excess mucus production and the coughing, the sneezing, the runny nose, the post-nasal drip, the coughing. In the GI tract, copious inflammatory issues with discomfort and pain and abnormalities in bowel motility like alternating diarrhea and constipation. There are inflammatory phenomena in the bowel that can lead to nutrient absorption problems that can have an awful lot of diverse downstream manifestations.
And in the genital urinary tract also. Many women with this disease have quite an array of inflammatory issues in the genital tract and in the urinary tract. Not to say that men don’t, but it’s more common in women because I mean, think about it, their genital urinary tracks are a little bit more exposed to the environment than the male genital and urinary tract. So there are plenty of women who suffer frightful amounts of vulvitis, vaginitis, dyspareunia, and excessive uterine bleeding. So, yeah, that’s, I guess a short summary of mast cell–
Eric Gordon, M.D.
No, what always is why I love your summaries of these things is because I like to think that I think of everything, but I don’t. You know, I mean, I said, you know, the GU tract yes, you know, some forms of interstitial cystitis even, but I didn’t really connect the excessive uterine bleeding, which makes sense, it’s inflammation.
Lawrence Afrin, M.D
It’s a little bit more than, it is inflammation, but there’s another aspect of biology too that’s relevant because I mean, where’s the bleeding coming from? From the endometrium which is a heavily vascularized tissue. So there are a lot of mast cells in the endometrium, including the walls of those vessels but another key piece of the biology here, the relevant biology here, it goes back to the media, these specific mediators. You know, again, you and I were taught the only mast cell mediators are tryptase and histamine, but it turns out the very first mast cell mediator ever discovered back in the 1930s and actually one of the dominant mediator products of the mast cell is heparin. And most people think of heparin just as a drug, and a very potent anticoagulant drug.
But it turns out heparin is not just a drug, it’s also a natural product of the human body. And for all intents and purposes, there’s only one type of cell in the human body that makes heparin and that’s mast cells. So if you have normal mast cells up in the endometrium, not a problem, you have normal functioning there, but if you’ve got a bunch of dysfunctional mast cells there in a heavily vascularized tissue, and these mast cells are frequently getting inappropriately activated and thereby dumping their loads of heparin into that heavily vascularized tissue, you’re gonna get exactly the same result as if you were to inject a load of heparin, say a subcutaneous tissue somewhere, and everybody knows you get plenty of bleeding and bruising when you do that, it’s the same thing going on.
Eric Gordon, M.D.
Wow, wow. I’m sure you have given courses for doctors just to, to remain… I mean, just going through the tissues because I said, we think about the things we think about, but are the known unknowns that really get us into trouble, you know? I mean, that was exactly what I was looking for. It’s like, okay, what’s the regulars? And what’s to those of us, you know, we call the zebras? Again, when you have a full understanding, they’re not zebras ’cause you would think about them, but when you don’t know enough, it’s the unusual event that’s fascinating. Let me just, just run back to, I’m gonna go to a few other symptoms, but one of the things that I’m interested in, I know you talk a lot about mast cells having mutations, but do you also have issues with just changes in the epigenetics in the mast cell of expressing different genes?
Lawrence Afrin, M.D
You’re right. And I was over simplifying before but–
Eric Gordon, M.D.
I just want you to clarify for me.
Lawrence Afrin, M.D
I think there may be an infinite number of dimensions of complexity of this disease but yeah the recent research suggests… ‘Cause you have to ask the question, you know, why are the mutations in these mast cell regulatory genes being acquired? We know from the research today that they’re fairly uncommonly inherited mutations. And rather most of these mutations are acquired or somatic mutations rather than germline mutations. So you have to ask, how are these mutations developing? How are they being acquired? And the research on that front is even more preliminary at this point but the idea that’s presently, the dominant idea that’s presently emerging is that there are epigenetic mutations and these most likely are inherited. And the effects of these epigenetic, the principal effects of these epigenetic mutations are to confer upon the genome the actual genes, not the epigenes, but the genes in the genome a state of fragility.
See ordinarily, our genome is very robust. Yes, mutations are developing all the time in our genome. You know, there are trillions of cells replicating every day and so you can’t help but develop mutations fairly frequently. But we’ve evolved very good mechanisms for detecting when a new mutation has arisen and then either fixing it or targeting that cell for essentially suicide apoptosis so that those mutations cannot persist. Well, if the mechanisms for identifying and fixing the mutations are no longer working as robustly as they ought to, that creates a state in which it becomes easier for an acquired mutation to persist. And furthermore, other research is suggesting that when you have that sort of a state of genomic fragility, that when that genome, that frail genome is assaulted by one sort of cytokine storm or another, that emerges rapidly from various organ systems in the body, anytime we’re under one sort of stressor or another, that there are very complex interactions that then go on between that cytokine storm and the frail genome that ultimately lead to the induction, the creation of a new mutation.
And when it happens to be a mutation that just happens to be in a stem cell, and it just happens to be a mutation in a gene that is of regulatory importance to the mast cell, then congratulations, all of the mast cell progeny of that stem cell, all the mass cell progeny of that newly mutated stem cell, are going to bear that same mutation and they will start misbehaving in whatever fashion is dictated by that particular mutation. And at that point, welcome to mast cell activation syndrome.
And over time as that frail genome gets exposed, just through the random acts of life, get exposed to more and more and more stressors, then more mutations develop and you develop further subclones, so to speak, of ever more dysfunction ever ever more mutated, and therefore ever more dysfunctional mast cells. So the disease, I mean, this is the observed natural history of the disease that over time it’s always active to some degree but that baseline about which it functions tends to be pretty stable over time. But then from time to time, there can be significant escalations in the baseline level of misbehavior of these dysfunctional mast cells and it’s been observed that these escalations, which tend to be permanent, tend to emerge fairly shortly, anywhere from a few days to at most, a few months, following a major stressor, either a major physical stressor or a major psychological or emotional stressor.
And because it’s mutations that are developing and being acquired, this is why these major escalations as differentiated from just a flare of the disease, these major escalations tend to be permanent because they’re the consequence of yet another mutation or two or three that have been acquired.So we’re not saying in a mass cell patient that all of their mast cells are mutated and dysfunctional, ’cause that’s not the case. As I said, these mutations almost never are germline. They’re not inherited rather they’re acquired and therefore it’s only a portion of the patient’s mast cells that are misbehaving but the mediators that are coming out from these dysfunctional mass cells in an inappropriate fashion are so potent. That’s how this disease is able to cause so much havoc at a clinical level..
Eric Gordon, M.D.
Yeah. Right, ’cause you, you might only have a few mast cells, but the language they speak is understood universally, you know? What they put out, the information. I don’t wanna digress too much, but someday you and I will have to have a long conversation about Dr. Navios concept of the CDR1, two and three because you see the CDR1 is when you have this acute inflammation stage and that’s when you’re not methylating and you’re kind of open Pandora’s box in your genome because you expose lots of parts that usually are nicely covered by histones, okay? And the CDR2 is actually what you and Dr. Shoemaker refer to as more like proliferative, when you start getting the hypertrophy of tissue because you get those co-factors being released by the mast cells, but this is a long story. I won’t digress.
I just want to throw that out there just for your brain ’cause I’m gonna come back at you someday with… Yeah, I’d like you to talk to a few other people. ‘Cause I’m a great believer in triangulation or just the fact that over the years, I just keep learning so much from different really smart people. And then what I find is that really smart people like you, you bring us this incredible amount of light, you know? But the very nature of your work, you’re working in one area and it’s nice to bring people from different perspectives together, you know? ‘Cause I have a superficial knowledge of a lot of things. You guys have deep knowledge and that’s what is really wonderful to get in the same room. Rarely happens, unfortunately because you’re all operating in different fields, you know? But I think there’s just a possibility of illumination because the more light you have, the better your brain is gonna work. Because you do a very good job. But just before we wrap up this, when I realized, are there a few more…
Well, I said in medicine, we call zebras, you know? The saying in medicine, if you hear horse beats, think horses, not zebras, you know? At least, in the United States in general, that would be a good thought, but the zebra is the thing you don’t expect to see, but it still could be there. I actually knew someone who had a ranch in Texas that had zebras, so it can happen. So on that note, I mean, what are some of the unusual presentations? I mean, I’m gonna throw out one that, probably not unusual to me, to you, but I mean, just the bone pain is something that, you know, I do believe and correct me, I now think in terms of histamine and mast cell.
Lawrence Afrin, M.D
Well, that’s an interesting symptom because it’s actually the mast cell patients who have that deep seated bone pain. It’s a pain that is essentially the same type of deep seated bone pain that sickle cell patients have. And this goes back to your notion of triangulation, connecting the dots. And it’s been very interesting if you follow the research in the sickle cell arena over the last decade, it has begun emerging from the Bench Researchers in that area that, you know, it always used to be thought that what was driving the pain of sickle cell disease, the bone pain in those poor patients was the basal occlusion. Well, from the sickled red blood cells. Well, it turns out, nope, it’s actually mass cell activation. And in fact, the drug that is most commonly used to help settle bone pain on a chronic basis in sickle cell patients, Hydroxyurea actually turns out to be a helpful drug in settling bone pain in a number of mascell activation syndrome patients.
And furthermore, if you wonder, I don’t know how much experience you’ve had with sickle cell patients in your career as a hematologist, I had quite a bit, but nobody was ever able to explain to me why about 80, 85% of sickle cell patients have a relatively benign phenotype of that disease. They’re fully functional people, they have a normal life. They work, they enjoy life. They do have an occasional vaso-occlusive pain crisis, but they’re almost always able to fairly easily manage that at home with relatively modest drugs. And the crisis comes and goes in just a few days. And it happens, you know, maybe once, twice, three times a year, that that’s it. But then there are the other 15 to 20% of sickle cell anemia patients who suffer every known symptom of that disease and they’re pricey.
They are almost always seemingly, almost always in crisis. When they have a crisis it doesn’t last three days, it lasts three weeks. They’re in the hospital for two, three, four weeks. They’re always in the emergency room with one problem or another. These are the sickle cell patients who have the gall bladder failures, the heart failures, the kidney failures and because all sickle cell anemia patients have exactly the same point mutation in their beta globin gene, how could there be such a division in these sub phenotypes of sickle cell disease? And as I was starting to get into the mast cell activation arena, I began realizing pretty quickly that the theme here was that all of the constantly sick sickle cell patients had sickness in a fashion that was potentially consistent with a mast cell activation. And so I began testing them and I actually published a paper on this some years ago. And it turns out that an awful lot of the constantly sick sickle cell anemia patients actually have a definable MCAS.
And when you start treating the MCAS in these patients, the previously uncontrollable sickle cell troubles, all of a sudden get better. And it actually is possible to transform one of these very high resource consuming sickle cell patients into a comparatively low resource patient just by recognizing, diagnosing and effectively treating the mast cell activation that’s in them. And the percentage even makes sense because the epidemiologic research in mast cell disease has suggested that about 15 to 20% of the general population actually has MCAS in one form or another, one fashion or another, to one degree or another and that’s pretty much the percentage of the sickle cell population that has bad sickle cell disease.
I’ve seen plenty of other zebras. I mean, heck just look at the first three chapters of the book. The first patient Polycythemia vera, which actually was not Polycythaemia vera. It was just an idiopathic Polycythaemia, an excess of red blood cells that made no sense until you learn what mast cell disease can do. The second patient had exactly the opposite problem of far too few red blood cells. She had a rare hematologic condition called pure red cell aplasia which usually is driven by one sort of viral infection or another, but she didn’t have any of these other identifiable causes of PRCA and ultimately we found it was mass cell activation. We treated it and this terrible transfusion dependent anemia she had had just went away in a month.
Eric Gordon, M.D.
You know, unfortunately we’re almost at a time and, you know, it’s funny, we didn’t even get to the mycotoxins, but it doesn’t matter because I think the point that I wanted to get, you know, and you’ve done beautifully, is that when the inflammation and when your symptoms just are all over, you know, talk to your doctor, think about, read about, that mast cells may be playing a role. You know, if you’re the person who, everything you take flares you, every time you take a binder, you flare, okay? Think about the mast cell, you know? You have a herx every time they try to put you on an antibiotic or herb, think about mast cells. I mean, these are the underlying causes of so much unnecessary misery, especially in our world. And there’s another topic that I’d love to discuss with you at another time: we’re seeing so much more of this, just because we’re seeing it or because I, you know, just seemed like allergies have… And which I think is the tiny tip of the iceberg.
Lawrence Afrin, M.D
That is a topic for another time for sure.
Eric Gordon, M.D.
Yes, but anyway, I just wanna thank you again, Dr. Afrin. It is a pleasure. I love listening to you and learning from you. It’s really an honor. So thank you so much for your time.
Lawrence Afrin, M.D
And thank you for the opportunity Dr. Gordon.