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While histamine intolerance is on the milder to moderate side of the spectrum, Mastocytosis is the most severe form of mast cell issues.
Unlike mast cell activation syndrome (MCAS), mast cell mastocytosis is often overlooked, taking patients nearly a decade to get diagnosed. Symptoms often span multiple organs and can include skin rashes, gastrointestinal distress, and life-threatening anaphylaxis.
Often, Mastocytosis patients have failed trialing very strict low histamine diets, antihistamine medications, supplements for histamine intolerance, and other lifestyle changes. Their quality of life is severely compromised and they have great difficulty leading any semblance of a normal life.
Many doctors aren’t aware of the labs available to test for mast cell issues, such as MCAS and mastocytosis, nor what treatment options are worth trying.
To dive into this topic today, I’m joined by Dr. Mariana Castells, M.D., Ph.D., a physician and researcher at Brigham and Women's Hospital with over 30 years of experience in allergy and immunology. She is Director of the Mastocytosis Center, one of the few nationally and internationally recognized centers of excellence providing diagnosis, management, and treatment options for patients with mastocytosis and mast cell activation disorders. She is also the Director of the Drug Hypersensitivity and Desensitization Center which provides over 900 high-risk desensitizations per year for over 20 years to patients with cancer, severe infections and inflammatory diseases who are allergic to their first-line therapy.
Though mast cell Mastocytosis is considered rare, there is so much that even someone with histamine intolerance or mast cell activation syndrome can learn from this conversation (especially when it comes to handling histamine in your diet and testing).
Because no one should lose years of their life to unexplained suffering when answers—and relief—are within reach.
Or, listen on your favorite app: iTunes (Apple Podcasts) | Spotify | Stitcher | TuneIn | Subscribe on Android
In This Episode:
- What is mastocytosis (and why it’s so often missed)
- Mast cells as “hidden” first responders of your immune system
- KIT gene mutation + mast cell problems
- Shocking link between bone loss + mast cell MCAS disorders
- Early warning signs to look for
- Why high-histamine foods aren't your biggest histamine problem
- Testing for mast cell MCAS + Mastocytosis: Blood vs. urine tests
- Newest mastocytosis treatment options
- If you suspect MCAS mast cell or Mastocytosis. here are your next steps!
Quotes
“The histamine that we actually ingest is 1,000 times less than the histamine we carry in the body.”
“Mastocytosis is a big deal. It takes sometimes nine to ten years for patients to be diagnosed.”
Links
Find Dr. Mariana Castells online
Healthy Skin Show ep. 265: Problem with Antihistamines That No One Tells You
Healthy Skin Show ep. 319: Mast Cell Activation Syndrome: What is MCAS + Why It's So Devastating
Mast Cell Current Diagnostic Criteria (Consensus-2)
390: Histamine Intolerance, MCAS + Mastocytosis: What’s The Difference? w/ Dr. Mariana Castells {FULL TRANSCRIPT}
Jennifer Fugo (00:16.122)
Dr. Castells, it is so wonderful to have you here on the show to talk about mast cell mastocytosis. Thank you so much for joining me.
Mariana Castells (00:23.512)
Thank you very much Jen, I'm glad to be here today. I'm glad to talk about cells of the immune system that people don't know too much that are called mast cells, and I'm glad to illustrate, maybe some of the people who will hear this, that they have a rare disease such as mastocytosis.
Jennifer Fugo (00:38.736)
Yeah, it's a big deal. It's a really big topic and it's an incredible specialty. So you are considered an expert in this field, could you just share with everyone a little bit about yourself? Like what are you working on right now, what your specialty is. I think that would be helpful for everyone to know where you're coming from in this conversation.
Mariana Castells (01:00.394)
Yes, thank you. I am a doctor at the Brigham and Women's Hospital, I am an MD-PhD. My PhD is in immunology, and the subject of my PhD was the mast cell biology. So unfolding what are the mast cells made of, where are they, and what do they do in the human body. I direct a center that's called the Brigham and Women's Hospital Mastocytosis Center, and I'm a Harvard professor of medicine. As you may realize, my name is MC, meaning mast cell.
Jennifer Fugo (01:35.883)
Oh my goodness, that is an interesting coincidence. Well, so speaking of mast cells, because I do, I think actually, before we dive into kind of like the more nitty gritty things, let's talk about quickly, what is mastocytosis? Being that I have discussed histamine intolerance and histamine intolerance testing on the show before, and we've talked about mast cell activation syndrome, but mast cell mastocytosis is kind of, it's a big problem. Like if you end up with this, to me, this feels like a big health issue that can feel overwhelming and all-consuming at times. So can you share with everyone, how would you define mastocytosis?
Mariana Castells (02:22.284)
I agree with you, Jen, that mastocytosis is a big deal, it's a problem, it's a rare disease. It takes sometimes nine to ten years for patients to be diagnosed. They suffer from symptoms for a long time until somebody discovers that they have mastocytosis. And to put it in perspective, mast cells, which is the basis of mastocytosis, mastocytosis patients have more of those mast cells in their body, in their bone marrow, in their skin, in their organs. Mast cells are cells of the immune system that protect us against Hymenoptera venom, against parasites, against many things. And those cells were discovered in 1878 by Paul Ehrlich to be present in all organs. So they are the cells that are at the port of entry, around the mouth, in the genitals, in the skin. Everywhere we have mast cells.
And those mass cells contain, in their granules, histamine, and they make prostaglandins, leukotrienes, what we call the mediators. They also have proteases such as tryptase. And when mast cells are active, for example, somebody has an asthma attack, the mast cells in the lung are opened, and they release histamine and they release leukotrienes, and the bronchial trees close up, so that wheezing sound. When somebody has peanut allergy, their mast cells in the throat or the gastrointestinal tract release, again, the histamine, the tryptase, the prostaglandins, and there is swelling and there is potential closure. So people enter into what's called anaphylaxis, which is a big deal and requires to use epinephrine. And so the mast cells can be the bad guys in the sense that when triggered by potential allergens, whether a medication, penicillin, whether a food, like a peanut, whether environmental allergens. Then they release those nasty mediators and people suffer the consequences, including having low blood pressure and passing out. So that can also happen.
In mastocytosis, what happens is the mast cells, to survive, have something on the surface that's called KIT, K-I-T, and that KIT receptor that's on the mast cells becomes mutated for some reason that we don't understand. And the signal to, actually, the mast cells to proliferate and multiply is on all the time, but also to activate.
Jennifer Fugo (04:51.075)
Wow.
Mariana Castells (05:14.914)
So patients have more, they can have spots on their skin and this is like the skin form of the mastocytosis, but they can also have mast cells in the rest of their organs in increased numbers. So that in the bone marrow, if the bone marrow is looked upon, they see more mast cells than normal, the liver, the spleen, the lymph nodes, and the gastrointestinal tract.
So essentially patients, because mast cells are in all organs, patients can have symptoms in all organ systems. They may have a little bit of abdominal bloating, a little bit of diarrhea, they may have flushing, they may have all those symptoms that are very nonspecific. And the doctor says, well, maybe you have inflammatory bowel disease, maybe you have some form of flushing associated with either menopause or some other diseases, pheochromocytoma, carcinoid, others, and they actually don't do the essential test for mastocytosis, which is called tryptase. And so when a doctor, or a nurse, or a physician assistant, or anybody says, okay, I'm going to do a tryptase level, that's when we start unfolding about mastocytosis.
Jennifer Fugo (06:04.314)
So just so I'm clear and everyone else listening, you're saying that mast cell mastocytosis is likely due to this mutation of the receptor, the KIT receptor on the surface of mast cells, that causes it to basically just be always on in terms of replicating. So it just keeps making more and more and more mast cells unendingly. So the person, so it's not that, is it that the mast cells become more easily destabilized, or is it that there's too much, or could it be both?
Mariana Castells (06:44.842)
It is actually both, it is actually both. Because the switch is on, there are more mast cells in the skin. So people have a form of rash that's called urticaria pigmentosa, and they see little dots, and those little dots that are small, brown, red, never go away. And when people are exposed to cold weather or to hot weather, when they eat hot and spicy foods, when they drink alcohol, when they don't sleep well, when they go to surgery, any of those potential triggers make those little dots inflamed. But also, other symptoms can also happen. They may have hot and spicy foods and they have severe abdominal pain, diarrhea. They don't kind of put two things together. Because what's important about mastocytosis is that normally, two organs work together, so the people may have flushing and abdominal pain.
Or they may have some other symptoms like bone disease, also one of the symptoms and signs of mastocytosis is that people in early age can lose bone mass. Like osteopenia and osteoporosis in young women and in young men can be associated, can be actually the first telltale sign of mastocytosis. So that is really important. Somebody is going, oh, you know, my bones hurt, I'm not really sure, or they break a bone, and they go and they say, well, you’ve been losing bone mass, osteopenia, osteoporosis, that might be mastocytosis. So a tryptase again is, here, essential.
And then somebody having a reaction. We had a young woman who delivered a baby, and during the delivery her blood pressure tanked and it was really, really dangerous. And her tryptase was elevated at the time of the event. Her doctor said you had an anaphylactic event during the delivery of the baby, we don't know why. And then she ended up having mastocytosis, so anaphylaxis is also a sign of mastocytosis.
Jennifer Fugo (08:44.582)
Wow, oh my goodness, I mean, that's a blessing that she was in a hospital that was able to help her.
Mariana Castells (08:51.522)
Right.
Jennifer Fugo (08:52.582)
I assume that could have been a life-threatening situation.
Mariana Castells (08:56.866)
Catastrophic, catastrophic.
Jennifer Fugo (09:00.804)
So, I think for someone listening to this who's heard about histamine intolerance, which I think is, I mean this is my clinical experience and opinion, but I think it's way overdiagnosed. I think it's an excuse to not look deeper into why someone is, for example, like you mentioned, developing urticaria and different forms of urticaria, or dermatographia, or angioedema. And we also have mast cell activation syndrome (MCAS). What separates this mastocytosis from those? Just so that the person listening to this understands maybe the degrees or the gradation of difference between them. Because sometimes I feel like they're used interchangeably, and they're really not.
Mariana Castells (09:48.194)
Right, right. So the World Health Organization has placed two diagnoses under what we call mast cell activation disorders. And one is the clonal disorders, meaning that you have a receptor that is mutated. So this is mastocytosis in any form, the skin form or the systemic form. And there is in mastocytosis, we can talk later, a good form, which is called indolent, and then advanced disease, where that is much more complex, associated to hematological disorders, even mast cell leukemia, goes into the advanced disease.
And then there is what we call non-clonal disorders, which is the MCAS, the mast cell activation syndrome. And in those ones here, it's important to indicate that the patients have to have those two symptoms, like we were saying, in two different organs, and that is the criteria. They have to have one of the mediators that is elevated with the tryptase. We also look in the urine, we look to see if there is histamine, leukotrienes, prostaglandins. And then they have to respond to what we call anti-mediator therapy, such that antihistamines seem to help, may not completely help, but seem to help, leukotriene blockers or prostaglandin blockers. And then there is something that has been used that's called omalizumab, Xolair, that some people have used for those mast cell activation syndromes.
So, essentially, how do you acquire non-clonal? Here on the left side we have hematological diseases, that's the mastocytosis and all the clonal disorders. Here on this side we have more like allergic diseases. So people with what we call secondary mast cell activation syndromes, they may have severe allergies, they may have urticaria, they may have also connective tissue disorders, thyroid disorders, diseases in which mast cells are activated because there is another disease. And then there is what we call idiopathic MCAS, where we don't really know why the mast cells are active.
Mariana Castells (12:10.902)
I wanted to tell you also that, since 2016, we have uncovered that there are in the population some people who have extra tryptase genes, and this is called hereditary alpha tryptasemia. And those people who have those extra tryptase genes in chromosome 16, we know now that they can be more prone to have severe anaphylactic events. So there was a recent study that showed that in children and adults who have peanut allergy, if they have those extra tryptase genes, that's called HaT, hereditary alpha tryptasemia, those people reacted badly to a peanut challenge and reacted badly when they were triggered. So it's like some signal that actually makes people more susceptible to severe and anaphylactic reactions, and it's called HaT.
Jennifer Fugo (12:39.206)
Interesting. Okay, so you mentioned tryptase a number of times, which you kind of shared with me that there seems to be a little bit of confusion because sometimes you might say, hey, we need a tryptase marker, but the patient will come back with something else. And so I think it would be good to clarify maybe the difference, since there is some confusion. So what is tryptase, and what should you not test for?
Mariana Castells (13:07.186)
Right. The tryptase, as we were saying, is a marker of mast cells and it has a double function. It can just indicate how many mast cells someone has. And if the tryptase number is 20, that is one of the criteria for mastocytosis. So there's criteria for mastocytosis that says if your tryptase is 20, you should look for potentially a mutation of that KIT, because that is the World Health Organization criteria. And that mutation is called the D816V, so it has a number, 816, so that's the magic number for that mutation. But in addition to indicating how many mast cells are there, it also indicates how active are the mast cells.
So somebody comes to the emergency room and has an acute event after eating a peanut, or being exposed to penicillin, or having had an encounter with something that someone might be allergic to, their tryptase goes up, and then after the event, it goes down. So the tryptase is what actually is the biomarker for an anaphylactic event, and an event that is mast cell activation. So when somebody wants to be diagnosed with, you know, I think I have a mast cell activation disorder, let's get your doctor to do a tryptase level, and let's get your doctor to do that or give you a slip to do that when you are in the worst case scenario. When you're flushing, when you have abdominal pain, when you have brain fog, and any other associated symptoms. When this is happening really actively because someone encountered a trigger, that's the right time to do a tryptase level, and also the right time to do potentially the urinary mediators.
Jennifer Fugo (14:48.88)
Wow. So what you're saying is that if you are really stable the day you go to the lab, it's possible the tryptase number could look normal.
Mariana Castells (15:02.062)
Totally normal, totally normal. With two caveats here, like we were saying, one of the caveats is that if the baseline tryptase is eight, it's also a magic number, then the likelihood that that person has this HaT, the hereditary tryptasemia, is pretty high. Because the normal number is not what the laboratory says, 11.4, anymore, it's below eight. So if somebody has a tryptase of six, five, three, up to eight, everything is okay, baseline is good. And at the time of the event, when they're really flushed, and itching, and diarrhea, abdominal pain, bloating, then another tryptase should be obtained because the difference between the two tryptases, 20% difference, makes the diagnosis of the MCAS.
Jennifer Fugo (15:51.43)
And you also said that there's a urinary test that you look for as well?
Mariana Castells (15:56.576)
Yes, there are three biomarkers that can be looked upon in the urine. It's called histamine, prostaglandins, and leukotrienes. So those we can measure now, either in spot urine or in 24-hour urine collection. Typically, Mayo Clinic has been kind of the place where all those tests go, they have a big laboratory operation for that, and they are developing something that we already use here at the Brigham, which is the spot urine. So you can actually, just at the time of the event, have a tube of urine, send it, and then have those mediators measured. Right now, again, this is coming of age, but up to now, we had to have a 24-hour urine collection.
Jennifer Fugo (16:43.462)
Oh, wow, so this is really like a developing, we are developing new tests and things to be more present to the moment when there's a problem, where you might not be able to get into a lab to go get it checked.
Mariana Castells (16:48.664)
Yes! Right. Right.
Jennifer Fugo (16:54.444)
Wow, that is so cool.
Mariana Castells (17:00.084)
One thing that I wanted also to mention is that hereditary alpha tryptasemia, which is something new, is an autosomal dominant gene. So in families, the grandmother, the mother, and the daughter or the son may have had the same symptoms and may have had those anaphylactic events. Because in the description by Jonathan Lyons and Josh Miller initially, it shows that this comes in pedigrees, so the families of, again, three generations can express those genes.
Jennifer Fugo (17:34.119)
Hmm, so interesting. And actually, I have one quick question. I just thought of this because obviously, you talked about histamine, testing for histamine levels, which I think I know the answer to this, but I think it would be great to get your take. Just like tryptase, does the histamine level also potentially fluctuate, such that if if you're stable that day and you go to the lab, the histamine level might not look elevated in the blood?
Mariana Castells (18:02.936)
I totally agree with you. And the blood is not the place to look for histamine because the histamine fluctuates every hour on the hour. One of the misconceptions that we have is that histamine intolerance comes from eating something and not being able to tolerate it. But the histamine that we actually ingest, it's 1,000 times less than the histamine we carry in the body. All the mast cells have histamine in the granules, and they release it constantly during the day because histamine is actually a good thing to have, it kind of cleans the organs. So histamine goes up and down, up and down, up and down during the day, so if you measure like 8 am, it would be high, you measure at 12, you would be low, you measure at 3, you would be high, measure at 4, you would be low. So there's very nice studies that show that you shouldn't measure histamine in the blood because it fluctuates.
Measuring it in the urine makes more sense because then all the histamine that has been released during the day then comes in the urine, so that it's a collection. And also even getting a spot urine makes sense because the histamine that you make during the day has to be filtered through the kidney, and so then you kind of collect it, and that makes a lot of sense. So essentially, the histamine intolerance is probably not something in terms of a diagnosis that we can make. We can measure the histamine in the urine and see, either in 24-hour or spot urine, is it elevated? And if it's elevated, what it means is that your mast cells produce a lot of histamine, they release a lot of histamine for things that should be investigated. But again, avoiding all the foods that have histamine doesn't make any sense because they don't even have one-tenth of what we have in our body.
Jennifer Fugo (19:54.535)
First of all, I have to say, thank you for correcting me because that was something I was told many, many years ago. I had a client, this was sort of how I learned about mastocytosis, I had this client that had really, really severe symptoms that didn't make any sense. And as I started to learn and she found a physician that was willing to work with her, so I was working on the more diet side trying to help support her, whereas she had all these blood markers run. And then in talking to other colleagues, they were like, oh, well, you know, histamine in the blood can be all over the place, so it's not a great marker for that. And so this is not, again, this is not my area of expertise, if you run a mastocytosis center, you have way more experience than I do. And the fact that you're saying that the amount of histamine consumed, and you're speaking from like a dietary standpoint, right? What we consume through diet, water.
Mariana Castells (20:52.366)
Tomatoes, strawberries, and you name it. All of that, you put it together, and smash it, and then you measure how much histamine there is. There is that amount, and the amount of our mast cells is this amount.
Jennifer Fugo (21:06.534)
Wow. So it's really, and you know what's very interesting? I have had some clients where a low-histamine diet does not help at all. They have no difference in their symptoms. And that makes so much sense now, because their body is producing so much, the amount, like you're saying, that's coming in from food is so minuscule. Wow.
Mariana Castells (21:33.624)
Yeah, I don't recommend anybody to kind of avoid foods that have histamine, just the foods that they don't feel comfortable with. So some people say, you know, with alcohol, I flush, and they have a mast cell activation disorder that we can diagnose, with hot and spicy foods, I flush, with cured meats, I flush, with chocolate, I flush. That is real, that is real. All those things can activate mast cells one way or another. It's not what they contain, it's what they do to the mast cell. The mast cells have receptors that sense how spicy is your food, how hot is your food. So, like I said, they are the prime cells that we encounter in our mouth when we ingest. And they are able to sense all those things. And truly, some people cannot tolerate well alcohol, and some people cannot tolerate hot and spicy food, but it's not because that contains histamine.
And so there is not one-size-fits-all, let's put it that way. Some patients tell me when I go and fly, and just not sleeping enough hours, it's totally disruptive. I totally agree, that is also a big trigger for many people. Exercise, stress, emotions, you know, people become upset and that triggers mast cells too. So definitely a lot of triggers, but histamine is not one of them or the principle.
Jennifer Fugo (22:56.294)
Can I also ask, and I know this is sort of a side issue, and you and I will discuss, hopefully at some point in the future, more about drug hypersensitivity and all of this stuff, because I just find all of this so fascinating. But I was curious, in a lot of cases that I have worked with where they have pretty significant, we'll just call it histamine intolerance, probably in some level of the lower end of mast cell disorders, of the spectrum. A lot of times I'll see really elevated total IgE, sometimes they'll have really high eosinophils. Is there any connection between those types of markers or the eosinophils? I know that they're not mast cells, but do you tend to see that at all in these patients, where maybe that too is also elevated?
Mariana Castells (23:45.21)
Right, I mean, it's a great point. Elevated IgE means that those people are what we call atopic. So they can actually react to many things, whether environmental things, you know, a cat, a pollen, dust mites, or a food or a drug. So IgE binds to the mast cells and makes the mast cells much more unstable. So as I was mentioning at the beginning, we have what we call secondary mast cell activation syndromes where people are very allergic. And in addition to being triggered by when they're exposed, they're triggered most of the time because putting a lot of IgE on mast cells makes them very unstable.
And that brings me back to initially when I was mentioning Xolair, omalizumab, one thing that has been used by many doctors for chronic idiopathic urticaria, for food allergies now, the FDA just approved it, and it is now approved for children six years of age. So it's a very safe drug. And we use it for asthma and for many other things. So that removes the IgE, and the mast cells become more stable per se. So it's not just that we're eliminating the allergy per se, whatever it is, but we are making the mast cells more stable. So IgE is definitely related to mast cell activation, definitely. Eosinophils are different because eosinophils are cells that become intertwined with mast cells, because mast cells produce the food for eosinophils.
Jennifer Fugo (25:13.295)
Really?
Mariana Castells (25:39.15)
In eosinophilic disorders, in those in which patients can have a lot of eosinophils in the esophagus, in the gastric mucosa, and that require a lot of things, whether modification of their diets or monoclonals, the mast cells are found there in huge numbers also. So there's cross-talk. Mast cells produce interleukin-3 and interleukin-5, that is the food for eosinophils, and they call them. In mastocytosis, for example, 30% of the patients that have more mast cells also have more eosinophils. So they kind of feed into each other. Whether the eosinophils participate in the symptoms of mast cell activation disorders, that's a little bit different, because flushing, itching, hiving, that doesn't come from eosinophils, or abdominal bloating. But hypereosinophilic syndromes, those are associated with increased mast cells also.
Jennifer Fugo (26:16.122)
And I wanted to ask you about another metabolite of histamine that you had mentioned in some of the notes that you had sent me, the N-methylhistamine, which is really the type of histamine that is more, I believe, intracellular. I think people don't realize that there's histamine within the GI tract that is broken down by diamine oxidase, the enzyme, and then we have our other enzyme that's intracellular, so it's inside the cells, because people get confused of how histamine gets broken down. Can you talk a little bit about N-methylhistamine and also the enzyme that breaks down histamine inside the cells? Just so that they know there's actually two different things, because I find that people will buy DAO enzymes and they think that's gonna solve their problem, and in reality, I tend to find that it doesn't really help in most cases. And this kind of, your, oh my goodness, what a light bulb moment to realize that the food portion responsible for histamine is so much smaller compared to what's happening inside the body. I mean, you've like flipped this on its head for me. So this is amazing, but I'd love to know more about that.
Mariana Castells (27:34.54)
Yeah, going back real quick to the food, there is only one syndrome, that's called scombroid syndrome, where the fish are spoiled, rotten fish, and they produce a ton of histamines. So the people eat it, and then they flush. And that has a sizable amount of histamines. For example, a family goes to a seafood restaurant, they all eat the same kind of meal, everybody can get sick. And that's called scombroid. And that scombroid is truly due to the rotten fish that releases a ton of histamine. So again, that's the only time in our lives where we can encounter from the outside more histamine than what we have inside. So that's the only one.
Histamine, like I said, is a biomarker of mast cells that also is produced by some other cells, like in the gastrointestinal tract there is also histamine production. Histamine has many functions, it closes the blood vessels, it opens pores in the connective tissue blood vessels, so histamine has to be tightly regulated. So there are three, the histaminases, the DAOs, N-methyltransferase, for example, there's three enzymes that metabolize the histamine. When histamine is released, what really counts is the histamine that is released in the extracellular space, histamine that is released in the gastrointestinal space, histamine that's released in the blood. So all of those are released from cells, and they are quickly metabolized.
So the metabolization of histamine leads to N-methylhistamine. So like I said, histamine is up and down, up and down, up and down, and it becomes really quickly metabolized to N-methylhistamine that goes to the urine. And so that is a more stable metabolite that we can measure. Because histamine has those three enzymes that actually break down histamine, it is kind of hard to capture them in the form of histamine. So then when it's metabolized, N-methylhistamine is actually captured in the urine, and it's more stable, like we can continue to measure, like in 24 hours, and we can continue to measure. But measuring histamine is a very fleeting thing because again, we should take like six or seven blood draws in a person in 24 hours to know how much histamine was made.
Jennifer Fugo (30:07.514)
Wow, and that's really only possible if you're hospitalized, essentially. That's not practical for most people.
Mariana Castells (30:14.534)
Right, and those studies had been done earlier by doctors because during major, for example, cardiac surgery, they were able to measure histamine on the hour. And that's how we discovered that histamine was up and down, up and down, up and down all the time. So a measurement was not sufficient to assess how much histamine was released.
Jennifer Fugo (30:38.052)
And just really quick, somebody might go, well, can't we just measure the mast cells themself? Is that possible?
Mariana Castells (30:46.05)
We cannot. We cannot, mast cells are not in the blood. So the same way that you can take a blood sample and measure your white cells, you know, and they are called leukocytes, and your red blood cells and your platelets, you can measure all of that. And from the white cells, you can measure how many lymphocytes, how many eosinophils, how many basophils, how many white cells like neutrophils. All of that can actually be measured. But in the blood there is only a very small number of what we call mast cell precursors that go unrecognized, and the mast cells are only in the tissues.
So like I said at the beginning, they are the first port of entry policemen that actually in the eyes, in the nose, in the mouth, in the gastrointestinal tract, in the vaginal area, filled with mast cells, but it's because they want not to have parasites, hymenoptera, everything that we potentially could be infected with, they are the ones that have got to get rid of it. And so we cannot measure directly how many mast cells we have or what they're doing.
Jennifer Fugo (31:57.393)
So thank you for sharing that, because I have gotten that question quite a lot, and I had no idea how to answer it. So I'm glad that we can help people ask for the right testing and kind of point them towards the right testing. Just one last quick question for you about this. Do you believe that, you had mentioned antihistamines and Xolair, and I don't remember the name of it, but I did see that the FDA did approve in quarter one of 2025 kind of like a sister medication to Xolair. Do you feel like mast cell stabilizing medications, like I've had some clients where they were prescribed ketotifen or cromolyn sodium, has been maybe helpful?
Mariana Castells (32:45.838)
Yeah, those have been fantastic medications. So in 2023, the first drug for mastocytosis, for the indolent kind, the good kind, the one that 80% of patients who have mastocytosis have, it's called indolent systemic mastocytosis, the first drug that was a one-stop for everybody is avapritinib. And that was approved by the FDA in 2023 because there was a pivotal trial that compared avapritinib with placebo, and they found out that there was a tremendous advantage lowering the number of mast cells, lowering the tryptase level, lowering the mutation, and then making the symptoms much better. Actually, one of the advantages is that people got rid of the skin lesions. That was phenomenal. And then people got rid of their bloating, of their flushing, of their diarrhea, of their brain fog.
So again, that happened in 2023. That was fabulous. I've been dedicating 35 years of my career to that moment actually. Because when I was a fellow, the instruments or the tools that you had to actually block mast cells were antihistamines, and we now have the new generation. The old generation antihistamines is to die because, for example, Benadryl has been associated with dementia. And so people who have been overdoing Benadryl really need to be careful, it really curtails the brain functions. Non-sedating antihistamines are great, they are the new generation, and we can use them up to four times a day with urticaria and others. They don't impair, they don't go to the brain. So antihistamines, fantastic.
And then leukotriene blockers are also good. And then we have two drugs that also actually are mast cell stabilizers, the ketotifen and the sodium cromolyn. And those two drugs truly, truly block the mast cell. The problem with sodium cromolyn, you have to take it four times a day. So it's like two little vials of 100 milligrams, so 200 milligrams four times a day. In some patients, even for mastocytosis, they swear by sodium cromolyn. So it's a really good drug, I've used it for 20 years, fantastic. And then ketotifen is also a really good mast cell stabilizer. So again, those two drugs work very well.
Now, in addition to those drugs, if the patient has to take another like four, five, six medications for indolent systemic mastocytosis, is something like avapritinib, potentially the solution, instead of taking six medications, taking one. And that is what this new era of targeted medications is coming along. So the treatment for mastocytosis, now called tyrosine kinase inhibitors, which avapritinib is part of that, and then there are many we have here at the Brigham for clinical trials. There is also what we call BTK inhibitors, which have been used for food allergy, and it's the next generation also for people with peanut allergy, it's a fantastic tool. So again, the new developments, we are repurposing what we did. But those medications in the past, as mast cell stabilizers, worked really well.
Jennifer Fugo (36:04.378)
That's wonderful to hear. And I think it just gives people more options. And that way too, for those who don't realize, maybe they're just doing Benadryl, as you said, we want to be careful with that, that they could talk to their doctor, whomever that is, whoever's helping them, potentially look at some other options. Especially if their quality of life is really compromised by what is happening, because that has been my experience, is that usually this is a huge quality of life issue. I have, I guess because my dad was a doctor, I just have come to realize that we don't get a prize for the level of suffering that we incur in life. When the quality of your life is really poor, you don't get that time back.
And so I really do, I've had clients where they're really not sure, they might be a little fearful of medication. And I get that, everyone, we all have to make our own decisions of what's best for us. But my feeling is you don't get the time back with your kids. You don't get the time back with your family. If you can't be the fullest you possible, right, you don't get that time back. So do you have any final parting words for someone who maybe is dealing with this, who is really, they want to get better, but they're not sure where to go. And is it possible, they're even thinking like, is it even possible for me to see any improvement to things? What would you share with them, Dr. Castells?
Mariana Castells (37:40.67)
Yeah, I think your words are really on target. You know, my mission has been to empower patients because they are the ones who know how much they suffer. They are the ones who know how much impairment is there to their social life, not being able to travel, not being able to go to a wedding, not being able to be with their kid outside, and also suffering professionally. There are patients who have become disabled with this. So my mission has been to empower the patients. I cannot fathom that, when I was a fellow, there was nine years before somebody would be diagnosed with a mast cell disorder or mastocytosis.
I published also, in the New England Journal, a paper in 2016 or 2017, a patient who was running marathons and he ran the Boston Marathon, he took two Advils and he became hypotensive. He was intubated for a week. And it happened that his trip days were 2000. But an episode similar to what happened to him had been happening along all the states where he had been running marathons, and nobody ever asked for a tryptase level. So my point is that many specialists will see patients who may have, potentially, mast cell disorders, from dermatologists to gastroenterologists, even to neurologists, allergists, hematologists, and I think it's important for the patient to educate their physician. Like, please can you do for me a tryptase level or the urinary mediators, because you know I have read, I have heard, I know the mast cell activation disorders can be diagnosed that way. And I don't think it's fair for the patients to wait that long to be diagnosed. So I think if we start here, I think we're going to shorten the suffering, we're going to shorten the time, and as you mentioned, then the patients can be directed to the right specialist.
We have a mastocytosis center here. There is another tool that is important, it's called AIM, American Initiative for Mass Cell Disorders. And they can google that, and wherever the state is where they are, there will be a mastocytosis center that can actually provide either guidance or can actually see those patients. So I think it's really important to know about how to educate health care providers.
Jennifer Fugo (40:01.158)
Well, thank you so much for joining us today. You have blown my mind, so thank you. Thank you for educating me and being here to share this with the patients and listeners, and even the physicians and physician assistants, and everybody who listens to this show who's dedicated to try to find a better way forward. Thank you so much for sharing your massive amount of wisdom with everyone. And I hope that you will come back sometime.
Mariana Castells (40:29.454)
Thank you very much, and congratulations on what you do to educate the public, to educate patients. This is phenomenal and we need more of that. So thank you for having me today.
