This was a fantastic discussion with clinician and researcher in Mast Cell Activation Syndrome (MCAS), Dr. Lawrence Afrin. MCAS is something to consider when you haven’t responded to anything else: diet, lifestyle, gut treatments, thyroid…. And, here is the kicker… it doesn’t require extensive lab testing nor expensive treatments for many cases.
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Mast Cell Activation Syndrome with Clinician and Researcher Dr. Lawrence Afrin
Dr. Michael Ruscio: Hey, everyone. Welcome to Dr. Ruscio Radio. This is Dr. Ruscio. Today, I am here with Dr. Lawrence Afrin. And I’m very excited to discuss mast cell activation disorder and/or histamine intolerance and kind of pick into some of these specifics and where to draw the line between the two and how we can diagnose, how we can treat, and really delve into this gentleman’s brain, who has quite a bit of expertise in that area.
So, Lawrence, thank you so much for being on the show.
Dr. Lawrence Afrin: Thanks, Michael. Larry, please.
DrMR: All right, Larry. Can you just give people kind of the brief synopsis on your background and your current involvement with mast cell disorders?
DrLA: Sure. My undergraduate was computer science, and then I did all my medical training, school and internal medicine residency, clinical and research hematology/oncology fellowships all at the Medical University of South Carolina in Charleston. Then went on faculty there for nearly 20 years. Spent the last three years at the University of Minnesota, and now I’ve headed off to work with another physician who gets it, so to speak, with regard to mast cell disease, to develop an independent institute for advancing the care, the research, and the education in this area.
Back around 2008 is when I started kind of serendipitously getting into this area, making the diagnosis in my first patient. And through all I learned in diagnosing her, I began to realize this might be a whole lot more common than anybody might’ve suspected previously. And the more I began looking for it in my other mysteriously ill patients, the more I began finding it. And the more I began treating it, the more folks began getting better, previously sort of unimprovable patients.
They actually started getting better. Well, one thing led to another, and here I am, getting interviewed by you.
DrMR: So it’s fair to say that you’re both participating in this area from a clinician perspective, treating patients, and you’re also performing research. Is that correct for me to say?
DrLA: That is correct.
Mast Cell Activation Disorder (MCAD)
DrMR: Great. I think that’s a terrific combination. And can you define for us what mast cell activation disorder is?
DrLA: Sure. The term mast cell activation disorder, or MCAD, actually is the new, call it an umbrella term, the term for describing the whole realm of diseases of the mast cell. I like to use an iceberg metaphor. There’s the part of the iceberg you can fairly easily see above the waterline, a waterline of relatively easy clinical recognizability, if you will. And then, there’s the much larger bulk of the iceberg below the waterline.
And above the waterline of this iceberg, at the very tip you’ve got the rare disease of mastocytosis, sort of a cancerous overgrowth of mast cells together with inappropriate mast cell activation. But that’s just the tiniest tip of the iceberg. Mastocytosis in its various forms is a pretty rare disease.
And then, the rest of the visible part of the iceberg are much more common forms of what, in truth, is mast cell disease, just not commonly thought of that way. And I’m talking about allergic-type phenomena, like allergies, urticaria, angioedema, and anaphylaxis.
And then, below the waterline, as we started coming to recognize in just the last decade, there is this much larger assortment of diseases that all have the common theme of inappropriate activation of the mast cells in one fashion or another. And we really haven’t learned very much yet about how to distinguish the assorted variants of what we’re now calling mast cell activation syndrome in the collective sense.
But we’ll get there. And in the meantime, the term MCAS is what we apply to these more nebulous disorders of activation that don’t otherwise fit all that well with the other forms of mast cell disease, which we had known about for a long time previously.
Mast Cell Activation Syndrome (MCAS)
DrMR: So would it be accurate to say that mast cell activation syndrome is more befitting for people that may not fit squarely into the box of mast cell activation disorder? Or are these just different names essentially for the same thing?
DrLA: No, not quite the same thing. Again, think of the iceberg, and the bulk of the iceberg below that waterline of easy clinical recognizability is what we’re terming collectively mast cell activation syndrome.
DrLA: Whereas, above the waterline, you’ve got the various allergic-type phenomena and then the rare disease of mastocytosis. So mast cell activation disorder or disease, MCAD, the whole iceberg, features just different patterns of mast cell activation, inappropriate, obviously, mast cell activation.
It used to be thought that when mast cells activated, pretty much all you saw with that from a clinical perspective was allergic-type phenomena. But we’re now coming to realize that when mast cells activate, they can drive a very wide range of processes that go well beyond the allergy box. And it’s starting to become apparent that there even are a lot of mast cell patients out there who, believe it or not, really don’t have a speck of allergy to them.
And the universal constant that I’ve been observing with mast cell activation disease actually is chronic inflammation. And then, beyond the chronic inflammation, there may or may not be various allergic-type phenomena in the individual patient with this disease. And there also may or may not be assorted abnormalities of growth and development in, well, potentially any tissue really.
So I usually describe this mast cell activation syndrome as a chronic, multi-system illness of general themes of inflammation plus/minus allergic-type phenomena, plus/minus abnormal growth and development in assorted tissues.
I know it’s a mouthful, and I wish there were a shorter way to encapsulate it. But it’s a very complex disease as a direct consequence of the underlying biology. And I hadn’t figured out a shorter way to describe it yet.
Common Symptoms & Systems Affected by MCAS
DrMR: Sure. So maybe a good transition there then would be to try to list—and I know this may be challenging—some of the most common symptoms. I know of course—and please correct me if I’m wrong or off on any of these, but we may be able to provide a few buckets here that we can organize these into neurological – irritability, depression, brain fog; dermatological – rash, flushing, hives, runny nose; rheumatological – joint pain; and then also maybe things like insomnia, fatigue, as being some of the more common symptoms but not only limited to those.
Would you agree with that, disagree, modify that?
DrLA: Well, I think probably the most important point about what you’re trying to get at here is that there really is no system in the body which is immune, so to speak, to potentially being affected by this disease, not even the immune system.
That doesn’t say, of course, that every system will be affected by the disease. But it’s just to say that it is possible to see any or, unfortunately sometimes, even all systems in the body affected by the disease. And so, you go system by system, and you can come up with a wide range of symptoms that are a result of this general theme of inflammation and allergic-type phenomena and abnormal growth and development that you can see in all of these systems.
So, neurologically, you already hit on a lot of things like fatigue and cognitive dysfunction that a lot of patients describe as “brain fog.” There can be a lot of other motor and sensory neurologic issues. And of course, if you’re talking about the central nervous system being affected, it’s certainly possible there could be psychiatric issues. Anxiety and depression are quite common. But a wide range of other psychiatric phenomena can be seen.
There’s the cardiovascular system with all sorts of autonomic issues, a lot of variability in pulse and blood pressure, palpitations, tachycardia. You mentioned in the musculoskeletal system a lot of pain, diffusely migratory pain. There can be skeletal issues like osteopenia and osteoporosis.
GI… When you think about the biology of this, where do mast cells reside in the body? Well, there are present in every vascularized tissue, but they dominantly site themselves at the environmental interfaces and also perivascular sites. So that’s where they’re best positioned to serve out their principal role and defense.
So where are the environmental interfaces? It’s the skin. So, sure, you get… Well, the integument in general. So in the skin you get all sorts of rashes. You can get issues with the hair and the teeth and the nails. So there’s the integument. There’s the GI tract; all sorts of issues in the GI tract with reflux and nausea, sometimes vomiting and diarrhea or constipation or, even more commonly, sort of an alternating back and forth between diarrhea and constipation, which is just one example of the many opposites you can see with this disease.
Even in the same patient, just from one point in time to the next, the disease can manifest opposite symptoms, which can really frustrate not only the patients but also the doctors trying to diagnose this. So the integument, the GI tract, the respiratory tract—another environmental interface. So a lot of patients describe intermittent problems with shortness of breath, much less commonly wheezing.
And then the genitourinary tract is another environmental interface. So all sorts of irritation and pain in the urinary tract, sometimes the genital tract, and there can be other inflammatory type problems in that area as well.
Effects on the Immune System
And then, you talk about the immune system, how that gets affected. And you know, Michael, that when the immune system isn’t working right, there’s a wide range of possible consequences, including increased susceptibility to infection and increased difficulty with healing or recovering from infections and wounds and increased risk for malignancies and even increased risk for autoimmunity of potentially any sort.
And I could go on to the other systems in the body, but I think you get the point that it’s just a bewilderingly large array of potential symptoms. And because what’s been appearing so far is that different patients present with very different patterns of mast cell activation, that gets us a situation clinically where different patients are presenting very differently. And it makes it a real challenge to recognize that what’s going on in the patient might be… You know the process of differential diagnosis. You’ve got to think of what diseases might fit the symptoms.
So physicians go through many years of training. We learn, all in all, probably a few thousand diseases. And we learn the specific patterns with which each disease presents. And that’s the art of diagnosis. It’s pattern recognition, whether you’re a doctor or a car mechanic or anybody else who needs to give diagnosis.
And now, all of a sudden, there comes a disease which by its essential biologic nature is actually capable of presenting a thousand different ways. And you can right off the bat see the challenges in just recognizing in the first place the possibility that this might be at the root of what’s been going on in the patient.
Moving Forward with a Proper Diagnosis
DrMR: I completely appreciate that. And one of the things that’s been helpful for me in sorting out how do we choose which potential differential diagnosis to pursue, when many of these potential differentials have so many wide varying symptoms they can present as, so one of the things I’ve found helpful to do in that case is to start with foundational therapies and foundational treatments first. See what symptoms abate. And then, you have much less symptoms present, and that may give you a more definitive window that can get you to that diagnosis.
So oftentimes, I start with the fundamentals, see what symptoms clear, and then reevaluate. And the picture sometimes becomes more focused at that point. Is that something that you would advise people as they’re wading into this?
DrLA: I think there are a lot of different ways to approach this very nebulous beast. It’s been my experience that most patients who are ultimately found to have MCAS have actually been searching for help with their symptoms for a very long time, typically for decades.
Very understandably, they come to acquire fairly long lists of diagnoses and problems. And it’s been my experience that most of those diagnoses are correct, but the problem is that each of those diagnoses accounts for only one subset or another of the totality of what’s been going on in the patient.
DrMR: They’re diagnoses of the symptom but not of the cause per se?
DrLA: Exactly. And so, you have to ask… When you’re faced with a patient who has 20 or 30 entries on the problem list, and you look at it and you think about it and you realize that most of these problems are of a chronic inflammatory nature or an allergic-type nature or perhaps some problems relating to abnormal growth or development, you’ve got to ask yourself, what’s more likely?
Is this patient really 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 the patient just has one thing going on, which is biologically capable of causing, directly or indirectly, most or all of what the patient’s been suffering?
Well, obviously, in the universe we live in, it’s more likely there’s one thing going on. And the problem is that up until a decade ago we didn’t even realize there existed a disease which was capable, which is capable, of causing so many different problems. So there’s a lot of learning that our profession has to do here.
DrMR: Sure. I agree with that. And I’ve seen something similar with how humblingly powerful the gut can be in terms of people can come in with symptoms of many different conditions. And when you resolve an inflammatory issue in the gut, many or all of those symptoms can abate.
So I absolutely appreciate your thinking here. And I think there’s definitely a gut tie-in to this. And I’m very curious in a little bit to get your perspective on the gut’s impact.
MCAS and Histamine Intolerance
But before we jump there, I just wanted to ask you one other thing, which is do you see a distinguishing—I’m assuming you do—between histamine intolerance and mast cell activation syndrome?
I feel like they’re probably opposite ends on one spectrum. But I’m curious how you think those two connect with each other.
DrLA: My suspicion, based on what I’ve been seeing, is that what we’re labeling in some patients as histamine intolerance is probably in most of those patients just a subset of the whole mast cell activation phenomenon in those patients.
When you talk about histamine intolerance, why would one be intolerant to histamine? Histamine is a natural part of us. There are histamine receptors on a wide variety of cells in the human body, including actually the mast cells. So that’s right: the mast cells produce histamine. They release histamine, and histamine can loop back and dock with the histamine receptors on the surface of the mast cell to further activate the mast cell.
But somebody who has histamine intolerance, that means that the various cells expressing histamine receptors are responding abnormally, in an excessive fashion. They’re getting excessively activated when histamine docks with those cells. That phenomenon, it strikes me as just part and parcel of the totality of what is going on in a mast cell activation syndrome setting.
So there are some patients with mast cell disease who respond well to histamine-directed therapies, whether you’re talking about trying to block the histamine receptors or you’re talking about decreasing the amount of histamine that the body is producing. And of course, you can also talk about the amount of histamine that’s being ingested.
There’s, as you well know, a wide variety of so-called low histamine diets that one can pursue. But let’s keep in mind that histamine is just one of a huge range of very potent signaling molecules in the body. And to my way of thinking, kind of unlikely that if you look at all the problems that a patient with so-called histamine intolerance has, it just seems kind of unlikely that all of those problems would be attributable to just an excessive responsiveness to histamine alone.
DrMR: I agree.
DrLA: It’s a lot more complicated than that. Mast cells actually produce more than 200 mediators, each of which has a huge array of effects throughout the body: direct effects, indirect effects, acute effects, chronic effects, local effects, remote effects. You can just start imagining just how many permutations there might be of mast cell activation syndrome with just different patterns of inappropriate mast cell mediator expression together with inappropriate patterns of inappropriate mast cell reactivity. And the numbers, the permutations, very quickly just get mind boggling.
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Factors That May Lead to MCAS
Now, I’m assuming that when we look to third-world countries that don’t have anywhere near the sterile-type hygiene that we have, we probably see quite a lower incidence of this. And so, I’m assuming to the question of what causes mast cell activation syndrome, I’m assuming that early life factors that are responsible for immune system programming are fairly important. But I’m curious what you think some of the fundamental causes of this are.
DrLA: Boy, that’s not only the 64,000-dollar question. It’s probably the 64-trillion-dollar question.
DrLA: Given some of the more recent estimates as to the prevalence and costliness of this syndrome, there’s some intriguing data out there. I know there are some folks in this area who suspect that the mast cells in these patients are normal and that they’re just reacting normally to something or multiple somethings yet unidentified in our environment.
That’s a possibility, but there are also some other studies out there, some intriguing work particularly coming out of the University of Bonn that is suggesting that virtually every one of these patients may have assorted mutations in the various regulatory elements in their mast cells. And it’s kind of curious that some of that work suggests that these mutations, actually most of these mutations, are not inherited or in-born but, rather, are acquired relatively early in life.
Now, why would one acquire such mutations? It’s a lot murkier at that point. There’s some thinking that maybe there are epigenetic mutations which actually might be inheritable, that might be at the ultimate root of this, and that there are interactions that occur between certain epigenetic mutations and various cytokine storm patterns that emerge from various stressors relatively early in life and that it’s the interactions between these cytokine storms and various epigenetic mutations that might be driving the formation of these mutations in the precursor cells to the mast cells.
So that’s an intriguing theory too. To my way of thinking, that actually fits fairly well with a lot of observations of the way the disease behaves not only in the individual but also within families and in the population. But to be sure, that intriguing data has come out of one institution. It hasn’t yet been verified, sort of independently confirmed by other institutions, and there’s just a whole lot more research that needs to be done to better understand the cause.
Relevant Testing and Treatments for MCAS
DrMR: Sure. Now, regarding testing, I think sometimes we fall into a pattern of over-testing and we test things that we don’t even have a way of treating. I’m curious what are some of the more—if there are any—highly clinically impactful or relevant tests? And just as a few examples, I know that in some of the research on histamine intolerance, the diamine oxidase enzyme, the DAO, is tested and I know values between 3.0 and 10.0 are considered low. I’ve heard about bone marrow biopsies and serum tryptase. I’m wondering if you find any of the testing to be particularly helpful in steering the clinical process.
DrLA: Yeah. But actually, even before I get into the testing, I just want to loop back to a brief comment you mentioned in that question about the treatments. And I just want to get out there the notion that we’re actually very fortunate with this disease in spite of how little we understand about it at present. There’s actually a veritable boat-load of therapies that have been shown helpful…
DrLA: Across the mast cell activation population. Sure, it’s frustrating for both the patient and the practitioner at present that we don’t yet have any methods for predicting which treatment will be most likely to help which patients. So there is required an awful lot of patience and persistence and a very methodical approach in stepping through trials of the different therapies.
But nevertheless, there are a lot of things we tried, and actually the majority—at least in my experience, the majority of patients with mast cell activation syndrome are able to eventually find significantly helpful therapy.
But you’re right. You’ve got to diagnose it before you get around to treatment. There is testing that can be done for this. You mentioned tryptase. Tryptase levels in the serum can be very helpful in diagnosing that rare disease of mastocytosis. We usually see tryptase levels elevated at least double the upper limit of normal and quite often much higher than that in mastocytosis.
But it’s turning out in mast cell activation syndrome, tryptase is usually normal. Or if it’s abnormal, it’s just very slightly abnormal. So it’s certainly a good idea to check a tryptase level. But just because it comes back normal or just slightly abnormal is certainly no reason to dismiss the possibility that what might be going on in the patient is a mast cell activation syndrome.
You mentioned bone marrow biopsies. Bone marrow biopsies very commonly are diagnostic in that rare disease of mastocytosis. And if the patient is presenting with a very high tryptase level or with the clinical manner in which mastocytosis typically presents, then absolutely, you need to undergo bone marrow biopsy. And quite often, it’s recommended to undergo what we call bilateral bone marrow biopsies, one on each side of the backside of the hip.
But in mast cell activation syndrome, marrow biopsies are usually unrevealing. You just don’t see anything useful either at the cellular level, under the microscope, all the way on down to the molecular level. You just usually don’t see anything helpful.
So instead, we need to go looking in the blood and the urine for elevated levels of various mediators that are relatively specific to the mast cell. As I said, the mast cell puts out more than 200 mediators. And on a practical basis, you just can’t be doing that many tests. But you also don’t want to be doing that many tests for the simple reason that the vast majority of the mediators put out by the mast cell are not particularly specific to the mast cells.
So for example, I can go measure an interleukin-6 level, an IL-6 level. It’s a good marker of inflammation, but if I find an elevated IL-6 level, that doesn’t tell me that the excess IL-6 in the patient is coming from the patient’s mast cells. It doesn’t tell me there’s a mast cell activation problem there.
So you take that list of 200 mediators and you cone it down quite a bit based on what’s available for testing in the clinical laboratory. A lot of the mast cell mediators you can’t even test in the clinical laboratory. We only have tests in the research laboratory for them. And you also cone the list down based on the mediators that are relatively specific to the mast cell.
And by the time you’re done doing all that coning down, you’re left with roughly eight or nine mediators. That’s about it that we can measure at present in the clinical laboratory and which are relatively specific to the mast cell. But because the disease presents so differently from one patient to the next and even can vary a good bit in its behavior within the same patient from one point in time to the next, it’s really difficult to say that, oh, it’s just this one or these two mediators that you can get away with testing. I’ve not found that approach to be particularly productive.
And instead, unfortunately, we do have to go to the effort of measuring this full panel of, like I said, eight or nine mediators. And I know it’s not the cheapest thing in the world, but at the same time, these patients typically have been mysteriously ill for decades, consuming huge amounts of resources. So the little bit extra that has to be spent to actually make a firm diagnosis, based on the lab testing, in these very complicated patients, it’s really a drop in the bucket compared to what’s already been spent on their behalf over the years and the decades.
And of course, once you finally nail down the right diagnosis, now you’ve got a path forward for treatment.
Specific Markers for Mast Cell Disease
DrMR: And what are those markers? Do you have those available?
DrLA: Sure. I typically look—well, first of all, I’m going to be looking… Not that they’re specifically diagnostic of mast cell disease, but I have learned there are certain patterns and routine blood counts and chemistries that can perhaps provide a hint or a suggestion that there might be mast cell disease there.
But if you’re talking specific mast cell mediators, the ones I typically look at are in the serum: tryptase and chromogranin A. Full disclosure, you have to be a little careful when interpreting chromogranin A levels.
There are some potential confounders of chromogranin A levels. You have to be sure the patient doesn’t have any heart failure or renal failure or hasn’t use any proton pump inhibitors in the last few days. And you have to make sure, of course, if you find a really elevated chromogranin A level, you have to do diligence and make sure the patient doesn’t have a neuroendocrine cancer.
But if you do, all of that rule-outs and you still find an elevated chromogranin level, pretty good bet that it’s coming from mast cell activation. So, again, in the serum, tryptase and chromogranin A. In the plasma, I look at prostaglandin D2. Pretty tough molecule to accurately measure because of how what we call thermolabile, or heat-sensitive it is. You’ve really got to take care to keep the specimen for that test continuously chilled, all the way from when it’s drawn to the point where it’s finally assayed at some distant reference laboratory.
So in the plasma, prostaglandin D2 and plasma histamine. Plasma heparin is actually turning out to be a pretty useful, pretty sensitive and specific test. Although, it’s kind of challenging to find a heparin assay that’s sufficiently sensitive for measuring the heparin levels that are put out by mast cells.
And finally, in the urine one can look at both random and 24-hour urine specimens for prostaglandin D2. There’s a metabolite of prostaglandin D2. It’s got a long name. You’re going to love this: 2,3-Dinor-11beta-prostaglandin F2 alpha. And, oh boy, do I wish there was a shorter name for that.
DrLA: But that is measurable at some reference laboratories and also as a marker of mast cell activation. There’s also—you can measure histamine in the urine, but you can also measure histamine’s principal and mediate metabolite N-methylhistamine in the urine. And there are certain reasons why it might be a little more useful to measure N-methylhistamine instead of histamine in the urine.
And finally, there’s a molecule sort of at the end of the leukotriene metabolism pathway, a molecule called leukotriene E4 that can be measured in the urine. And that can also be a marker of mast cell activation.
That’s really the suite of what I measure when doing the initial diagnostic work in these patients.
Finding Reliable Labs for Testing
DrMR: And can you get this at a LabCorps or a Quest, or do you need a specialty center to do this assay?
DrLA: There are various and sundry—I think that’s the phrase, various and sundry—of these tests which are available at different reference laboratories. I actually have not yet run into any one reference laboratory that actually runs all of these specimens. There are maybe one or two reference labs to which you can send specimens for all of this testing. But even those labs, for example Mayo in Rochester, some of this testing even Mayo doesn’t do. So what they will do with the specimen is sort of ricochet the specimen out to the boutique reference laboratory that actually runs that test.
So it can be convenient to send the whole package of specimens to these various reference labs that offer all of these tests in their catalogues. You just have to understand these labs may not be actually running all of these tests in house.
Natural vs. Conventional Treatments
DrMR: Gotcha. Now, what about treatment? And I’d like to, if we can, organize these down into natural treatments. And I think much of our audience may have heard of some natural treatments. And I’ll just rattle off a few as kind of fodder for the discussion, and then we can talk about medications. And I’m getting the inkling that the medications here may be more of the brunt of the argument.
Most of what I’ve seen has been relative to really histamine and histamine intolerance. One study in particular showed 22% of patients with non- or idiopathic gastrointestinal symptoms had histamine intolerance. A low FODMAP diet has shown the ability to cause an eight-fold decrease in histamine. Glutamine supplementation has been shown to lower histamine. Some probiotics may lower histamine. I certainly see patients who have signs of histamine intolerance improve after treating SIBO, small intestinal bacterial overgrowth.
A low histamine diet, as you alluded to earlier, certainly can be helpful. There are natural agents like vitamin C and B6. There’s supplementation with DAO enzymes. But a lot of these bring us back to I think the end of the spectrum clinically that I think many of the gamut natural providers may be working with. And what I’m more so curious to get your take on is for people who fail out of those therapies and we need to kind of escalate up perhaps a level of the ladder to mast cell activation syndrome, where should they go?
So, happy to hear your thoughts on anything natural that could be helpful and then we can springboard into the pharmaceutical or other more kind of conventional medical treatments.
DrLA: Sure. Well, I think you and your listeners would appreciate in terms of natural therapies that step one in treating mast cell activation syndrome that I’ve seen prove most productive actually is no medication at all. But rather, step one is identifying the patients triggers as precisely as possible and then doing the best that one can to avoid them. It’s very difficult for any medications, whether you’re talking about prescribed medications, over-the-counter medications, supplements.
In my experience, it’s very difficult to tame these dysfunctional mast cells when the patient is simultaneously, persistently ingesting or otherwise exposing himself/herself to triggers of activation of the mast cells. So I ask my patients to try to stay alert to what their triggers are anytime they suffer a flare of symptoms. Once they’ve recovered, they need to just think about what they were doing, what they were exposing themselves to in the minutes, the hours before the flare emerged to try to figure out what their triggers are.
And I’d like to mention along that line too that mast cell patients seem to have quite a propensity for reacting to various medication products too. But when that happens, it seems to be more likely that what they’re reacting to is not the drug itself, the active ingredient, but more likely that they’re reacting to one or more of the excipients, the inactive ingredients, the fillers, the binders, the dyes, the preservatives in their medication products.
DrLA: So you have to keep an eye out for that. Now, to be sure, there certainly are certain medication classes which themselves can have a propensity for driving mast cell activation. I’m just saying that overall, when mast cell patients have reactions to medication products, it’s a bit more likely that it’s an excipient reaction rather than a true drug reaction.
So step one: identify the triggers. Do one’s best to avoid them. Step two: I like to have the patient identify an optimal antihistamine regimen, by which I mean a combination of an H1 blocker and an H2 blocker. And when it comes to the H1 blockers, since fatigue is such a common symptom in this disease, I prefer the patients try the non-sedating H1 blockers rather than the sedating H1 blockers.
But after the patients have experimented with the different non-sedating H1 blockers and the different H2 blockers, and they’ve identified an optimal antihistamine regimen, well, then we get to what I call steps 3 through N.
Non-Sedating H1 Blockers
DrMR: Sorry, doctor, but before we move onto that, are you having people start off with over-the-counter preparations? Are you giving them prescriptions? Are you doing a combination? Are there any of those that you find more effective?
DrLA: Yeah, all of the non-sedating H1 blockers and H2 blockers, at least here in the US, are over-the-counter. So you’ve got Claritin. We’ll stick to generic names because I don’t want to endorse any product. But you’ve got loratadine and cetirizine and fexofenadine and even levocetirizine just went over-the-counter. So all four of the commonly available non-sedating H1 blockers in the US are all available over-the-counter.
DrMR: What are the trade names on those, because I’m sure for people listening it would take a step out of the equation for them just to know that?
DrLA: Well, loratadine is Claritin. That’s the common trade name. Other manufacturers have their own trade names for it. The most popular trade name for cetirizine is Zyrtec. And the most popular trade name for fexofenadine is Allegra. And the most popular trade name for levocetirizine is Xyzal.
Sedating H1 Blockers & H2 Blockers
DrMR: And these are all the H1s?
DrLA: Those are all the non-sedating H1 blockers. Of course, you’ve got the sedating H1 blockers. Benadryl is the prototype. But again, it’s probably better to try to go with the non-sedating H1 blockers if you can.
And then, there are the H2 blockers. And again, everybody’s heard of these medicines. They’re not advertised as histamine H2 blockers. They’re advertised as medicines for stomach upset, but they’re histamine H2 blockers. So you’ve got famotidine, whose most popular trade name is Pepcid. You’ve got ranitidine, most popular trade name is Zantac. You’ve got cimetidine. Most popular trade name is Tagamet. And lots of people forget about the other one. There’s nizatidine, and its usual trade name is Axid.
So you make your way through the H1 blockers, the H2 blockers. Typically, these patients are going to be on antihistamines for a very long time to come. So it just doesn’t make sense to not take the time to figure out which H1 blocker and which H2 blocker is going to serve the individual patient the best. Why would you want to be on suboptimal therapy for the next two, three, four decades?
So I counsel my patients, patience, persistence, a methodical approach, trying to make just one change in the regimen at a time. Take the time, figure out which antihistamines are going to serve you best.
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MCAS Treatment Response Rates
And so, to the point of time, I’m curious about time and dose. Are you recommending people use kind of the standard dose range? And is there a certain timeframe in which they should be noticing a response and, if they don’t, they should be moving on?
DrLA: In my experience, most patients figure out within a month at most if any given medication being tried for MCAS is going to be significantly helpful or not. If the patient comes back after a month and the best that they can say about a given drug is, “Well, I kind of sort of…”
DrMR: Yeah. Maybe.
DrLA: “Feel a little bit better.” Nope. Not nearly good enough. Ditch it. Dump it. Be ruthless about it and move on. I promise you and the patients out there that when you happen to find the drugs or other interventions that happen to be the right molecular keys for fitting into the particular molecular lock that is any given mast cell patient’s particular variant of the disease, they will come back in just a month. And you’ll walk in the exam room, and you the doctor, your head will spin 360 because you can’t believe how much better they look. Quite often, you don’t even have to have a conversation with them because it’s so obvious that this drug is a keeper.
It may not solve all of the patient’s symptoms. And the symptoms that it does improve, it may not completely get rid of those symptoms. But, nevertheless, it’ll be an obvious, significant improvement. Those drugs are the keepers. Everything else, we dump and we move on.
Because otherwise, if you keep a drug in the regimen just because it kind of sort of maybe makes a patient feel a little bit better, and you will so rapidly that to the point of utterly unmanageable, unsustainable polypharmacy.
DrLA: Grossly excessive medication list. And it’s just toxic and unsustainable for all sorts of reasons. And you just don’t want to go there. Although, it’s the case that most mast cell patients aren’t going to reach optimal improvement with one medication. In my experience, for most mast cell patients, it’s a pretty small number of medications they need to gain optimal control over their disease.
So ditch the stuff that isn’t clearly working, and that kind of brings up another important point of having a reasonable expectation or goal in treating this. At present, you can’t cure it. We’re nowhere close to being able to cure it. And it’s way too complex of a disorder for it to be rational to expect to get to the point of feeling perfect.
You can’t even get to the point of feeling significantly improved all the time. There’re going to continue to be ups and downs with the disease. But in my experience, the great majority of people with MCAS actually are able to eventually, some patient sooner, some patients later. The average patient is somewhere in the middle. But most mast cell activation patients eventually can identify some mast cell-targeted regimen, usually pretty unique to just them, that gets them to the point of feeling significantly better than the pre-treatment baseline the majority of the time, more than 50% of the time.
And given how sick they’ve typically been in how many different ways for how long they’ve been sick, most patients are actually pretty happy to achieve that goal.
DrMR: Sure. That’s a terrific insight. I’m glad you made that remark about noticing if a therapy is working, and then, if not, moving on. Something that I’ve noticed in the clinic is patients want to cling to a therapy that they’ve read is supposed to help, even though it’s not helping them. They’ve kind of indoctrinated themselves into thinking that this therapy should help because they’ve read of some benefit, which could be true. But you want to really qualify that for an individual.
Proper Medication Dosages
So I’m very grateful that you said that. Coming back just to that for a moment, the dosing. Are these normal, over-the-counter recommendation dosages?
DrLA: Actually, the dosing is pretty close to normal. In my experience, the antihistamine doses that typically are effective are the standard over-the-counter doses with the caveat that for most mast cell activation patients, they need to be taking both the non-sedating H1 blockers and the H2 blockers twice a day. Whereas, for some of these medications, I know they get advertised as just once a day dosing is adequate. But in my experience, most mast cell activation patients need to be taking these medications at least twice a day, although at the standard over-the-counter dose.
Now, to be sure, there are occasional mast cell activation patients who clearly find significantly better response at a slightly higher dose than the entry-level dosing. For example, loratadine or Claritin at 20 mg instead of the entry-level 10 mg.
And there are occasional mast cell patients who notice a pattern where, let’s say, Claritin 10 mg really does help them significantly. But they can tell that it wears off before they’re due for the next twice-daily dosing, which means every 12 hours. So in those patients, they need to take it a little more often, three times a day, every eight hours instead of every 12 hours. That’s a minority of patients, but people can start once they’re diagnosed.
My style is I like to really nail down the diagnosis before getting started on treatment. But once my patients are diagnosed, then we get started on the H1 blockers at standard over-the-counter doses twice a day and identify which one is best and then move onto the H2 blockers. And then, if you want to do additional tweaking in terms of tweaking the dose or tweaking the frequency, nothing wrong with taking the time to run those experiments.
But let’s be careful too, because if you find that Claritin at 10 mg twice a day is helpful and you want to try, say, 20 mg twice a day or 10 mg three times a day, nothing wrong with trying that. But if you get to the end of, say, a two to four-week period with that and you can’t honestly say that you’re doing significantly better at the higher dose or frequency than you were doing at the lower dose or frequency, then forget it. The higher dose or frequency is not going to be the answer for you. You need to back off to the lower dose or frequency.
No patient should be taking one more milligram of one more medication than is clearly significantly benefiting them.
Cromolyn & Other Medications
DrMR: Well said. Completely agreed. Are there some other medications? I know disodium cromolyn, and I think there’s another one—Gastrocrom, if I’m remembering correctly.
DrLA: Well, Gastrocrom is just a brand…
DrMR: Trade, a brand name. Okay.
DrLA: …name for the oral form of cromolyn. Cromolyn’s an interesting molecule. In contrast to most drugs, it is not absorbed to any significant extent. So if you swallow oral cromolyn, it can be helpful in some mast cell patients at controlling the inappropriate activation of the mast cells in the GI, the luminal GI tract.
But it’s not going to get absorbed. It’s not going to circulate. It’s not going to help control other mast cells. Now, let’s be clear on this. That doesn’t mean that the impacts of oral cromolyn are necessarily limited to just GI tract symptoms. You brought up earlier that there’s an awful lot of interaction between the GI tract and the rest of the body. Every doctor who works in the mast cell disease arena has seen plenty of cases in which patients take oral cromolyn, and they wind up having improvement in symptoms that seem to have nothing to do with the GI tract.
But at the same time, again, cromolyn is not absorbed to any significant extent. So if you find that it’s helpful in one area of the body, the GI tract being the example, then it makes all the sense in the world to try it in other areas of the body. And there’s a NasalCrom that’s actually over-the-counter. There’s an Opticrom, a cromolyn eyedrop that’s over-the-counter. At least I think it is over-the-counter.
And there’s nebulized cromolyn, and that, like the oral cromolyn, is prescription-only. But there’s a nebulized cromolyn that you can inhale into the lungs. And some patients even get or make compounded cromolyn cream for application on the skin.
Finding a Qualified Physician
DrMR: Because I’m assuming there’s going to be people out there who are not going to have a doctor who’s going to be willing to humor them with this, is there an easy way to take maybe the nasal preparation and ingest that orally or to convert that to a dosing form that you think would be effective?
DrLA: I would really encourage patients who are suspecting they might have a mast cell disorder to find a local doctor they really can work with on this. And to be clear, it’s not that there’s any expectation that, at least for most patients, that you’ll be able to find a local doctor who’s already experienced with this.
Again, up until 10 years ago, we didn’t understand that MCAS exists. And the only other mast cell diseases we knew about were the rare disease of mastocytosis that oncologists dealt with and an allergy that any primary doctor and allergist, too, can manage. It’s very unlikely you’re going to find local physicians who are familiar with this.
But as long as the physician is willing to learn about this, and there is literature out there for physicians to read and they can learn about this, but as long as the physician is willing to learn and willing to at least try to help the patient. One of the nice things about treating this—I mentioned before there are a lot of drugs to be tried. But it’s also the case that most of the drugs that are reasonable to try for this disease are drugs that are well within the ability of any physician to prescribe and manage.
You really don’t need to be a specialist to prescribe and manage most of the drugs that make sense to try for this. So as long as the doctor is willing to learn and willing to try and is accepting of the fact that it’s a highly variable disease because of the biology that we haven’t had time to go into, and, therefore, it may well be the case that the patient’s going to have to try a number of different therapies. But like I said, it only takes about a month with each therapy. If the patient fails that therapy, then you move onto another one.
And because the state of the science in this area is so immature, we don’t yet have any ways to predict which treatments are most likely to help which patients, I tend to go in order of cost. I start with inexpensive treatments, and I proceed, for the most part—there are always exceptions of course. But for the most part, I tend to proceed in order of cost. And it’s usually not until you get to the really expensive drugs that you’re going to need to putting yourself into the hands of real specialists who are familiar with these much more expensive drugs to give you a one-month trial of them.
DrMR: I think that’s a terrific statement. And I would love to have you back on for maybe a part two, because I’m sure many of the practitioners following this are going to have their interest piqued. And they will probably have follow-up questions that may be a little more advanced. So hopefully, I can twist your arm into getting you maybe some point six months from now to come back on, and we can do a part two to this discussion.
DrLA: Always happy to educate.
DrMR: And where can people, if they wanted to, read some of your papers or hear more from you and/or just learn more about this area at large? Are there some resources you can provide for them?
DrLA: Yeah. There are some papers that I’ve published, some papers that others have published. If folks go to the National Library of Medicine’s PubMed.gov medical literature searching website and just punch in “mast cell activation syndrome” or even the abbreviation “MCAS,” there are probably going to be quite a number of publications that come up.
And although not all of them are going to be open access, a good number of them are. There’s that approach. There’s some literature, obviously not formal academic literature, but there’s some information about this out on various patient self-help groups. For example, the Mastocytosis Society has some information about this.
I really don’t want to go tooting my own horn here, but I did publish a book last year on MCAS that was intended for the public, the lay community. It’s a long title. The first part of the title is Never Bet Against Occam. And there’s a long subtitle to it. So there’s that out there.
I actually did also publish a formal, sort of academic type chapter on this. And that’s in a mast cell biology and disease textbook. My chapter is freely available for those that want to sort of get into more academic type reading in a long chapter. That’s searchable out there. I think it’s from Nova Scientific, I think was the publisher. That’ll get folks…
DrMR: Keep people busy. Yeah. Great. We’ll put the link to your book in there. Thank you for mentioning that. Certainly, it’s not tooting your own horn. It’s a lot of work to write a book, and it’s a lot of benefit. Gosh, it’s a lot of information and a lot of time for 15-20, 30 bucks. So I think just having written a book myself I really realize that you get such a tremendous value for such a little cost. I’m glad that that resource is there for people.
And this has been just a fantastic discussion. I really cannot thank you enough. I think there’s definitely a subset of patients that don’t respond to some of the therapies that we’re doing in complementary and alternative or integrative medicine. And this discussion I think will really help people find some solutions that are helpful for them and get something different than maybe pursuing some of the typical secondary and tertiary diagnoses we consider, things like Lyme or heavy metals or mold toxicity.
Not to take anything away from them, but this seems like a fairly reasonable and not incredibly hard or expensive therapeutic avenue to at least give a trial to and may help people find what really they are needing if it’s not one of these other different diagnoses.
So, thank you. I think you’re really going to help a lot of people with this conversation today.
DrLA: You’re very kind. I appreciate the opportunity. Like I said, happy to come back at any point and share… I’m always happy to share with patients, with other professionals what I’ve learned about this. It’s a good thing when I can help an individual patient with this.
But obviously, when I can help other professionals learn about this, that’s an even greater thing simply because of the multiplier effect.
DrMR: Exactly. Agreed. Well, thank you again, sir. It’s been terrific, and we’ll definitely look forward to having you back on.
DrLA: All right. Thanks a lot, Michael.
DrMR: Take care. You too.
NOTE: Dr. Lawrence Afrin works with Dr. Tania Dempsey at Armonk Integrative Medicine. For more information on Dr. Afrin or to read his latest blog posts on Mast Cell Activation Disorder, please visit https://www.drtaniadempsey.com/aboutdrafrin
What do you think? I would like to hear your thoughts or experience with this.
Dr. Ruscio is your leading functional and integrative doctor specializing in gut related disorders such as SIBO, leaky gut, Celiac, IBS and in thyroid disorders such as hypothyroid and hyperthyroid. For more information on how to become a patient, please contact our office. Serving the San Francisco bay area and distance patients via phone and Skype.