Can you discuss the co-existence of Mast Cell Activation Syndrome (MCAS) and Eosinophilic Esophagitis in so many patients?

Eosinophilic esophagitis is sometimes suspected in patients whose true diagnosis turns out to be MCAS. I have also seen eosinophilic esophagitis in a small subpopulation of MCAS patients and suspect — since the EoE can’t possibly account for the full range and duration of all the symptoms and findings in those patients — that the EoE in those patients is just another consequence of their MCAS. This is not hard to envision given that some of the mediators produced by mast cells can drive eosinophil reproduction and activation. I cannot put a specific number on the fraction of the EoE population that has underlying MCAS because there has not been any more study of that subject than there has been of the proportion of the fibromyalgia population, chronic fatigue syndrome population, irritable bowel syndrome population, or Gulf War Illness population that could have underlying MCAS.

Such studies of the chronic idiopathic inflammatory diseases, including EoE, are greatly needed so that useful new directions for research can be identified for those diseases which have a significant underpinning in MCAS. Although the overall MCAD population seems to bear quite a menagerie of mutations in various regulatory genes in their dysfunctional mast cells, we could wind up discovering that EoE/MCAS patients carry more specific mutational patterns which differ from those seen in fibromyalgia/MCAS, chronic fatigue/MCAS, IBS/MCAS, GWI/MCAS.


Please discuss the root cause of Mast Cell Activation Syndrome (MCAS). Is it exposure to environmental toxins which causes limbic system dysfunction, over-reactivity and a fight or flight response?

Ah, the 64 trillion-dollar question. Bottom line at present: we don’t know. Many hypotheses have been presented. The one I feel is most credible (certainly subject to change as new data emerges!) is that it’s a combination of genetics and environment. It’s increasingly evident that most MCAS patients have mutations in one or more of the regulatory genes in their dysfunctional mast cells. These mutations are almost never inborn (i.e., “germline,” or inherited, mutations) and instead are almost always acquired (“somatic” mutations), typically at a relatively early age (in some patients perhaps even in utero). The particular set of these mutations present in any one patient (their “mutational profile”) is usually different from any other patient’s mutational profile. Even in families affected by MCAS, the disease may not affect every member of the family, and the mutational profiles of the different MCAS-affected members of the family are usually different. This goes a long way toward explaining why the clinical presentation/behavior of the disease can be so different from one member of an affected family to the next affected member of an affected family, in turn making it difficult to recognize the infiltration of the disease throughout the family. How can we reconcile the familial propensity of the disease (implying that something ought to be getting inherited in MCAS-afflicted families) with the somatic rather than germline nature of the mutations and the distinction in mutational profiles among different affected members of an affected family? Current thinking suggests that perhaps something really is getting inherited in MCAS-afflicted families, but it’s not the genetic mutation which is being inherited. Instead, it may be epigenetic mutations which are being inherited. Epigenes can be thought of as non-DNA “modifiers” of various sorts to our DNA-based genes — and we know that epigenes can be mutated and epigenes — normal and mutated — can be inherited. Mutated epigenes can create states of fragility in our genes themselves.

And that’s where the environmental side of the equation comes in. Various potent chemical messengers in our body — cytokines and other classes — can interact with fragile genetic states to cause genetic mutations. These “cytokine storms” typically emerge when we are facing significant physical or psychological stressors.

It may be the interaction between certain cytokine storm patterns, induced by various stressors, and certain genetic fragility states, induced by various epigenetic mutational profiles, which give rise to mutations of a wide variety of sorts in the mast cell regulatory genes in any of the precursor cells (e.g., the stem cell) which give rise to the mast cell. Once enough mast cells with dysfunctional regulatory genes have emerged, welcome to MCAD/MCAS.

Obviously, the number of possible permutations of these various factors is gargantuan, perhaps explaining why MCAD/MCAS clinically presents/behaves with such tremendous, confounding, diagnostically challenging variability.

This is just one hypothesis. Other causes of the disease are possible, too. For example, in some patients, autoantibodies may arise which stimulate mast cell activation. It’s even possible that some MCAS patients have entirely normal mast cells which are normally reacting to some potent trigger which may or may not be identifiable.

Keep in mind, too, that in some patients, MCAS may simply be a secondary/reactive phenomenon to some other disease such as cancer.

Ultimately, it is going to require a lot more research to answer the question as to what causes MCAS, but given what is increasingly appearing to be a high rate of prevalence of the disease, and given the financial and human costs of the disease causes, it seems worth investing in that research.


Why are the urine tests for Mast Cell Activation Syndrome (MCAS) often negative when the disorder is present? For example, having all of the symptoms / responding to treatment/ other illness ruled out.

One could also ask why the blood tests are often negative. Accurate measurement of mast cell mediators is challenging under the best of circumstances. For example, many mast cell mediators have very short half-lives and quickly break down when exposed to heat (certainly body heat, and perhaps even room temperature heat). For example, prostaglandin D2 and heparin — both mediators relatively specific to the mast cell — have very short half-lives, on the order of about one minute. Therefore, if the blood or urine specimen in which we intend to measure levels of these mediators is left exposed to heat (even room temperature) for one minute after collection from the patient, one-half of the prostaglandin D2 and heparin in that sample is now gone, leaving one-half of what was originally there. And if the specimen is left unchilled for a second minute, then one-half of the remaining one-half is now gone, leaving only a quarter of what was originally there. You can see how a specimen for prostaglandin D2 or heparin testing doesn’t have to be left unchilled for very long before most of what you’re looking for has disappeared — leaving the patient and her doctor to ponder why somebody with so many symptoms could have a normal (or even below-normal) prostaglandin D2 or heparin level. Furthermore, most mast cell mediator tests are not done at the laboratory where the specimens are collected and instead are shipped hundreds or thousands of miles to distant reference laboratories, perhaps sitting overnight in an unventilated cargo container on a hot airport tarmac. Clearly, the personnel and logistical challenges with regard to maintaining continuous specimen chilling are considerable, but there are other challenges, too. For example, certain drugs and other substances can greatly confound certain mast cell mediator tests, and ensuring abstinence from such confounders in the few days prior to specimen collection can be challenging.

It also has to be kept in mind that the few mediators we measure in a diagnostic work-up for MCAS are a very poor surrogate for the totality of the signaling chaos in the disease. Mast cells produce and release more than 200 mediators, each of which has a very wide range of effects. Most of these mediators, though, are presently measurable only in research laboratories, not clinical laboratories. Furthermore, of the minority of mast cell mediators which are presently measurable in clinical laboratories, most of that minority are not specific to the mast cell. For example, we can measure an interleukin-6 (IL-6) level in clinical laboratories today, and IL-6 is a reasonably good marker of inflammation and is definitely produced by the mast cell, but lots of other types of cells, too, make IL-6, so if we find an elevated IL-6 level in a patient, that doesn’t tell us anything about whether that excess IL-6 came from the patient’s mast cells (i.e., was a consequence of inappropriate mast cell activation) or came from other types of the patient’s cells not including the mast cell. In the end, we’re left with very few of the mast cell’s great many mediators which can be measured in the clinical laboratory and which are relatively specific to the mast cell. But if we’re measuring so few of the mast cell’s mediators, and if each mediator causes such a wide range of effects, why on earth would we think that the mediators we’re actually measuring necessarily have much to do with the symptoms the patient is suffering? It could easily be the case that the patient’s symptoms are coming about from mediators which are *not* being measured. In fact, given that we’re measuring such a tiny fraction of the mast cell’s total mediator set, it should be *expected* that the mediators we’re measuring probably have relatively little to do with the symptoms being seen in the *average* MCAD/MCAS patient. As such, then, it shouldn’t be surprising that the mediators we’re measuring often show unremarkable levels — even when the specimens are obtained at particularly symptomatic times.

It’s quite a feat when elevated levels of any of the mediators relatively specific to the mast cell are actually detected in a patient who clinically appears to have MCAS, but nevertheless, if everybody in the chain of testing (from the patient straight on through to the final technician actually running the testing instrument) does his/her job correctly, then it’s not only possible but in fact quite common to find elevations in the mediators we test in patients who clinically appear to have MCAS. That said, the challenges are such that nobody should “give up” looking for MCAS after just a single negative round of mediator testing. There’s nothing about a negative initial round of testing which invalidates/refutes/negates even a single piece of the patient’s history — a history which was suggestive enough of MCAS to lead to testing in the first place (and usually at a point in the patient’s course when every other diagnosis worth considering has already been ruled out). No, if there’s a negative initial round of testing, the doctor and the patient (and the laboratory which collected the specimens) should try to “debug” what may have led to falsely negative results — and then try again, albeit preferably at a point when the patient is even more symptomatic. I typically pursue up to three rounds of mediator testing before giving up on this route to diagnosis, and I don’t even count any round of testing which yielded negative results if I manage to identify a clear point of specimen mishandling or confounding substance use. In my experience, the vast majority of MCAS patients are diagnosable within three rounds of “non-invasive” blood and urine testing. After three rounds of negative results (during which time the history that’s suggestive of MCAS of course hasn’t changed a bit), I think about pursuing “invasive” gastrointestinal tract endoscopies with biopsies to look for increased numbers of mast cells in the GI tract, but I hate to do invasive testing when non-invasive testing gets the answer most of the time. (Of course, many MCAD/MCAS patients have long had GI symptoms which led to endoscopies with biopsies, and if that’s the case in the individual patient, then I try to make use of that “low-hanging fruit” and ask early for the pathologist to review all of the biopsies still on file with the additional special staining needed to reveal the mast cells in the specimens.)

It’s always possible, of course, that the patient might have a rare variant of MCAS which simply does not manifest elevated levels of any of the mediators we presently test and does not manifest any increased numbers of mast cells in any tissue, but, well, that’s a pretty rare scenario. Rare things do (rarely) happen, though, so when we find a patient whose history appears best explained by MCAS but who manifests no laboratory evidence of the disease on three rounds of mediator testing plus a reasonable extent of tissue biopsies, it’s then time to go “back to the drawing board” and re-think the entire case, trying to identify whether there are any other human diseases which might also explain most or all of the symptoms and findings in the case.

MCAS may explain much chronic mysterious illness of general themes of inflammation, allergic-type phenomena, and abnormal growth/development in assorted tissues, but it likely doesn’t explain all such illness, so the diagnostician is cautioned to always think carefully about other diseases which might mimic at least some aspects of MCAS.


How can one deal with histamine migraines? No one seems to know ANYTHING about this. What are the top 3 things someone can do if they have a histamine migraine?

I’m not exactly sure what you mean by a “histamine migraine.” I presume you’re talking about a migraine which appears to be induced by intake of histamine, but I can’t say for sure I’m interpreting that right. Migraines are common problems in MCAS, but — as with most of the symptoms the disease can produce — there can be different mechanisms by which the disease can produce migraines, and thus there often are different treatments which work to control these different mechanisms to yield therapeutic success. At present, it’s not possible to predict which medications are most likely to help which symptoms in which mast cell patients, so it requires patient, persistent, methodical “trial-and-error” (on the parts of both the patient and the treating provider) to identify which treatments will help which patients. To be sure, though, “Step 1” in treating MCAS is not even any particular drug. No, “Step 1” is identify the patient’s triggers — as precisely as possible — and then do one’s best to avoid them. So if one has determined that histamine ingestion is a trigger for an MCAS patient’s migraines, then avoidance of histamine ingestion by that patient (for example, by adhering to a “low-histamine diet” — of which there are many types, with no one of these clearly better than any other) is probably the single best thing that one can do to decrease “histamine migraine” headaches. “Step 2” in treating MCAS is identifying the patient’s optimal antihistamine regimen, by which I mean a combination of an H1 blocker (and usually a non-sedating H1 blocker) and an H2 blocker. This often requires spending a few months simply trying the different H1 blockers and the different H2 blockers (virtually all of which are available over-the-counter) to identify which ones serve the patient best. (MCAS patients usually need antihistamines long-term, so why not spend the time needed to figure out specifically which antihistamines will serve the patient best?) Sometimes, simply adding an H1 blocker to an H2 blocker (or vice versa), or increasing the dosing frequency of these drugs (for example, from once a day to twice a day) is all that’s needed to see significant improvement in an MCAS patient’s symptoms including migraines. “Steps 3 through N” in treating MCAS are for the patient to work closely with his treating provider to patiently, persistently, methodically try the boatload of other interventions found helpful in various MCAS patients.


If someone has been diagnosed with Mast Cell Activation Syndrome (MCAS), but the waiting lists for knowledgeable MCAS doctors are months if not years long, what are the most important steps patients can take in the meantime?

At present, only a decade into our understanding that the disease we now call MCAS exists, there unfortunately (but not surprisingly) are still only a few doctors who are knowledgeable in this area, so for most patients, it’s unlikely they’ll find an “MCAS-aware” doctor locally. Nevertheless, what every MCAS patient needs more than anything else (to have a good chance at successfully controlling the disease) is a *local* prescribing provider (whether an M.D., D.O., P.A., N.P.) to serve as his/her “principal partner” for dealing with the disease (note this can be, but certainly does not have to be, a “primary care physician”) — but since it’s unlikely one will find a local provider who already knows about the disease, then one needs to find a local provider who at least is willing to *learn* about the disease and willing to at least *try* to help the patient manage it. Such physicians should be encouraged to reach out to MCAS experts, too, to discuss challenging cases and other questions about the disease. It can be difficult finding local physicians willing to learn about, and try to help with, MCAS, but in my experience, most communities have at least one or two such physicians. It’s worth noting, too, that even if it’s still the case at present that most physicians have never heard of MCAS, most of the drugs which are reasonable to try in this disease are drugs which most physicians have used, or heard of using, for conditions likely related to MCAS, and thus are drugs which most physicians should feel comfortable in prescribing and managing regardless of how limited their prior experience with MCAS may be. Only when one gets to the point of needing to try a particularly expensive or unusual drug should the patient’s “principal partner” refer the patient to a local specialist with experience in using that drug (even if that experience in prescribing/managing that drug has not been for MCAS) so that the patient can at least be considered for a short trial of the drug to see if there’s any signal of effectiveness.

If absolutely no local prescribing providers can be found to help, some patients nevertheless can still make significant progress by attending diligently to “Step 1” and then “Step 2” as described above. It’s hard to see how empiric trials of antihistamines — taken at reasonable doses — can be significantly harmful either medically or financially (they are available without prescription, after all), but it is difficult to advocate for pressing on beyond antihistamine trials until a diagnosis of mast cell disease is clearly identified and a local physician is identified to help the patient work through trials of other therapies.


Is hypermobile elhers danlos (hEDS) the core of Mast Cell Activation Snydrome (MCAS) and pots? Or has MCAS been triggered by something else and has no link with hEDS?

Ah, another $64 — well, perhaps $64 billion instead of $64 trillion — question. Simple answer: we don’t know. It’s of course possible that in most patients with both hEDS and MCAS, or both POTS and MCAS, there might not be any linkage at all between the two conditions. Sir William of Occam, though, would argue it’s more likely there *is* a linkage, even if we don’t presently know what it is. It’s not that the linkage cannot be determined; rather, it is that not enough research has been done yet to determine it. As is the case with most problems, the problem of what the nature of an hEDS-MCAS linkage (if any) might be is solvable; it just needs sufficient research.

With regard to POTS, mast cells are commonly found in the walls of blood vessels, and mast cells certainly have the ability to output mediators which can cause blood vessels to acutely dilate, which of course leads to loss of pressure, so it’s possible that in at least some cases of POTS, dysfunctional mast cells in arterial walls might be periodically releasing vasodilatory mediators to acutely cause “POTS symptoms.” But, again, that’s just a hypothesis, so appropriately rigorous study is needed to prove or disprove it.

With regard to hEDS, it should be noted that it’s now pretty clear that mast cells, through their mediator output, are integrally involved in guiding growth and development in all tissues. That is not to say that mast cells are solely responsible for guiding growth and development but rather to say that mast cells are so closely involved in guiding growth and development that without mast cells, it should not be surprising if growth and development in any particular tissue were to go awry. Therefore, it’s not that great a leap of the imagination to envision the possibility (i.e., a hypothesis) of aberrant connective tissue growth (in potentially a wide variety of manners) in a person if that person’s mast cells were to chronically operate incorrectly/abnormally in a fashion which influences connective tissue growth (as opposed, so to speak, to a fashion which drives inflammation or allergic-type phenomena). I often analogize to my patients the *potential* MCAS-hEDS connection in the following fashion: imagine one starts at the beginning of the Lexus assembly line — that is, the assembly line for normal connective tissue, which is a finely “engineered” piece of (biological) machinery — with all the normal parts needed to make a Lexus (all the normal proteins needed to make healthy connective tissue). And now imagine there are various errors in the assembly instructions — mutations in the genes producing mediators which influence assembly of connective tissue out of the protein components of such tissue — at various stages along the assembly line. In such a scenario, one should be so lucky to get something off the end of the assembly line that’s even remotely drivable, let alone an actual Lexus. And thus, it doesn’t seem surprising to get weak connective tissue off the end of the connective tissue assembly line in a patient with MCAD/MCAS. But, again, all of this is just a hypothesis, so appropriate rigorous study is needed to prove or disprove it.

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If you would like to see a NY Mast Cell Activation Disorder specialist, Dr. Lawrence Afrin is now seeing patients in a private practice setting at our office in Armonk, NY. To make an appointment with Dr. Afrin, please call the office or contact us here