Mast Cells: Friend or Foe? with Dr. Theoharis Theoharides

[01:02] Dr. Linda Bluestein: Welcome back, every bendy body, to the Bendy Bodies Podcast with your host and founder, Dr. Linda Bluestein, the Hypermobility MD. Today we're going to be digging into so many more things about mast cells and mast cell activation, and hopefully this episode will help so many more people get accurately diagnosed and treated. But first, let me share with you a very special treat. My friend and pain medicine colleague Dr. Pradeep Chopra is back as a guest co-host. Most of you know Dr. Chopra for his incredible work in EDS, POTS, MCAS, CRPS, and central sensitization disorders. For the 2 or so people on the planet who don't know Dr. Chopra, he is a Harvard-trained, board-certified pain medicine specialist with over 25 years of experience treating complex pain and multisystem disorders. Jennifer Milner and I interviewed Dr. Chopra for episodes number 70 through 73, which covered the impacts of EDS in a head-to-toe fashion. Dr. Chopra also joined me as a guest co-host for episode 77, where we interviewed world-renowned EDS specialist neurosurgeon, Dr. Paulo Bolognese. So I'm so excited to have Dr. Chopra back today. How are you?

[02:13] Pradeep Chopra: Good. Happy to be with you again.

[02:16] Dr. Linda Bluestein: And our guest today is Dr. Theoharis Theoharides. For part 1 of that conversation and to hear the more detailed bio, please check out my first interview with him on episode 139. As always, this information is for educational purposes only and it's not a substitute for personalized medical advice. Stick around until the very end so you don't miss any of our special hypermobility hacks. Let's get started.
[02:43] All right, I am so excited to have Dr. Theoharides back today because we had a great conversation in part 1, which was episode 139. And as you know, I have Dr. Chopra here as my guest co-host, and we're going to have a great conversation. I'm so excited to chat with both of you.

[03:02] Dr. Theoharis Theoharides: Same here.

[03:03] Pradeep Chopra: Thank you.

[03:04] Dr. Linda Bluestein: I think that today it would be really helpful if we can really present information about mast cell activation syndrome that would be applicable to primary care providers. So that patients, when they go to primary care providers, they can say, I heard from this expert, Dr. Theoharides, this is what he says we need to do in terms of the symptoms we should be looking for, the tests that we should be looking for, and some of the treatments that can be useful. I think if we can have this conversation through that lens, it would help a really large number of people. Does that sound okay?

[03:41] Pradeep Chopra: Yes.

[03:42] Dr. Theoharis Theoharides: It's a loaded topic, but yes.

[03:45] Dr. Linda Bluestein: Yeah, we could talk about this for hours and hours and days. And I know that we wouldn't even scratch the surface of what you know. But I think it would help so many people because we know that not everyone can access the three of us. A lot of people have to work with the doctors that they have local to them. And so I think we can help a lot of people by really thinking: what should a primary care provider be thinking of when they see a patient with certain symptoms? When should they start thinking about, could this be mast cell activation syndrome?

[04:21] Dr. Theoharis Theoharides: Well, this is very opportune because my good friend and colleague that you all know, Anne Maitland, and I just submitted a huge review — about 600 references, an invited review — and the title is Mast Cell Activation Disorders: Comorbidities and Lookalikes. That will explain a lot of the things in much more detail that you're asking.
[04:50] I don't like the word or the title mast cell activation syndrome simply because it is very restrictive and it doesn't really help our patients. I like the term mast cell activation disorders because there are 3 diagnostic codes. There is other mast cell activation disorders, there is mast cell activation unspecified, and there is mast cell activation syndrome. Starting backwards, if you wish, all of those need a medical history of telltale signs of activation of mast cells. And those could vary, of course. It could be itchy eyes, it could be runny nose, it could be flushing of your neck and torso, it could be itching of the skin, it could be diarrhea, and then further down the line, headaches, sometimes difficulty breathing, bloating, et cetera. That's number one.
[05:57] Number two is that at least the use of some drugs that help in such conditions — such as the so-called antihistamines or the antileukotrienes — might have helped you in the past, should anybody have suggested those. And now comes the tricky part. What are the objective findings? For mast cell activation syndrome, there's got to be elevation of this unique mast cell enzyme called tryptase within 48 hours of an episode. But that makes it extremely restrictive, because number one, you've got to have an indwelling catheter to draw blood within 48 hours. If you go to an emergency room, no one knows what you're talking about. And most places don't even measure tryptase. That's problem number one.
[06:48] Problem number two, even if tryptase is elevated — which in most cases of even mast cell activation syndrome, tryptase is not elevated — we have no way to address that anyhow. So when we talk about treatment, the treatment approach is the same whether it's mast cell activation unspecified or syndrome.
[07:10] Now, Dr. Butterfield from Mayo Clinic published a number of papers where he measured some metabolites or breakdown products of mediators from mast cells, such as leukotriene C4 and prostaglandin F2-alpha. And elevated levels of those, along with N-methylhistamine, were more predictive of bona fide mast cell activation syndrome than tryptase elevations. He looked at a whole bunch of patients, and only one-third of the patients that he — who is an expert — identified as having mast cell activation syndrome had elevation of tryptase. But two-thirds had elevation of the other breakdown products in the urine.
[07:57] And finally, a paper was published about a year ago, and my friend and colleague Mariana Castells wrote an editorial about it, where some colleagues measured serum tryptase levels without necessarily any diagnosis, just to see if they were elevated and then try to relate it to a diagnosis. In that study, the cutoff was 11.5 nanograms per milliliter. And as it turns out, one-third of those had what we call hereditary alpha tryptasemia, which is non-mast cell activation. The other third surprisingly had chronic kidney disease. And the remaining had aggressive mastocytosis. Not a single patient with a randomly measured tryptase had mast cell activation syndrome. And because of that, our colleagues who usually write about criteria raised the bar, and now the cutoff point for tryptase is 15 ng/mL, up from 11.5.
[09:05] So all in all, to the patients out there: if you have these symptoms of being sensitive to everything, then do see whichever physician you can see and just say, I have mast cell activation, and here is why. Don't necessarily say syndrome, because then they will say, well, tryptase is not elevated, you have nothing, go home. So let's start with that.

[09:30] Dr. Linda Bluestein: So when I first learned about mast cell activation, I thought, wow, they're putting everything in this bucket. The GI symptoms of course are quite common, headache is quite common. A lot of these things — the flushing of course is more specific — but how do we know when this constellation of symptoms is due to something else and when it's more likely to be mast cell activation?

[09:57] Dr. Theoharis Theoharides: Dr. Chopra, your input.

[10:03] Pradeep Chopra: In the diagnosis of MCAD — from now on I'm going to call it disorder, mast cell activation disorder — there are three parts to it. For the primary care physician who's listening to this podcast and trying to learn about MCAD: what would be a typical presentation of a patient coming in with MCAD? It looks a lot like body-wide pain, skin flushing, itching. Anything else you'd like to add?

[10:33] Dr. Theoharis Theoharides: Do you want to discuss a difficult case or a rather simple case? The simple case would be someone who itches like crazy. They're going into the shower, hot water makes them itch when they get out. They smell some perfumes and they flush. In other words, these are symptoms that are not typical allergies.
[11:03] In a typical allergy, so to speak, you might be allergic to, let's say, pollen and you get all stuffed up and get rhinitis. You might have chronic rhinosinusitis. You might itch if you touch certain things. Those are kind of more typical allergies. In the mast cell activation disorder patients, they respond to things that are not allergic — not necessarily IgE-mediated. The risk of someone having allergic reactions is roughly the same within the overall population and within the MCAD group. It is that they respond to everything else.
[11:48] So today, for instance, I had a patient — without even saying what she may or may not have — I did what we usually do. I just scratched her underarm. Within 1 minute, you had a red line. That means that the mast cells in her skin reacted just to the pressure and nothing else. So I know this patient is likely to have MCAD, because the mast cells responded not necessarily to an allergen.
[12:20] Maybe we should just mention the categories first, because in the categories of mast cell activation disorders, we have the primary, which is systemic mastocytosis or cutaneous mastocytosis, and a few extremes. Then you have the secondary category, which is kind of the bread and butter of the allergist — so it'll be rhinitis, conjunctivitis, eczema. And then you've got what we don't understand in medicine, the idiopathic. And under that you have idiopathic anaphylaxis, idiopathic edema, and then mast cell activation disorders and mast cell activation syndrome. So that's kind of where it is.

[12:58] Pradeep Chopra: So to the primary care physician: patients will present with — and I have a list of symptoms that I look for — skin flushing, unexplained itching, multiple chemical sensitivities, headaches, sweating especially at night, flushing after a hot shower or hot-to-cold temperature change, brain fog, abdominal discomfort usually being bloating, diarrhea, fatigue, and symptoms that get worse during their menstrual periods. Not pelvic symptoms — I'm talking about generalized symptoms. And of course dermatographism. But here's one that's also baffling: weight gain, or weight loss, or weight fluctuation. Is that correct to add to the list?

[13:00] Dr. Theoharis Theoharides: I wouldn't necessarily include that. And going back to the symptoms you mentioned — and that's why in this recent chapter that we submitted, we take extremes going after those — clearly, anybody has to make sure we exclude other possibilities, even though some of those possibilities may or might not involve mast cells.
[14:31] For instance, let's say you've got hypertension, diarrhea, headaches, and flushing. It could be carcinoid syndrome, in which case it is enterochromaffin cells involved and it's serotonin, not mast cells. And unfortunately, some of our colleagues say that chromogranin A is released from mast cells. It is not. It's released only from chromaffin cells or enterochromaffin cells. And not only that — for those who are listening — you have to be off all antacids if you measure chromogranin A, otherwise you turn out to be false positive.
[15:08] So there are a few things we have to worry about. Whenever we measure the metabolites in the urine — and we can go over those metabolites in a few minutes if you wish — the urine has to be collected cold, stored cold, and reach the laboratory cold. And the technicians better know they have to process it cold. If it stays at room temperature for about 10 minutes, it's gone. You can't measure the metabolites. So we get all these results: "Oh, it was negative. There's nothing there." So there are a lot of these tricky things.

[15:40] Pradeep Chopra: I was thinking of connecting the dots. I know that brain fog can come from other sources. A lot of the patients have POTS or dysautonomia and so they have brain fog. But in this category where we are connecting the dots or the jigsaw puzzle pieces fit, so—

[16:01] Dr. Theoharis Theoharides: Well, let me stop you for a second. The pieces don't necessarily fit. And as I might have said with Linda in the previous episode, I tell patients: go into your physician with about 5 symptoms, stop. The moment you start reaching 10 and 15 and 20 symptoms, they're going to think you're crazy. And they won't know what to do — it's too confusing and too time-consuming and they're not going to do anything.
[16:26] So if you start focusing on brain fog in a patient with mast cell activation syndrome, they're probably going to say you're off your rocker. I've seen that so often. I will take the information down, but I would not necessarily make it an absolute critical part of getting through the door.
When mast cell activation syndrome was first reported by Metzger and Valent, they did have neurologic symptoms, and it was music to my ears because I've been studying brain mast cells for 30 years. But subsequently they took that off. Maybe for the reasons we're discussing, or maybe they just got tired of people showing up with neuropsychiatric symptoms and not necessarily other symptoms. So we'll go back and forth. I'm not being negative, I'm just trying to—

[17:18] Pradeep Chopra: So can we divide it into major criteria and minor criteria?

[17:26] Dr. Theoharis Theoharides: That would be fine. I wouldn't call it criteria. I would call it major and minor symptoms, or major and ancillary symptoms. I don't like major and minor because in some people, the minor might be major, and in others it might be the other way around. But it's definitely got to have at least one of the more classic symptoms — whether it's eye symptoms, nose symptoms, flushing, skin itching, some gastrointestinal problems. Those are kind of the more typical things we see, although it can be any organ.

[17:59] Pradeep Chopra: So I have a major criteria. The major criteria is flu-like symptoms.

[18:01] Dr. Theoharis Theoharides: Okay, well, why would that be a major criterion since flu-like symptoms can happen in 20 different diseases?

[18:16] Pradeep Chopra: If they don't have a viral condition or bacterial condition.

[18:20] Dr. Theoharis Theoharides: Well, we will not know that until we investigate. I mean, someone comes in with viral symptoms — anyhow, it's hard for me to call that a major criterion when it's prevalent in so many other conditions. I would start with the ones that are definitely associated with mast cells.

[18:40] Pradeep Chopra: So that would be skin flushing, itching, multiple chemical sensitivities.

[18:46] Dr. Theoharis Theoharides: Yeah. And maybe diarrhea, GI symptoms. That's what I would call major. And everything else you said is there.

[18:53] Pradeep Chopra: So GI symptoms being abdominal bloating and acid reflux.

[18:58] Dr. Theoharis Theoharides: Well, acid reflux — you know, there's a separate diagnosis and the gastroenterologist will give you a separate diagnosis for that. So yes, that comes to mind, but you can have acid reflux because you've got Helicobacter pylori, not necessarily mast cells.

[19:12] Pradeep Chopra: So among the GI symptoms, bloating would be one of them, right?

[19:16] Dr. Theoharis Theoharides: Bloating would be one, abdominal pain off and on would be another, and then alternating constipation and diarrhea, which is very similar to IBS. And I've published papers that I think IBS is literally based on mast cell activation in the gut.

[19:28] Pradeep Chopra: I am so glad you said that. Thank you so much.

[19:34] Dr. Theoharis Theoharides: I'll say other things that you might like in a second. But you see, the difficulty is — and this is something I addressed in one of my papers on IBS — that the number of mast cells is not important. It's the activation of the mast cells. Because many of our colleagues will look in the gut, and I've been in endoscopy suites with patients of mine where my GI colleagues will try to find where to look. Most of the time there are no lesions to biopsy, so you don't know where to biopsy. Dr. Minor many years ago said that most of the mast cells are in the ileocecal junction. So I usually say, okay, let's biopsy there. And then you take random biopsies.
[20:16] But what I do — and we might talk about this in the objective criteria — is I actually request stool analysis for 3 things. Total histamine. Why? Histamine systemically is broken down within 1 minute. It will end up in the urine as N-methylhistamine or MIAA, methylimidazolacetic acid. If it is released from the gut, it shows up in the stool. It doesn't get broken down because the enzymes that break it down won't have enough time to work on it. So if I have severe GI problems, total histamine in the stool is off the roof.
[20:57] Eosinophilic cationic protein, or eosinophilic protein X — both of them go hand in hand with mast cells and they're very strong triggers of mast cells. And we don't necessarily have to have elevation of absolute numbers of eosinophils in the blood for these proteins to be high. So I measure that as an index of the mast cells being activated by something I can at least put my finger on.
[21:24] And then a measure called calprotectin, which is a good index of inflammation.
[21:28] So those three — just to make sure that if those are high, I'll tell GI people, go and look for something that might indicate GI mastocytosis. And then the question is, how do you define that? Most colleagues say it's got to be between 20 and 30 mast cells per high-power field to be pathognomonic of something. But again, you can have 10 mast cells firing like crazy, and you might have 50 mast cells that don't do anything. So it's not enough.
[22:05] That's why I ask my GI colleagues when they biopsy to stain for both tryptase and C-KIT or CD117. Why? C-KIT is on the surface. It will not change whether the mast cells have degranulated or not. But tryptase will come out and the granules will be empty. So if you have, let's say, 100 mast cells with C-KIT and they're all positive for tryptase, that means they're not degranulating. If they're empty, that means they spilled out their tryptase. So that gives us an index of at least rough degranulation of mast cells, which is true not only in the gut but in the skin or anywhere else you might want to biopsy.
[22:52] Anyhow, back to the clinical picture.

[22:55] Dr. Linda Bluestein: So I have a follow-up to that real quick. These 3 stool tests — stool histamine, eosinophilic cationic protein, and calprotectin — can those be done through a regular lab, or does it have to go someplace special? And if they're positive, would you be concerned about mastocytosis, or could those be positive in mast cell activation?

[23:26] Dr. Theoharis Theoharides: Those are excellent points. On the first point, both calprotectin and eosinophilic cationic protein are measured by typical labs like Quest and LabCorp. Total histamine in the United States is not measured routinely. In Europe, most labs do it. I don't know why. So that might be a little bit of a problem — I don't think Quest and LabCorp measure total histamine in the stool. So you might have to go to a special lab.
The first thing those results tell me is that the mast cells are being activated in the gut. Now it could be — and of course whenever we send stool, we do ova and parasites. So it might be a parasitic infection that we missed. I would usually ask, especially for children, do they itch around the anal opening? Because most of the parasites come out at night and deliver their eggs in that area. When I was at Yale studying medicine, we used to use a tape and just pull the eggs off and look at them under the microscope. Some parasites are impossible to see, like Giardia lamblia — you've got to actually put in a drop of fluid and see if they swim. But who does these things anymore? A long time ago we used to do them. I don't think anybody does them anymore.
[29:39] And now more and more, laboratories are doing the whole microbiome analysis in the gut, as they do it in other places like the bladder or the vaginal vault, et cetera. That might be a way to go, because it might indicate there are actually species there that we just didn't pick up with a regular ova and parasite test.
[29:39] Now, if those are negative, then one would suspect intestinal mastocytosis, not systemic mastocytosis. Not very many colleagues believe in intestinal mastocytosis because they cannot find the mast cells. But there are papers, especially in children. I had one child from Denmark a long time ago who was going to be taken by social services because he couldn't eat — constant diarrhea, couldn't eat. Eventually I had him biopsied, and it was about 40 mast cells per high-power field. The kid absolutely had GI mastocytosis.
[29:39] Now, if we talk about systemic mastocytosis — as you know, it presents with all the symptoms that Dr. Chopra mentioned earlier, but tryptase is almost invariably elevated no matter when. So if you've got an elevated tryptase and these symptoms, you're not dealing just with mast cell activation anymore, in which case there are one of two things one can do. Either you can do flow cytometry on peripheral precursor mast cells that express receptors such as CD117, CD23, et cetera — but you've got to have very good flow cytometry and antibodies for those antigens to pick it up. Otherwise, you do a bone marrow biopsy. And I'll stop by saying no one should do an aspiration. The sheer force of aspirating will degranulate the mast cells. So it's got to be a biopsy. And then we're not looking at 5, 10, 20 mast cells — we're looking at clusters, islands of like 50 mast cells. And the shape is spindle rather than round.
[29:39] Anyhow, go back to—

[29:39] Pradeep Chopra: So you just referred to mastocytosis, not mast cell activation disorder.

[29:39] Dr. Theoharis Theoharides: If tryptase is very elevated regardless of the timing — remember, in mast cell activation syndrome, tryptase has to be elevated within 48 hours of an episode. In systemic mastocytosis patients, tryptase is elevated regardless, every day.

[29:39] Pradeep Chopra: Regardless.

[29:39] Dr. Theoharis Theoharides: You don't have to have an episode. It's just high because it's an expression of the number, the volume of mast cells you have, not their activation. And at some point we should talk about hereditary alpha tryptasemia because it's very, very confusing. But maybe later.

[29:39] Dr. Linda Bluestein: Yes. That would be a perfect — we're going to take a quick break and when we come back, let's talk about hereditary alpha tryptasemia because you're right, it's very confusing and I want to make sure that people get a little bit of an idea of what that is.

[30:19] Dr. Theoharis Theoharides: I was going to say that the first thing is how do we educate — and I mean it in the good sense — the general practitioner, the internist, about these things. Because what will happen is if someone sees these symptoms, they're going to send them to an allergist. Very few people, maybe unlike you and me and Linda, will actually deal with these patients.
[30:41] And that's why I think we should join forces and write a very good article for Journal of Family Practice. I just Googled it and there's hardly anything on mast cells. Because these are the kind of journals that our colleagues are likely to see — they're not likely to look at the more specialty journals. We usually all publish in the more esoteric journals because they have better impact factors. But we've got to get to the very basic at this point.
[31:31] So having said that, how many general practitioners or internists do you think are likely to deal with MCADs rather than sending someone to an allergist? Just throw a percentage.

[31:46] Pradeep Chopra: In my area, there's no one.

[31:48] Dr. Theoharis Theoharides: There you go. Same with me.

[31:48] Pradeep Chopra: No one.

[31:50] Dr. Theoharis Theoharides: So even though my heart bleeds for how to educate our colleagues — in the good sense — at the end of the day, they're not going to deal with these patients for all kinds of reasons. And now we're going to the allergist. How many of the typical allergists do you think know about what we're talking about?

[32:12] Pradeep Chopra: One.

[32:12] Dr. Linda Bluestein: Not many, yeah.

[32:13] Dr. Theoharis Theoharides: Very few.

[32:13] Pradeep Chopra: In my entire state, there's only one.

[32:15] Dr. Theoharis Theoharides: Very few.

[32:15] Dr. Linda Bluestein: Very, very few, unfortunately.

[32:19] Dr. Theoharis Theoharides: And I think I might have mentioned this in the last episode, but I will reiterate it. About a year ago, a relative of one of my previous doctoral students — a physician himself, who was actually vacationing in Tampa, Florida — had to go to the emergency room because his wife had an anaphylactic reaction, and she already had a history of MCAD. Now this was related to me by her husband, the physician. They went to the emergency room and explained that she's got a history of mast cell activation problems. And the attending physician — it might have been a resident — the first question was, "What's wrong with your breasts?" Because she said "mast cell activation." This was 6 months ago in Tampa.
[33:14] So the issue is very, very difficult and very important. And that's why we should try to clarify this as much as possible, even though we would love to be talking about all the complicated aspects thereof. We've got to sensitize the physicians that patients who are essentially sensitive to everything have MCAD. And if tryptase is elevated within an episode, they've got MCAD. That's it.
[33:40] But I don't like the word "allergic" because, as I said earlier, allergic implies IgE. So: sensitive to everything, like a multiple chemical sensitivity-type patient with no other explanation.

[33:52] Pradeep Chopra: So these patients will present with sore throat.

[33:58] Dr. Theoharis Theoharides: Okay.

[34:00] Pradeep Chopra: Most times when I examine their throat, it's red and inflamed.

[34:04] Dr. Theoharis Theoharides: Okay, so you do a strep test quickly.

[34:08] Pradeep Chopra: But they don't complain about that. That's the thing.

[34:14] Dr. Theoharis Theoharides: So what do you mean they have a sore throat if they don't complain?

[34:22] Pradeep Chopra: Would that be one of the signs of MCAD?

[34:28] Dr. Theoharis Theoharides: Sore throat by itself would not necessarily trigger me, but if they have swollen lips, redness around the lips, swollen tongue, then absolutely yes. And then we have another syndrome — we're covered with syndromes — red tongue syndrome, and then we've got geographic tongue, et cetera. Many of them overlap.
[34:45] And since you mentioned that — and I might have mentioned this before, Linda, I apologize — one of the things that is becoming more apparent is individuals who get swelling around their lips. I had a wonderful lady from Boca Raton about a month ago that not only had this swelling, but her whole face would swell up so much. She was literally a model, and if you saw her face, you'd think it was like out of some horror movie. It was that bad. I've never seen that swollen a person.
[35:30] And as it turns out, after digging into it, she literally had what we call alpha-gal syndrome, which is another thing we should talk about in addition to alpha tryptasemia. In alpha-gal, as we all know, it's an antigen present in mammals, but humans don't have very much of it — it's much more present in cows and pigs, et cetera. And if you're bitten by a tick, you might not get Borrelia or Babesia or some other bacterial disease, but they will carry the alpha-gal to you. And now you become super sensitive to it and super sensitive to anything that has a mammalian product, including drugs, supplements, and cosmetics. Her mascara actually had gelatin in it, which was from a mammalian source. And she reacted to that.

[36:25] Pradeep Chopra: I have a question on alpha-gal syndrome. It's only to beef and pork, right?

[36:32] Dr. Theoharis Theoharides: Correct. Not chicken and not fish.

[36:34] Pradeep Chopra: No fish, right.

[36:36] Dr. Theoharis Theoharides: Correct. However, now that you mention it, carrageenan — which is used in many capsules of supplements and drugs, the clear cap is made of carrageenan from seaweed — carrageenan cross-reacts with alpha-gal. You can look it up. So someone could be reacting even to the gel caps of drugs and supplements. And we just don't say that. That's why I say we're making life more complicated, but at least there are specific things that are measurable.

[37:10] Pradeep Chopra: So if a patient comes in saying, doctor, I react to beef and pork, but I'm okay eating fish and chicken—

[37:20] Dr. Theoharis Theoharides: That's a good indication. But the patients are not going to say "allergic." They're probably going to describe something.

[37:25] Pradeep Chopra: They're going to say react to it.

[37:28] Dr. Theoharis Theoharides: Yeah. I would definitely think of alpha-gal.

[37:34] Pradeep Chopra: And we can send them to Quest or LabCorp asking for alpha-gal antigen?

[37:41] Dr. Theoharis Theoharides: No, no. What you ask — just like when we do an allergic panel — many of these companies have panels. You can ask specifically, but it's more complicated. They have, for instance, food panels. So if you search for alpha-gal, you might be able to find it, but if you look at a food panel, it might be listed underneath.

[38:07] Pradeep Chopra: It'll be there.

[38:07] Dr. Theoharis Theoharides: Okay.

[38:08] Dr. Linda Bluestein: Yeah.

[38:08] Dr. Theoharis Theoharides: So I would measure that. And then of course, food sensitivity is a whole different ballgame that we can talk about later, because food sensitivity is immunoglobulin G subclass 4, IgG4 — it's not IgE. And the mast cells are triggered through IgG4.

[38:33] Pradeep Chopra: Just before we leave meat alone.

[38:34] Dr. Theoharis Theoharides: Sure.

[38:36] Pradeep Chopra: If you eat reheated meat — meat that has been put in the fridge and then the next day you reheat it — the histamine level goes up, right? Because the DAO comes down.

[38:48] Dr. Theoharis Theoharides: I have seen that happening with fish, not so much with meat, to be honest. In fact, I tell all patients, don't reheat your fish. You eat it, you throw it away.

[39:00] Pradeep Chopra: But not with meat.

[39:01] Dr. Theoharis Theoharides: I haven't seen it as much. I usually say if you can eat it fresh, it's better. But if you were to ask me to put my finger on a publication with meat, I don't have it. With fish, I do.

[39:11] Pradeep Chopra: And when you say fish, you mean fish that swims and not scallops or shrimp?

[39:15] Dr. Theoharis Theoharides: Yes, yes.

[39:17] Pradeep Chopra: Not those.

[39:19] Dr. Theoharis Theoharides: People might be sensitive to those regardless.

[39:22] Pradeep Chopra: That's different.

[39:23] Dr. Theoharis Theoharides: Yeah, that's different. But we should talk about diaminoxidase later. So maybe Linda can make a list of all the things we should cover.

[39:31] Dr. Linda Bluestein: Yeah. We did talk about that in the first part. I would love to talk about hereditary alpha tryptasemia. I know we could talk for hours and hours, but I don't know if there was something else more pressing before we transition to that, because I know we kind of went from symptoms and then we—

[39:51] Dr. Theoharis Theoharides: Well, we didn't cover the objective measurements.

[39:54] Pradeep Chopra: Right.

[39:54] Dr. Theoharis Theoharides: So maybe we should say a few words about that before we go to the other topic.

[39:58] Dr. Linda Bluestein: Sure. And that kind of folds in because we're talking about tryptase and the objective measurement for hereditary alpha tryptasemia. So I always ask for total alpha tryptase.

[40:06] Dr. Theoharis Theoharides: IgE, total IgG1 and IgG4 — because usually it's a yin-yang. The IgG1 tends to be the good guy, IgG4 kind of the bad guy. I will measure a plasma histamine, but it invariably is going to be very low unless someone has chronic itching, so chronic idiopathic urticaria. And that is important to measure because in about 50% of the patients, the plasma histamine is high. If it is high and someone doesn't have an anaphylactic reaction, I'll think of chronic spontaneous urticaria, because about 50% of those patients have an autoimmune condition where they make antibodies against either the IgE receptor or the IgE itself. And those are gain-of-function — they stimulate the mast cells.
That test is called the basophil activation test, because we cannot isolate the mast cells to test it, but we can isolate the basophils. Now, that is buried under the chronic urticaria panel in Quest. So you can't just ask for a basophil activation test or anti-IgE receptor antibody test — it's a chronic urticaria panel and it's listed underneath. And within the chronic urticaria panel, they also have antithyroid antibodies, which is somewhat confusing.

[41:34] Dr. Linda Bluestein: I'm very interested in that because I have chronically elevated histamine and I have antithyroid antibodies and I do have chronic itching. So—

[41:42] Dr. Theoharis Theoharides: There is an association, but I'm not sure I would call that MCAS or MCAD as of yet. But for instance, I would be more interested in parathyroid hormone measurement if someone has intractable itching, because PTH is one of the strongest triggers of mast cells. In about 1 in 20 patients I've dealt with who have chronic such problems — including an unfortunate but wonderful little kid who had both mast cell activation and autism and Down syndrome and was itching himself like crazy — PTH was off the roof. Now, it could be primary or secondary hyperparathyroidism, but it doesn't matter. It will stimulate the mast cells. So we have to bring it down, whether you give calcium supplementation so you can lower it, or you remove some of the parathyroid glands.
[42:36] So I will measure those for that reason. Then I will ask for a food intolerance test, but there's a caveat. If you eat something every day, it turns out to be false positive. So I usually say organic boiled chicken and rice for 3 days, then do the test. I've hardly ever seen any reaction to chicken, and rice doesn't have gluten, so we're kind of on the safe side. If you do that for 3 days, then do the test, I'll sort of believe the results. So that's food intolerance IgG, not IgE.
[43:15] Then there are certain molecules that come from the mast cells other than tryptase that would be important to measure, especially if there are some other telltale signs. For instance, tryptase is stored in the secretory granules of the mast cell together with another enzyme called chymase. Chymase converts angiotensin I to angiotensin II, and not only converts it, but it's resistant to the drugs. So if someone has very high blood pressure that's unexplained, I will measure chymase for that reason.
IL-6 is definitely coming from the mast cells, and both Dr. Metcalfe and colleagues, Dr. Escribano in Spain and colleagues, and I, at different times in different journals, published that IL-6 elevated in the blood was a better indicator of mastocytosis severity than even tryptase. But hardly anybody measures IL-6. Why? Because it can come from other cells. But if no one has any other condition and IL-6 is high, I would be remiss not to consider it might be coming from the mast cells.
[44:40] I will definitely measure vascular endothelial growth factor because it comes out of the mast cells without necessarily histamine or tryptase. It is incredibly important under stress. We've published numerous papers — and so have others — that the corticotropin-releasing hormone, the first hormone released under stress, which we always thought was only released in the hypothalamus, is actually released in every organ in the body. We've published papers that chronic itching in eczema and psoriasis had CRH elevated both in the skin and the blood. And other colleagues have shown it in the bladder, GI tract, et cetera. When CRH stimulates the mast cells, they release only VEGF, no histamine or tryptase.
[45:23] And more recently, a paper was published that in systemic mastocytosis, angiopoietins — which are like vascular endothelial growth factor, but there are about 5 of them — were very high. And the German group has shown that heparin is also quite high in systemic mastocytosis patients. And keep in mind, half of the granule of the mast cell is actually chondroitin sulfate and heparin sulfate. And yet the mast cells don't circulate. So obviously these molecules do something else.
[45:58] The reason I'm saying that is because if I see bruising — and of course, if it's not from trauma or abuse — I might think that the mast cells are spitting out heparin because heparin is anticoagulant and causes bruising. And we've seen that in some cases of aggressive mastocytosis. Now, why heparin would be released and not other molecules like tryptase still baffles me, because we've been taught that they're all in the same granules. Maybe they're not.

[46:31] Pradeep Chopra: So in MCAD, do you think we should measure heparin?

[46:36] Dr. Theoharis Theoharides: Laboratories in the States don't measure it. In Europe, they do. You can measure it indirectly, but I don't think anybody measures heparin as such. But if I see bruising, I'll do all the testing that is likely to tell me if there's actually a bleeding diathesis of some sort.

[46:54] Pradeep Chopra: Right, right.

[46:55] Dr. Theoharis Theoharides: So that's pretty much in terms of blood measurements. And then we go to the urine measurements that we mentioned earlier, which would be either N-methylhistamine — which is the breakdown product for about 30% of the histamine — or MIAA, methylimidazolacetic acid, which is another 60%. And both I and Dr. Butterfield and others believe that one measurement is not enough because these are episodic. Histamine is released episodically, as you know. You might have a reaction and tomorrow might not have a reaction. So I usually measure it at least twice within 3 months.

[47:31] Dr. Linda Bluestein: And when you're doing the urine tests, are these spot urines or is this a 24-hour urine collection?

[47:40] Dr. Theoharis Theoharides: It used to be 24-hour urine, but Dr. Butterfield at the Mayo Clinic said that first morning void might be sufficient unless someone has interstitial cystitis or enuresis and they're up all night urinating. And I think it's fair — first morning void.

[47:56] Pradeep Chopra: Does it matter whether the patient is on mast cell stabilizers or antihistamines?

[48:01] Dr. Theoharis Theoharides: That's a very good point. So antihistamines block the action of histamine after it's been released.

[48:07] Pradeep Chopra: After it's been released.

[48:09] Dr. Theoharis Theoharides: So it's not going to make any difference to the amount of histamine. Now, there are some antihistamines like Rupatadin — which is available in Canada and Europe — that also blocks mast cells to some extent. So if you were to tell me someone should be off Rupatadin to do this test, I'd say yes. But if someone is on Zyrtec or one of those, it doesn't make a difference.
The same applies to Singulair — it blocks the action, not the production. Definitely they should be off steroids because steroids will block the production of everything. And they should not be on any foods that contain high amounts of histamine. That takes us to another topic, which is histamine intolerance.
[48:59] Foods like fermented foods, cheese, tomatoes, spices, avocado, pineapple, cumin, curcumin — they have a lot of histamine. And sometimes colleagues will give a flavonoid because it's anti-inflammatory and anti-allergic, but unless it's 98% pure, it's going to have a lot of histamine. Curcumin has histamine. Cumin has histamine. Cinnamon has histamine. So I see all these dietary supplements marketed as immune support that have about 10 different things in them, and unless they're pure, who knows what they do.

[49:34] Pradeep Chopra: You said pineapple has a lot of histamine in it?

[49:37] Dr. Linda Bluestein: Mm-hmm.

[49:41] Pradeep Chopra: So quercetin — I thought it was made from pineapple, right?

[49:45] Dr. Theoharis Theoharides: Well, that's why it depends how pure it is. And unfortunately, what you see out in the market — I'll give you an example. You can try to buy quercetin or luteolin, which is more favorable in my mind than quercetin, or the combination. And you see a price of $20 for a month's supply. And I say — excuse the expression — no way. I know how much it costs to buy a kilogram of this in 98% purity. There's no way on earth that someone could be selling 60 capsules with 500 milligrams per capsule for $20. They're just lying. That's it, period.
[50:21] So cost alone should not be the determinant factor for either patients or physicians. I've got many colleagues who call me, "Well, why should we get Neuroprotect? It costs $35 and not the cheaper one?" And what I do, I send both for analysis to Eurofins, and one comes back at 50% purity and the other at 98% purity. And if it's not pure, what does it have in it? Histamine, for one thing.
[50:48] In fact, one of the cheapest sources of quercetin is actually peanut shells — but they don't tell you that. So if you're allergic to peanuts, you're doomed. Or fava beans. 20% of Mediterraneans have G6PD deficiency. If they eat fava beans, they get hemolytic anemia. Who tells you that on the label of a dietary supplement? So don't get me going on the supplements. Billions of dollars are spent all over the world for supplements and maybe 10% of them are worth anything.
[51:29] As you probably know, Amazon announced that as of May 1st — I don't know how strongly they will implement this — any dietary supplement sold on Amazon going forward will have to be analyzed by 3 laboratories that they actually selected, one of which is Eurofins. So they will send it to Eurofins, get the results, and if the results are not within 50% of what you claim on the label, you're out. The FDA should have done this a long time ago, but they haven't, and they're not likely to do it either.
[52:01] All right. Back to alpha tryptasemia.

[52:05] Dr. Linda Bluestein: Yeah, because we definitely want to talk about treatment — which you kind of were talking about when you were discussing supplements. Alpha tryptasemia.

[52:11] Dr. Theoharis Theoharides: As I said earlier, in the study that was published — and the first report was by Dr. Lyons at NIH — they found it's a genetic condition where you actually make the alpha type of tryptase. Let me explain what that means. Inside the secretory granules of the mast cell, you have a beta tetramer, beta tryptase tetramer. It's inactive inside the granules because it's bound to chondroitin sulfate and heparan sulfate. The moment the granule is released, that bond is dislodged and now tryptase is active. We still don't have a drug to block the action of tryptase, but it is active.
[52:49] Now in this condition, it is alpha-2 — it's a dimer, not a tetramer. And alpha-2 is inactive and it is not inside the granules. So question number 1: where is it coming from if it's not in the granules? Question number 2: if it's inactive, why on earth do these patients have almost all the symptoms of mast cell activation patients? I have no clue. And I don't think anybody does, for that matter.
[53:15] So, if someone has tryptase elevation without necessarily having all the symptoms — which is very hard to discern — or if someone is telling you as you take the medical history, "You know what, my aunt has similar problems, my daughter has similar problems," then it's worth doing a genetic analysis for the gene. How will we treat this patient? Probably the same way we treat anything else, and we will get to that. But I'm not sure what I'm treating because, as I said, alpha tryptase is not in the granules, and I don't know how it's coming out. So it's wishful thinking. But it's becoming much more common.
[54:00] Now, according to Dr. Lyons, about 8% of the population has hereditary alpha tryptasemia. That's a very high number.

[54:06] Pradeep Chopra: Very high number. So the symptoms of alpha tryptasemia are almost the same as MCAD?

[54:13] Dr. Theoharis Theoharides: Almost. There are a number of tables you can look at, but they do have itching and they have a lot of GI problems, not so much flushing and not so much neurological problems. So if I were to give it a number: in MCAD, the neurological problems — at least in my book — might be 70% of patients. In tryptasemia, maybe 5%. But skin is about 70% and GI is about 70%.
And clearly, tryptase binds to protease-activated receptors, PARs. So it might be that the alpha-2 binds to a different PAR receptor and causes these problems, while the other tryptase binds to a different receptor. But we don't have a way of blocking either the release or these receptors, at least not for the time being.

[55:11] Pradeep Chopra: So can we go to treatment?

[55:16] Dr. Theoharis Theoharides: Sure. So invariably we start with an antihistamine, and invariably we like the non-sedating or second-generation antihistamines. And invariably we can go up to 4 times the recommended dose. So let's say cetirizine is 10 milligrams — we can kind of slowly bring it up to 40 milligrams. But the moment you start going upward, you're likely to get sedation. That's one.
[55:41] Second point is that about 15% of patients don't get sedated, but get wired. They get very anxious. I don't understand the pathophysiology, but they get wired.
[55:56] Third point is that all of the first-generation antihistamines, like Benadryl and hydroxyzine, are also anticholinergic. So they block acetylcholine receptors. And therefore, if you start pushing the dose, you might put someone in urinary retention — they might not be able to urinate — or they might not sweat as much anymore, or they might have dry eyes and dry mouth, and you might start thinking Sjögren's syndrome because of that. So keep that in mind. Also, at very high levels — like over 100 milligrams — I would never give them to people who have a history of seizures, because they can increase seizure activity. And even though what I'm about to say was true for the early first-generation antihistamines, it's been creeping up for cetirizine and hydroxyzine: they might actually increase the QT interval. So cardiologists worry about that. And if we have someone who has QT prolongation, I might go very slow on the dosing.
[57:05] Okay, so that's for H1. Now, any time you have a chronic problem — whether it's itching, gut problems, et cetera — you're going to be stressed. And of course, we're swimming in stress these days, whether it's political, financial, or whatever. So histamine is going to be stimulating the parietal cells in the stomach to make acid. So we've got to block those. I invariably give an H2 blocker.
[57:31] And there's another reason for the H2 blocker that is not very well known. The mast cells have H2 receptors on their surface, and histamine activates the mast cells through the H2 receptor. So by giving an H2 blocker, not only do we reduce the amount of acid produced, but we might keep the mast cells from overfiring.
[57:57] Other issues: the first drug, cimetidine — which was very popular and is over-the-counter, of course, as Tagamet — inhibits the P450 system in the liver. And because all males have a little estrogen, if you block the P450 system, you build up the estrogen and you get gynecomastia and loss of libido and loss of erection. So we've got to tell patients going on Tagamet to watch out. It's likely reversible. The others, like famotidine and ranitidine, are a little better, even though there was a scare about some other side effects with ranitidine.
[58:35] Now, individuals who have chronic gastritis or chronic GERD — I would worry about H. pylori. As I said earlier, H. pylori likes an acid environment and is very difficult to eradicate. So if someone has chronic GERD, you've got to think about doing an endoscopy or a breath test for H. pylori. The treatment is 2 antibiotics and 2 antacids for about 2 weeks.
[59:03] However, there's GERD that is eosinophilic esophagitis. And in eosinophilic esophagitis, we're looking at eosinophils, but I always urge my colleagues to look for mast cells because I said earlier they go together. Same thing with eosinophilic gastroenteritis.
[59:22] So those are the beginning. Then if there's a lot of itching — before we talk about chronic spontaneous urticaria — you might give a steroid cream if it's localized, or you can give a cream that I helped develop called Gentle Derm. That has tetramethoxyluteolin, which is very well tolerated. There are a couple of publications, and you can use it together with an antihistamine.
If there are GI problems, then you do the food intolerance testing or food allergy testing that we spoke about. Then you might consider DAO — we spoke about it last episode, diaminoxidase. Just keep in mind that diaminoxidase will be destroyed in the stomach, which has acidity of 1. Enzymes work at an acidity of 7, just like our blood. So I like one or two preparations that are actually acid resistant or enteric coated. And I think I sent you that list, Linda.

[1:00:25] Dr. Linda Bluestein: Yeah, you sent it to me. I'll put it in the show notes so people have it.

[1:00:29] Dr. Theoharis Theoharides: Okay. So now what do we do then? Then is where I look for natural molecules that might block the mast cells. Quercetin can block the mast cells. Luteolin is a little better. And we published that both quercetin and luteolin are better inhibitors than Cromolyn, the only drug sold as a mast cell blocker. And there are issues with Cromolyn.
[1:00:48] Number one, the new preparation in the United States is horrible. It causes all kinds of problems. Hardly anybody can tolerate it. I don't know what on earth they did, but it cannot be tolerated.
[1:00:58] Number two, it shows rapid tachyphylaxis. The body gets used to it. So you start at about 100 milligrams once or twice a day, and by 3 or 4 months, you're at 400 milligrams 4 times a day. And it stops working after that. Then you start getting about 15% diarrhea, about 10% alopecia. And Dr. Church in England published 2 papers that if you push the biphasic curve, you actually start stimulating the mast cells to release histamine. So if I don't get any results by 400 mg 4 times a day, that's it. Stop it cold turkey. It's not going to do anything more.
[1:01:35] So then what do we do after that? Well, we measure the mediators. If leukotrienes are high, Singulair. If prostaglandins are high, some kind of NSAIDs if tolerated. And then either at that point or from the very beginning, you give them liposomal luteolin, or liposomal luteolin and quercetin together.
[1:01:47] And then we go to what is left in terms of symptoms. If there's a lot of itching, the so-called biologics — injectable, of course — Dupixent blocks some of the cytokines that stimulate mast cells. There's now an IL-31 inhibitor, and IL-31 is more pruritogenic than histamine. So that's available on the market. And of course, there are 3 or 4 new biologics that block the receptor for interleukin-5, which stimulates the eosinophils. So for chronic asthma, eosinophilic esophagitis, et cetera, those drugs might be good.
[1:02:27] But you see how we're now limiting ourselves to specific symptoms, not the overall picture. So the overall is not going to be helped by these drugs, but the itching would be.
[1:02:38] And then we have those patients that might have autoimmune chronic spontaneous urticaria because of antibodies. What do we do for those? Well, very little. In those cases, either we use immune IG — IVIG or subcutaneous IG — which seems to work, but I don't know why it works. Or we use low-dose naltrexone, which also works, and I don't know why it works. By LDN, we mean 0.1 milligram, which is incrementally increased over about 2 weeks to no more than 4 milligrams a day. And by 4 milligrams, if it doesn't work, it's not going to work. And patients experience nightmares and all kinds of other such symptoms. That's it.

[1:03:27] Pradeep Chopra: We forgot ketotifen.

[1:03:27] Dr. Theoharis Theoharides: Ketotifen is a misnomer. Ketotifen is a very good antihistamine. It's not a mast cell blocker. The only publication that ever showed that ketotifen blocks anything was in conjunctival mast cells — single publication. But ever since, everybody calls it a mast cell blocker and it is not. Rupatadin is a mast cell blocker. There are 5 publications.
[1:03:56] Now, having said what we said about antihistamines, some antihistamines work better than others. So I would not give up on ketotifen — it would definitely be up my sleeve. Not because it's a mast cell blocker, but because it's a different antihistamine and some people tolerate it and do well. Though it is very sedating and it causes an increase in appetite, just like the tricyclic antidepressants. So sure, we would use it, but it's not a panacea. I would put it probably in the category along with the quercetins and the luteolin.
[1:04:35] But before we leave the topic, I do want to mention that not all flavonoids are necessarily good. Luteolin and quercetin of course are flavonoids. So is resveratrol, so is curcumin, et cetera. You see soy flavonoids, for instance. God forbid if someone has estrogen-dependent breast cancer — soy flavonoids will actually increase the cancer because they're estrogenic. So we've got to be a little smart about what we recommend. Of course, patients cannot make out the difference, but I'm just saying.

[1:05:07] Pradeep Chopra: So the mast cell stabilizers are only Cromolyn?

[1:05:10] Dr. Theoharis Theoharides: Cromolyn is not a mast cell stabilizer. I published the first paper on Cromolyn in the journal Science as an undergraduate at Yale — and I'll brag about it. But it worked like a charm in rats. Dr. Galli, who is chief of pathology at Stanford — he was previously at Beth Israel before he moved to Stanford — published that it doesn't even inhibit mouse mast cells. And as I said earlier, we showed that luteolin and quercetin are much better inhibitors than Cromolyn.
[1:05:44] Now, I give credit to Cromolyn because as a student at Yale, I used one of the first programs NIH had for comparing molecules. And why did I find luteolin and quercetin? Because Cromolyn looks like a butterfly with two wings, and the flavonoids are like a butterfly with one wing — with 90% structural similarity. So when I was looking at natural molecules and I saw the structure, I was stunned by the fact that they're very similar. But to this day, no one has identified a receptor on the surface or inside the cells for Cromolyn. We have no idea.

[1:06:22] Pradeep Chopra: Just to clarify: if I'm going to treat a patient with MCAD, I start with an H1 blocker, H2 blocker.

[1:06:22] Dr. Theoharis Theoharides: Correct.

[1:06:30] Pradeep Chopra: What would be my third drug?

[1:06:33] Dr. Theoharis Theoharides: As I said, if leukotrienes are high in the urine, then you give them—

[1:06:36] Pradeep Chopra: Montelukast.

[1:06:38] Dr. Theoharis Theoharides: Right. If prostaglandins are high, you give them a little NSAIDs. And then either at that point or from the very beginning, you give them liposomal luteolin, or liposomal luteolin and quercetin together.

[1:06:52] Pradeep Chopra: Got it.

[1:06:53] Dr. Theoharis Theoharides: Because it will block the mast cells, but it takes weeks before the mast cells really calm down. It doesn't work like an antihistamine, where overnight your hives will disappear. And then you start tolerating foods. You start tolerating exposure to some other triggers. I wish we had better drugs. We published a paper just a couple of weeks ago where two newer flavonoids are even better, but we've tested them so far only in microglia, not on mast cells. We are in the process of doing that. And one of them is partially water-soluble, which makes it better.

[1:07:32] Dr. Linda Bluestein: Oh my gosh. We could talk about this for really a long time. This is such an incredible conversation.

[1:07:38] Dr. Theoharis Theoharides: There is a condition that we should touch upon — or maybe Anne Maitland should do it — but there's periodontitis now in a subgroup of patients with EDS. And we've published a lot of papers about mast cell periodontitis. So maybe we should talk about that some other time. It's an incredible new entity that I don't quite understand as of yet.

[1:07:59] Dr. Linda Bluestein: I have discussed that with her, but not during a recording. So we'll have to figure out how to have that conversation.

[1:08:07] Dr. Theoharis Theoharides: Maybe you should bring Anne and myself back.

[1:08:11] Pradeep Chopra: I have a question which is a little bit out of the box.

[1:08:15] Dr. Theoharis Theoharides: Sure.

[1:08:15] Pradeep Chopra: Now, in MCAD, we know that there is extensive metabolism going on and there are a lot of free radicals in our bodies.

Dr. Theoharis Theoharides: Okay.

[1:08:23] Pradeep Chopra: Are there free radicals? First, I want to ask you that question.

[1:08:33] Dr. Theoharis Theoharides: Well, anytime we have inflammation, we have oxidative stress.

[1:08:36] Pradeep Chopra: Yeah, free radicals, right?

[1:08:38] Dr. Theoharis Theoharides: That goes without saying.

[1:08:38] Pradeep Chopra: So would antioxidants or free radical scavengers be a good idea?

[1:08:47] Dr. Theoharis Theoharides: Sure, no harm done. And besides, both quercetin and luteolin are antioxidants. In fact, they were identified as such. Anything that has color — like up in New England where the leaves change color — it's all flavonoids that do the color and they protect the tree. The more phenolic the flavonoid is, the more antioxidant it is. So pycnogenol has 15 hydroxy groups, so it's a much better antioxidant than quercetin, which has 5, and luteolin, which has 4. But the more methylated they are, the more anti-inflammatory they are. So tetramethoxyluteolin, which is present in the Gentle Derm that I mentioned earlier, is actually a better anti-inflammatory molecule. It's an antioxidant as well, but doesn't have color because it doesn't have the hydroxy groups. So it's a yin-yang.
[1:09:47] If I have individuals, especially children, with a lot of neuropsychiatric problems — autism, ADHD — I might measure glutathione levels, because our body's own antioxidant is glutathione. Some laboratories don't measure glutathione, but they measure glutathione peroxidase, which is kind of the same idea. If that is low, then I'll give them glutathione. You can give it in spray, sublingual, by mouth, or injectable as well. And vitamin C is an antioxidant here as well. But that would be a subclass of individuals with more neuropsychiatric problems.

[1:10:46] Pradeep Chopra: Got it.

[1:10:46] Dr. Theoharis Theoharides: Now, before we leave, there are publications that berberine also blocks mast cells. Berberine, as you know, is an antioxidant, antibacterial, antifungal. It's actually as good as Ozempic at stimulating GLP-1, by the way. So if anybody wants Ozempic, just take 1 gram a day of berberine. You'll do better. So it blocks mast cells. And if you have a lot of GI problems and you suspect mast cells, butyrate also inhibits mast cells, but it acts primarily in the gut and doesn't get absorbed very much.
[1:11:24] So if I have patients that don't do well at all with anything that we spoke about, I might add some berberine, I might add some butyrate — especially because some people just cannot tolerate flavonoids because they have phenol intolerance.

[1:11:38] Dr. Linda Bluestein: Okay.

[1:11:40] Dr. Theoharis Theoharides: The same way we measured diaminoxidase as an enzyme, we can measure the enzymes that break down phenols — one of which is catechol-O-methyltransferase, COMT, of course. So if they've got polymorphisms there, they cannot tolerate the flavonoids. In that case, berberine and butyrate would be possible choices.

[1:12:00] Dr. Linda Bluestein: It's so interesting that you brought up berberine, because when I interviewed Dr. Karen Herbst, she talked about berberine as a — she called it a baby GLP-1. And we know now there have been good studies looking at GLP-1s with mast cell activation. I wanted to ask you about that, but in the interest of time, because I feel like people are already going to be overwhelmed and you have such an incredible wealth of knowledge, we may have to do another part of this conversation. I wish we had time to cover it all.

[1:12:28] Dr. Theoharis Theoharides: I love our conversations.

[1:12:29] Dr. Linda Bluestein: Yeah. It's just so great to chat with you again. And of course, so great to have Dr. Chopra here this time. Thank you very much. Thank you so much for sharing this incredible amount of information. I feel like people are going to have to listen more than once.

[1:12:51] Dr. Theoharis Theoharides: But seriously, I'd love us to work on a more practical mini review about mast cell activation disorders, maybe for Journal of Family Practice or something else that is likely to be seen by a lot of physicians and not necessarily specialists.

[1:13:13] Dr. Linda Bluestein: Yeah, I think that would be great.

[1:13:16] Pradeep Chopra: Like a review article?

[1:13:16] Dr. Theoharis Theoharides: Yeah, a mini review. Not a review to cover all the literature, but more along the lines of what we were discussing. What are the confusing aspects? Why is it confusing? What does it mean if you have one and not the other? Is the treatment the same or is it really different? Et cetera. It might not amount to anything eventually, but I think if we kick it around a few times, it will probably be decent.

[1:14:10] Pradeep Chopra: I like that idea.

[1:14:11] Dr. Theoharis Theoharides: Worst comes to worst, we'll put it on your website. Yeah.

[1:14:16] Dr. Linda Bluestein: I think we should shoot for something more, because then we could do blog posts about the article. So I think it's a great idea. I would love to do it. And I know we shared a lot last time, and I want people to go back and check out that episode so they can find out more about Dr. Theoharides. And I'll put in the show notes all the relevant links so that you have all that information. And just, I want to thank you so much for coming on the show again and sharing your knowledge with us. I really, really appreciate it.

[1:14:45] Dr. Theoharis Theoharides: Thank you. By the way, if someone is desperate to see me, they can reach out to Nova Southeastern at the Institute of Neuroimmune Medicine. I do see patients once a month — just 5 or 6, however many they can fit in. I have 2 wonderful nurse practitioners that help me out. There were so many requests that I slowly started saying okay. And as I said, if anybody's interested in some of the supplements I mentioned, either Amazon or algonot.com — they can find all of those.

[1:15:24] Dr. Linda Bluestein: Yeah, we'll have all that in the show notes so that they can easily find that.

[1:15:28] Dr. Theoharis Theoharides: Wonderful. And I don't have anybody, Dr. Chopra, in your part of the woods anymore seeing these patients. So I don't want to start sending a lot of patients your way unless you tell me so, but I've got a lot from New England that are desperate, especially because Dr. Mariana Castells at Brigham is leaving, if she hasn't already left. And from what I understand, she shifted her patients to some allergists who don't even believe that MCAD exists. So these patients are desperate now. I mean, I get it.

[1:15:59] Pradeep Chopra: There's no one in New England who understands MCAD.

[1:16:05] Dr. Theoharis Theoharides: Same thing with interstitial cystitis. Same thing with chronic fatigue syndrome. Same thing with fibromyalgia. I don't know why, but we're just so intransigent. There are some up there that I used to send to Mariana, but she had shifted to seeing only mastocytosis patients. And then, as I'm hearing, she's leaving, if she hasn't left already.

[1:16:32] Pradeep Chopra: I think she has already left.

[1:16:33] Dr. Theoharis Theoharides: Yeah, she may have. It's a tremendous vacuum.

[1:16:35] Pradeep Chopra: She's going to do research.

[1:16:35] Dr. Theoharis Theoharides: Right.

[1:16:36] Dr. Linda Bluestein: Yes, absolutely. Thank you so much.

[1:17:43] Dr. Linda Bluestein: To unpack from this conversation with Dr. Theoharides, I think I'm going to create some newsletters specific to this topic, so be sure to sign up for my Substack newsletter at hypermobilitymd.substack.com. Thank you so much for listening to this week's episode of the Bendy Bodies with the Hypermobility MD podcast. You can help us spread the word about joint hypermobility and related disorders by sharing the podcast. This helps raise awareness about these complex conditions. If you would like to dig deeper, you can meet with me one-on-one — check out the available options on the services page of my website at hypermobilitymd.com. You can also find me, Dr. Linda Bluestein, on Instagram, Facebook, TikTok, Twitter, or LinkedIn at hypermobilitymd. You can find Human Content, my producing team, at humancontentpods on TikTok and Instagram. You can also find full video episodes up each week at Bendy Bodies Podcast on YouTube. To learn about the Bendy Bodies Program disclaimer and ethics policy, submission verification and licensing terms, and HIPAA release terms, or to reach out with any questions, please visit bendybodiespodcast.com. Bendy Bodies Podcast is a Human Content production. Thank you for being a part of our community, and we'll catch you next time on the Bendy Bodies Podcast.