Mast Cells: Friend or Foe? with Dr. Theoharis Theoharides (Ep 151)

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Dr. Theoharis Theoharides: [00:00:00] Any dietary supplement, uh, sold moving forward on, uh, Amazon will have to be analyzed by three laboratories that they actually selected, one of which is Fins. So they will send it to Fins, they'll get the results. And if the results are not within 50% of what you claim on the label, you're out.

Dr. Linda Bluestein: Welcome back every bendy body to the Bendy Bodies podcast with your host and founder. Do Yolinda Bluestein in the Hypermobility MD. Today we're going to be digging into so many more things about mast cell 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. PDE Chopra, is back as a guest co-host. [00:01:00] Most of you know Dr. Chopra for his incredible work in EDS Pots, M-C-A-S-C-R-P-S, and Central Sensitization Disorders for the two 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 multi-system 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.

Paolo Boase. So I'm so excited to have Dr. Chopra back today. How are you? Good. 

Dr. Pradeep Chopra: Happy to be with you again, 

Dr. Linda Bluestein: and our guest today is Dr. Theoharis Theoharides. for part one of that conversation and to hear the more detailed bio, please check out my first interview with him on episode 1 39. As [00:02:00] 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 don't miss any of our special hypermobility hacks. Let's get started.

All right. Well, I'm so excited to have Dr. Theoharides back today because we had a great conversation in part one, which was episode 1 39. And as you know, I have Dr. Chopra here. It was my guest co-host, and we're gonna have a great conversation. I'm so excited to chat with both of you. 

Dr. Pradeep Chopra: Same here. Thank you. 

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 really applicable to primary care providers, and so that patients, when they go to primary care providers, they can say, I heard from this expert, Dr. Athea Harti, like 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 [00:03:00] for.

These are some of the treatments that can be useful. So I think if we can maybe have this conversation through that lens, I think that is a way to help a really large number of people. Does that sound okay? 

Dr. Theoharis Theoharides: Yes, it's a loaded topic, but yes, 

Dr. Linda Bluestein: yes, yes. Uh, yeah. We could of course talk about this for, you know, for hours, um, hours and hours and, and days.

And I know that, uh, we wouldn't even scratch the surface of what, you know, so, um, but I think it just, 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 doctor be?

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? 

Dr. Theoharis Theoharides: Well, this is very opportune, uh, because my good friend and colleague that you all know, uh, and [00:04:00] Mike and I, uh, just submitted a huge review, about 600 references and invited review, and the title is Ma Cell Activation Disorders Colon.

Comorbidities and lookalikes. So that will explain a lot of the things in much more detail that you're asking. So I don't like the word or the title must activation syndrome simply because it is very, very restrictive and it doesn't really help our patients. So I like the term must cell activation disorders because there are three diagnostic codes.

There is other must cell activation disorders. There is must cell activation unspecified and there is

backwards if.[00:05:00] 

Medical history of telltale signs of activation of MA cells. Those could vary, of course, it could be et, it could be runny nose, it could be flashing of your neck and torso. It could be itching of the skin. You could diarrhea. And then further down the line, headaches, sometimes difficulty breathing, you know, bloating, uh, you know, et cetera.

That's number one. Number two is that at least use of some quote unquote drugs that help in such conditions such as the so-called antihistamines or the anti might have helped you in the past should anybody have of course suggested those. And now comes the tricky part. What are the objective findings for muscle activation syndrome?

There's gotta be elevation of this unique must cell enzyme called [00:06:00] tryptase within 48 hours of an episode. But that makes it extremely restrictive because number one, you've gotta 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. Problem number two, even if tryptase is elevated, which in most cases of even must, 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 muscle activation, unspecified, or syndrome.

Now, Dr. Butterfield from Mayo Clinic published a number of papers where he measured some metabolites or breakdown products of mediators from mass cells. Such as Leukotriene, c4, and such as prostaglandin F two Alpha. [00:07:00] And elevated levels of those along with n methyl histamine were more predictive of bonafide muscle activation syndrome than tryptase elevations.

So you looked at a whole bunch of patients, and only one third of the patients that he was an expert identified muscle activation syndrome had elevation of tryptase, but two thirds had elevation of the other breakdown products in the hearing. And finally, paper was published about a year ago, and my friend and colleague, Mariana Castel, wrote an editorial about it where some other colleagues measured serum T tryptase levels without necessarily any diagnosis.

Just to see if they were elevated and then try to relate it to a diagnosis. And in that study the cutoff was 11.5 nanograms per milliliter. And as it turns out, one 

third of those had [00:08:00] what we call hereditary alpha semia, 

which is mast cell activation. The other third, surprisingly, had chronic kidney disease.

In the remaining was aggressive mastocytosis, not a single patient with randomly measured tase, had mast cell activation syndrome. And because of that, our colleagues who use write about criteria raise the bar. And now the cutoff point for days is 15 per liter up from uh, 11.5. So all in. To the patients out there.

If you have these symptoms of being sensitive to God knows what, then you do see whomever physician you can see and just say, I have muscle cell activation, and here, why don't necessarily say syndrome, because then they will say, well, triplet agent not elevated, you have nothing go home. [00:09:00] 

Dr. Linda Bluestein: So let's start with that.

So when I first learned about mast cell activation, I thought, wow, they're like putting everything in this bucket because, you know, the GI symptoms, of course, are quite common. Headache is quite common, you know, a lot of these things. The flushing, of course is, is you know, more specific, but how do we know these, this constellation of symptoms when it's due to something else and when it's more likely to be mast cell activation.

Dr. Pradeep Chopra: Dr. Chopra, your input. So my, my thing is that in the diagnosis of, uh, m. From now on, I'm gonna call it disorder, mast cell, uh, activation disorder. There are three, there are three spots to it. For the primary care physician who's listening to this podcast, who is trying to learn about mc a, what would be a typical presentation of a patient coming here with Mc C?

It looks a lot like body wide pain, [00:10:00] skin flushing, itching. Anything else you'd like to add? 

Dr. Theoharis Theoharides: Do you want to discuss a difficult case or, or a rather simple case? I mean, the simple case would be someone itches like crazy, they're going to the shower. Hot water makes them, uh, each when they get out of the shower, uh, they, uh, they smell some perfumes and they flush.

Um, in other words, these are symptoms that are not typical allergies. In other words, if, if someone is not, and we'll talk about, you know, the diagnostic objective, diagnostic parts, but the, in a typical allergy, so to speak, uh, you know, you, you might be allergic to let's say pollen and you get all stuffed up and you get, you know, rhinitis.

You might have chronic sino, you know, rhinitis, um, you know, you, you might eat if you, you know, touch certain things. So these are kind of more typical allergies in the muscle cell activation disorder. Patients, they respond to things [00:11:00] that are not allergic, they're not necessarily IgE mediated. 

Correct. You 

know, which the, the, the risk of someone having allergic reactions.

It's almost the same roughly within the overall population and within the MCU group, it is that they respond to everything else. So today, for instance, I had a patient. Without even saying what she or may or might not have, I did what we usually do. I just scratched her underarm within one minute. He had a red line, so that means that the mu cells in her skin reacted just to the pressure and nothing else.

So I know this patient is likely to have am cut 'cause the muscles responded more necessarily to an allergen that would qualify them under the category of number two cell activation disorders. And maybe we should just mention that first. Because in the categories of ma cell activation disorder, we have the primary, which is [00:12:00] 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 aller. So it'll be rhinitis, conjunctivitis, you know, eczema. Then you've got what we don't understand in medicine, the idiopathic. And under that you have idiopathic anaphylaxis. You've got idiopathic, you know, edema, and then you have muscle cell activation disorders and muscle cell activation syndrome.

So that's kind of where it is. 

Dr. Pradeep Chopra: So to the common, uh, to the primary care physician. Patients will present with. And I have a list of symptoms that I look for. Um, skin flushing, unexplained itching, multiple chemical sensitivities, headaches, sweating, especially at night, uh, flushing after a hot shower. So hot to cold temperature change.

Uh, brain fog, uh, [00:13:00] belly abdominal discomfort usually is bloating, diarrhea, fatigue and symptoms that get worse during their menstrual periods. Not, not pelvic symptoms. I'm talking about generalized symptoms. Uh, and of course dermato, which, uh, but here's the one that's, that's also baffling is weight gain or weight loss, or weight fluctuation.

Is that, is that correct to add in the list? 

Dr. Theoharis Theoharides: Well, then I wouldn't necessarily, no honesty, uh, you know, going back to the symptoms you mentioned, and that's why in this recent chapter that we submitted, we take extremes, uh, you know, going after those, you know, clearly you've got to, when I say you, I mean anybody, of course, I don't mean, you know, you, uh, we have to make sure that we exclude other possibilities, even though some of the [00:14:00] possibilities may or might not involve ma cells.

So for instance, 

right? 

Let's say you've got hypertension, you've got diarrhea, you've got headaches, you've got flushing. It could be carcinoid syndrome. Yeah. In which case it is enter chromin cells involved and it's serotonin that is involved and not MA cells. And unfortunately some of our colleagues say that chromogranin A is released from MA cells.

It is not. It's released only from chromin cells or enter chromin cells. And not only that, for those who are listening there, but you have to be off all antacids if you measure chromogranin A, otherwise you turn out to be false positive. So there are, you know, a few things that we have to worry about as we worry about the fact that 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, reach the laboratory cold and the technicians better know they have to actually process it [00:15:00] cold.

If it states a room temperature of about 10 minutes, it's gone. You can't measure the metabolites and we get all these results. Oh, he was negative. There's nothing there. So. Uh, 

Dr. Pradeep Chopra: so there, there, there are a lot of these tricky things. So I was thinking of in terms of connecting the dots, I know that mental brain fog can be from other symptoms.

A lot of the patients have have pots or omi and so they have brain fog. But in this category where we are connecting the dots or jigsaw puzzle and the pieces fit, uh, so 

Dr. Theoharis Theoharides: well, lemme, lemme stop you for a second. The pieces don't necessarily fit. And as I might have said with Linda the previous episode, I'll say it again.

I tell patient, go into your physician with about five symptoms. Stop the moment you start reaching 10 and 15 or 20 symptoms, they're gonna think you're crazy. And they know they won't know what to do and it's too confusing and it's too time consuming and they're not gonna do anything. So if you start know, if you start [00:16:00] focusing on brain fog, when a patient with otherwise, you know, muscle activation symptoms, they're probably gonna say it's, you know, it's you for the birds.

Seriously, I've seen that so often that, I mean, I'll take the information down, but I would not necessarily make it an, an absolute critical part of getting through through the door. Okay. I mean, when the first, when Muscle Activation Syndrome first was reported by Met Calak and, and, uh, you know, inval, they did have neurologic symptoms and it was music to my ears because I've been studying brain mass cells for 30 years.

But then subsequently they took that off. So maybe for the reasons that we're discussing or, or maybe they're just got tired of people showing out with the neuropsychiatric symptoms and not necessarily other symptoms. So, uh, we'll go back and forth. I'm not being negative, I'm just trying to, 

Dr. Pradeep Chopra: so we can we, can we divide it into major criteria?

Criteria? I wouldn't call it criteria. I 

Dr. Theoharis Theoharides: would [00:17:00] call it major minor symptoms. Symptoms, okay. Or MA or major And, and ancillary symptoms. I don't like the word major minor because in some people the minor might be major and in others might be the other way around. So, but definitely it's gotta have at least one of the sort of more classic symptoms, whether it's ets, it's nose, you know, flashing, uh, you know, skin eating, you know, some castrate decal problems.

Those are kind of the more typical things, uh, we see. Although it can be any, any organ. 

Dr. Pradeep Chopra: So I have a major, major criteria. Okay. The major, major criteria is flu-like symptoms. 

Dr. Theoharis Theoharides: Okay, well, why would that be a major criteria since flu-like symptoms can happen for 20 different diseases? Why would that be a major criteria?

Dr. Pradeep Chopra: If they're not having, if they don't have a disease, if they don't have a viral condition or, we'll know that until 

Dr. Theoharis Theoharides: we, of course, investigate that. I mean, you know, someone comes in with viral symptoms. Anyhow, I, [00:18:00] I, 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 definitely are 

Dr. Pradeep Chopra: associated with mast cells and yes, that, so that would be skin flushing, itching, multiple chemical sensitivities. 

Dr. Theoharis Theoharides: Yeah, 

Dr. Pradeep Chopra: these would be, you know, maybe 

Dr. Theoharis Theoharides: symptoms. That's what I would call major. And that everything else you said is there. 

Dr. Pradeep Chopra: So GI symptoms being abdominal bloating and acid reflux?

Dr. Theoharis Theoharides: Well, acid reflux, you know, there's a separate diagnosis and the gastroenterology will give you a separate diagnosis for that. So yes, that comes in mind. Yeah, but you know, you can have acid reflux because you've got helicobacter pylori, not necessarily mast cells, you know, 

Dr. Pradeep Chopra: so among the GI symptoms, uh, uh, bloating would be one of them, right?

Bloating would 

Dr. Theoharis Theoharides: be one. Abdominal pain, often on would be another. And then alternating constipation, diarrhea, which is very similar to IBS. Uh, and I, I've published [00:19:00] papers that I think IBS is literally based on muscle cell activation in the gut. 

Dr. Pradeep Chopra: I am so glad you said that. Thank you so much. Oh, I'll see 

Dr. Theoharis Theoharides: other 

Dr. Pradeep Chopra: things 

Dr. Theoharis Theoharides: that you might like in a second.

Um, but you see the difficulty, the difficulty becomes in the paper, one of the papers I wrote about IBS is that number of MA cells is not important. It's the activation of the MA cells because many of our colleagues will look in the gut. And I've been in endoscopy switch with patients of mine who my colleagues at GI physicians will try to find your word.

Where should we look? So we will be looking the endoscope together, and most of the time there are no lesions to biopsy. So you don't know where to biopsy. I mean, Dr. Minor many years ago said that most of the muscles are in the ileocecal junction. So I usually say, okay, let's biopsy there, and then you take random biopsies.

But what I do, and when I talk about this in the objective criteria, is I actually request to send stool for three analysis of three things, total histamine. Why histamine [00:20:00] systemically, it's broken down with one minute and it'll end up in the urine as ethyl histamine or MI, aa methyl loc acidic acid. If it is released from the gut, it shows up in the gut, in the stool, it doesn't get broken down 'cause the enzymes are broke.

Breakdown will not have enough time to actually work on it. So if, if I have severe GI problems, histamine, the stool is off the roof, total histamine, then I measure eosinophilic onic protein where eosinophilic protein x. Both of them go hand in hand with mu cells and they're very strong triggers of mu cells.

And we don't necessarily have to have elevation of absolute numbers of phis in the blood for this proteins to be high. So I measure that as an index of the muscles being activated by something that I at least I can put my fingers on. And then a measure called protecting, which is a good index of inflammation.

Inflammation. 

Dr. Pradeep Chopra: Okay. Yeah. 

Dr. Theoharis Theoharides: [00:21:00] So those three, just to make sure that if those are high, then I'll tell GI people go and look for something that might have GI mastocytosis. And then the question is how do you define that? I know we're going in an angle for a second, but we'll come back because most colleagues say it's gotta be between 20 and 30 mass cells are high power field to Beog Monic of something.

You know, 10, 15, it might be okay, but again. You can have 10 MA cells firing like crazy. You might have, you know, 50 MA cells that don't do anything. So it's not enough. That's why I ask my GI colleagues when they biopsy to stain for both trip days and C kit or CD one 17, why C kit is on the surface, it will not change whether the muscles have de or not, but trip days will come out and the grounds will be empty.

So if you have, let's say a hundred mast cells with sick [00:22:00] kit and they're all positive for trip days, that means they're not de granulating. You know, they might be releasing with other means, but they're not frankly de granulating if they're empty, that means they spilled out their their trip days. So that kind of gives us an index of at least rough de granulation of MA cells, which is true not only the gut, it's true in the skin or anywhere else you might want to biopsy anyhow.

Back to 

Dr. Linda Bluestein: clinical 

Dr. Theoharis Theoharides: science. 

Dr. Linda Bluestein: So, so, so I have a follow, I have a follow up to that, uh, real, real quick. So these three stool tests that I think some of these you mentioned last time is really important. So, stool, histamine, uh, uh, eosinophilic cation, protein, and calprotectin, right? Correct. Those are the three that you mentioned.

Okay. Can those be number one done just through a regular lab or does it have to go someplace special? And number two, um, are these, if they're positive, then you mentioned mastocytosis. So would you be concerned about masto, uh, mastocytosis then, or could those be positive in mast cell [00:23:00] activation? 

Dr. Theoharis Theoharides: Those are excellent points.

Uh, on the first, uh, point, both calprotectin and ion protein are measured by typical labs like Quest and LabCorp, what have you. Uh, total histamine in the United States is not measured routinely in Europe. Most of the labs do it, I dunno why. So that might be a little bit of a problem. But I don't think Quest, LabCorp measure total histamine in, in the stool.

Uh, so you might have to go to a special lab. So the first thing that is telling me is that the muscles are being activated in the. And of course whenever we send stool, we do, you know, over parasites of course. Uh, so it might be a paracetic infection that maybe we missed. So I would usually ask, especially for children, do they eat around the anal, uh, you know, opening because most of the parasites, you know, come out at night, deliver their eggs in that area.

And here, when I was at the Yale starting medicine, we used to use a tape and just, you know, pull, pull the eggs off the tape and look them under the microscope. [00:24:00] Okay. So, so that might be a possibility in some parasites. You know, it's impossible to see, like li jar, RIA, you can't really see, you know, you've gotta actually put in a drop of, you know, fluid and see if they swim.

But who does these things? You know, long time ago we used to do them. I don't think anybody does them anymore. So when we ask for ine and parasites, in all honesty, I'm not quite sure what, what kind of parasites are looking at, whether they're looking at the waterfront or, or not. Now, more and more now, the laboratories that they do, of course, the whole microbiome 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 without gonna extremes at some point, because that might indicate that there are actually species there that we just didn't pick up with a regular, uh, you know, of a and, uh, you know, parasite test. Um, now if those are negative, then one would suspects.[00:25:00] 

Now in Tesla, mastocytosis, not very many colleagues believing that because they cannot find the mast cells. But there are papers, especially in children. You know, I had one child from Denmark a long time ago that was going to be taken by social services because he couldn't eat. He was constantly, you know, diarrhea, diarrhea and diarrhea, couldn't eat, and eventually had to broke him to Greece of all places.

Uh, but they did the biopsy and it was about 40, uh, muscles per per high power field. The, the kid had absolutely, uh, gi mastocytosis, and then we kind of did whatever we did, uh, et cetera. So, so that part is hard. Now, if we talk about systemic mastocytosis, as you know, it's all the symptoms that Dr. Chopra mentioned, uh, earlier.

A tryptase is almost invariably elevated, no matter when. So, so if you've got high elevated tryptase and the symptoms, you're not dealing, you know, with, uh, just muscle activation anymore, [00:26:00] in which case they're either one of two things. One can do either. You can do flow cytometry on peripheral precursor muscle cells that express the receptors such as CD one 17, CD 23, you know, et cetera.

But you've gotta have a very good, good flow cytometry and, you know, antibodies for those antigens to pick it up. Otherwise you do bone marrow biopsy. And I'll stop by saying no one should do an aspiration. Just the sheer force of aspirating will de granulate the mast cells. So it's gotta be a biopsy, and then we're not looking at 5, 10, 20 ma cells.

We're looking of clusters, islands, like 50 mo cells, uh, uh, et cetera. And there, and the shape is spindled rather than round. Anyhow, go back to. 

Dr. Pradeep Chopra: So you just referred to Mastocytosis, not mast Cell Activation disorder. If tryptase is very elevated, 

Dr. Theoharis Theoharides: regardless of the timing, remember in mast [00:27:00] cell activation syndrome, tryptase has to be elevated within 48 hours of an episode.

In mass, in systemic mastocytosis patients, tase is elevated regardless. Every day. Regardless. Yeah. You don't have to have an episode. It's just high because it measures, it's an expression of the number of volume. The masters you have, not their activation. And at some point we should talk about Heredi Alpha trip emia, because it's very, very confusing.

But maybe later. Yes, 

Dr. Linda Bluestein: that, you know what, that would be a perfect, we're gonna take a quick break and when we come back, let's talk about hereditary alpha semia, because you're right, that's, it's very confusing and I wanna make sure that people get a little bit of an idea of what that is. So we're gonna take a quick break and we'll talk about that when we come back.

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Okay, we're back with Dr. Thetis and Dr. Chopra. Okay, go ahead Dr. Thetis. I think you had something very valuable to say. Yeah, I was going 

Dr. Theoharis Theoharides: to say that the first thing is how do we educate, and I mean it in the good sense, the general [00:29:00] practitioner, the internal, you know, the internist about these things.

Because what will happen is if someone sees these symptoms, they're gonna send the ologist. Mm-hmm. Very few people, maybe unlike you and me, uh, and Linda, you know, will actually deal with this patients. Mm-hmm. Um, so, and that's why I think we should join forces and write a very good article for journal family practice.

Seriously, I just, just Googled it and there's hardly anything on ma cells. Let's do it because these are the kind of journals, you know, we might, there might not be, you know, significant journals. We get to, we have to get to our colleagues who are likely to see these journals because they're not likely to look at, you know, Jackie Journal or you know, Val's journals or whatever.

Okay. And we, we usually all publish in the Morter journals because they have, you know, better impact factors or what have you. But we've gotta get to the very [00:30:00] basic at this point. So having said that, how many do you think general practitioners or internists are likely to deal with MCATs rather than sending someone to an neurologist?

Just, let's just throw a 

Dr. Pradeep Chopra: percentage in my area. There's no one. There you go. Same with me. No 

Dr. Theoharis Theoharides: one. Mm-hmm. 

So, so even though my heart bleeds for how to educate and even the good sense, I mean, educate our colleagues at the, the end of the, the day, they're not gonna deal with this patients for all kind of reasons.

And now we're going to the allergist. How many of the typical allergists. Do you think? No. About what we're talking about, 

Dr. Pradeep Chopra: one, not, not yet. Very few in my entire state, there's only one. Very few. Yeah. Very, very few. Unfortunately. 

Dr. Theoharis Theoharides: Very few. Very. And I think I might have mentioned in the last episode, but I will reiterate it, uh, but a year ago or so, maybe less, the, a relative of one of my [00:31:00] previous doctoral students, physician himself, uh, who was actually vacationing in, in Tampa, in Florida, uh, had to go to the emergency room because his wife had an anaphylactic reaction, and she already had a history of t So when, now this was related to me by her husband, the physician, they went to the emergency room and they explained that, you know, she's got a history of mass cell activation problems and the attending physician, it might have been a resident or some serious attending.

The first question was, what's wrong with your, with your breasts? 'cause she said mass cell activation. This is six months ago in Tampa. Okay. Uh, so, so the, the, 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 are of, so we've gotta sensitize the [00:32:00] physicians that patients who basically are allergic to life have my mcu.

And if triase is elevated within episode, they've got mcu. That's it. Let's call it this. But I don't like the word allergic because allergic, again, as I said earlier, implies IgE so sensitive to everything like multiple chemical sensitivity 

Dr. Pradeep Chopra: type of, of patient with no other explanation. So these patients will present with, uh, they'll present with sore throat, okay?

Most times when I examine their throat, it's, it's red and inflamed. Okay? So you do a strep test. You do a strep test quickly. But they don't have any complaints. Well, they have sore throat. That's a complaint. They don't complain about that, that's the thing. So, so what do you mean they have sore throat then?

If they don't complain? So is that the sign of a, among other signs, would that be one of the symptoms of, or sign of mcad? 

Dr. Theoharis Theoharides: Sore throat by itself [00:33:00] would not necessarily trigger me. But if they have swollen lips, redness around the lips, swollen tongue, then absolutely. Yes. You know, and then we have another syndrome.

We're gonna, we're covered with syndromes, you know, red to syndrome, and then we've got, you know, geographic, you know, et cetera, et cetera. Many of them overlap. And since you, me, that, uh, and again, I have me this before, I apologize.

Becoming more apparent, uh, is individual who actually get swelling around their lips. And I had a wonderful lady actually from, uh, Bocca Raton about a month ago that not only would have this swelling, but your whole face would swell up so much. I mean, she was literally a model. And if you saw your face, you know, you think it was like out of, 

you know, 

some 

horror movie 

tattoo, it wa it was that bad.

I mean, I've ne I've never seen that swollen person. [00:34:00] And as it turns out, after digging into it, she was, she literally had what we call Alpha G syndrome, uh, which is another thing that we should talk about in, in addition to Alpha Semia. So in Alpha ga, as we all know, of course it's an antigen, it's present in mammals, but humans don't have very much.

So it's much more present in cows and pigs and, you know, et cetera. And if you're beaten by a tick. You might not get bor or BIA or some other, you know, bacterial uh, disease, but they will carry the alpha girl to you and now you become super sensitive to it and you become super sensitive to anything that has mammalian product, including drugs, supplements, and cosmetics.

And she mascara that she was using had actually gelatin in it, which was actually of course from mammalian source and she responding to, to that. 

Dr. Pradeep Chopra: I have a question on that Alpha Gal syndrome, uh, [00:35:00] it's only to beef and pork, right? Correct. Not chicken fish. Not chicken. And 

Dr. Theoharis Theoharides: no fish. No. 

Dr. Pradeep Chopra: No fish, right? Correct.

Okay. 

Dr. Theoharis Theoharides: However, now that you mentioned it, Carin, which is used in many capsules of supplements and drugs, you know the Clear Cup is made of Carin Carin from seaweed, Carin Cross reacts with Alpha Gal. You can look it up. So, so someone could be reacting even to the hard gel caps of, of drugs and supplements, and we just don't say that, you know, that's why I'm saying it.

We're making life more complicated, if you wish, but at least there's specific things that are measurable. 

Dr. Pradeep Chopra: So if a patient comes in with saying that, doctor, I am allergic to meat, beef, and pork, but I'm okay eating fish and chicken, then that's a good indicator. That's a good, 

Dr. Theoharis Theoharides: but you see the patients are not gonna say allergic, they're probably gonna describe something, right?

They're gonna say, 

Dr. Pradeep Chopra: react to it. Yeah, react 

Dr. Theoharis Theoharides: to it. [00:36:00] You know? Yes. I, I would definitely think of alpha 

Dr. Pradeep Chopra: and, and, and we can send them to Quest. LabCorp asking for alpha antigen? 

Dr. Theoharis Theoharides: No, no. What you ask is just, we ask for if. And unfortunately, many of these companies have panels you can't ask specific, you can ask specifically, but it's more complicated.

So they have, for instance, IRO allergen panels, you know, they have foot panels, so it's probably gonna be under the foot panel before you, so if you search for Alpha Gal, you might be able to find it, but if you look at a foot panel, it might be listed underneath. It'll be there. Okay. Yeah. So I usually for any, but we'll talk about the specifics in a second, what we measure.

Um, but yes, I, I would measure that. And, uh, and, and then of course food sensitivity is a whole different ball game that we can talk about later because food sensitivity is immunoglobulin gsap, class four, IgG four, it's not ig, [00:37:00] and the are triggered through IgG four. 

Dr. Pradeep Chopra: Just before we leave meat alone. Sure. Um, if you eat reheated meat.

Yes. Meat that has been put, put in the fridge and then the next day you reheat it. The histamine level goes up. Right, because the DAO comes down. 

Dr. Theoharis Theoharides: I, 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, your fish, you eat it away. Um, because, but not with meat.

I, I haven't seen it as much. I mean, I, I usually say if you can eat it fresh, it's better. But if you were to ask me to put my finger in a publication with meat, I don't have it with fish, I do. Okay. 

Dr. Pradeep Chopra: When you say fish, I mean, you mean fish that swims not Yes, yes, yes. Not the scallops or No, no, not, not those.

Or shrimp and all that. I mean, people 

Dr. Theoharis Theoharides: might be allergic and sensitive to those regardless. 

Dr. Pradeep Chopra: That's different. Yeah. Yeah. That's different. 

Dr. Theoharis Theoharides: But we should talk about the diamond oxidase later, so maybe Linda can make a list of all the [00:38:00] things we should cover. 

Dr. Linda Bluestein: Yeah, we did talk about that in the first part, so, so I think.

I would love to talk about hereditary alpha semia. 'cause we're, we, I we could talk for hours and hours and hours, but, but I don't know if there was something else more pressing on someone's mind before we trans transitioned to that because I know we kind of went from like symptoms and then we, we didn't, we didn't cover 

Dr. Theoharis Theoharides: the objective measurements.

Right. So maybe we should say, so we can go back some words about that before we go, uh, to the Sure. 

Dr. Linda Bluestein: And that, and that kind of folds into, 'cause we're talking about tryptase and then tryptase. Correct. The objective measurement for the hereditary alpha tryps. So, so, 

Dr. Theoharis Theoharides: so I always ask for total ig, total IgG one and IgG four.

'cause usually it's a ying yang. The IG one tends to be the good guy IG four, kind of the bad guy. I'll measure a plasma histamine, but it invariably it's gonna be very low unless summer is chronic itching. So chronic idiopathic utic area. And that is [00:39:00] important to measure the plasma histamine 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 think of chronic urticaria. 'cause 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, and that test is called basophil activation test because we cannot isolate the mast cells to test it.

We can isolate the basophils now that is buried.

Panel inquest. So you can't ask for look for activation test or anti IG 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. God knows [00:40:00] why. So, so it's not really, you know, it's kind of confusing. 

Dr. Linda Bluestein: I, I, I'm very interested in that because I have chronically elevated histamine and I have antithyroid antibodies and I do have chronic itching.

Dr. Theoharis Theoharides: So right there, there are, there, there, there is an association, but I'm not sure I would call that MCA or MCA as of yet. Mm-hmm. Mm-hmm. But for instance, I would be more interested in parathyroid hormone measurement if someone has incredible intractable eating because PTH is one of the strongest triggers of mar cells.

Mm. In about one in 20 patients I've dealt with, with chronic such problems, including and unfortunate. Wonderful little kid has both muscle activation and autism and down syndrome, and he was itching himself like crazy and not believe that the mighty P-T-H-P-T-H was off the roof. Now it could be primary or secondary, PTH [00:41:00] thyroidism, but it doesn't matter.

It'll stimulate the muscle cell. So we have to drop it down, whether you, you know, you give calcium levels so you can lower it or that, you know, you take some of the parathyroid blends out. Um, so I'll measure those. For that reason, Jenna will ask for food intolerance test, but there's a, there, if you hit something every day, it turns out to be false positive.

So I. Organic boiled chicken and rice. I've hardly ever seen any reaction to chicken and rice. Doesn't have a gluten, so we're kind of on the safe side. So if you do that for three days, then you do the test and sort of believe the, the results. Okay, so that's food intolerance, IgG, not IGE. Then there's certain molecules that come from the mast cells other than trep days.

That would be important to measure, especially if there's some other Dale signs. For instance. Rease [00:42:00] is stored in the secretory granules of the mast cell together with another enzyme called kinase. Mase convert angiotensin one to a genten two. And not only converts it, but it's resistant to the, to the drugs.

So if someone has very high blood pressure that's unexplained, for instance, I will measure kinase for that reason. Uh, IL six. It's definitely coming from the mast cells and both Dr. Metcal and colleagues Dr. Banano in Spain and colleagues and I at different times, different journals published that IL six elevated in the blood with a better indicator of mastocytosis severity than even Tase days.

But hardly anybody measures IL six. Why? 'cause it can come from other cells. But going back to what Chopra said, if no one has no other condition [00:43:00] and IL six is high, then I'll be dentist not to consider. They might coming from the mast cells, you know, if someone has inflammatory bowel disease, well yes, it could be coming from that.

Okay. Uh, so I'll measure I six. I'll definitely measure vascular endothelial growth factor because it comes outta the MAs cells and it comes outta the MAs cells without necessarily system in tryptase. And it is. Incredibly important under stress. We've published numerous papers on so of others, the corticotroph releasing Hormone First hormone released under Stress, which we always thought and thought it only released in the hypothalamus.

It's released in every organ in the body. We've published papers that chronic etching in pro, in in eczema and psoriasis had CRH elevated both in the skin and the blood, for instance. And other colleagues have shown it in the bladder, GI tract, et cetera. And when CRH stimulates the mu cells, they released only VGF, no, his amery taste.

[00:44:00] And more recently a paper was published that in systemic mastocytosis angiopoietin, which is like vascular endothelial growth factor. But there about five other angiopoietin were very high. And the German group has shown that heparin. It's also quite high in systemic mastocytosis patients. And keep in mind, half of the granule of the mass cell is actually chondroitin sulfate and heparin sulfate, and yet the MA cells don't circulate.

So obviously these molecules do something else. Um, and the reason I'm saying that, because if I see coming back to what you said, Dr. Chopra earlier, you know, bruising, and of course you know, if it's not, you know, trauma or abuse, you know, whatever, I might think that the muscles are spitting out heparin because heparin's anti clotting is caused bruising.

And we've seen that in some cases of aggressive mastocytosis. Now why heparin would be released and not other molecules like rib days. It still buffs me because we've been taught that they're all in the [00:45:00] same 

Dr. Pradeep Chopra: granules. Maybe they're not. So in, do you think we should measure heparin? Laboratories in the states don't 

Dr. Theoharis Theoharides: measure it.

In Europe, they measure it. Now you can measure it indirectly, you can measure it, but I don't think anybody measures heparin as such. Um, so, but if I see bruising, I'll do all the testing that are likely to tell me if there's actually, you know, bleeding, uh, di of some sort. Right, right. So that's, that's pretty much, uh, in terms of, in terms of blood measurements.

And then we go to the urine measurements that we mentioned earlier, which would be either end methyl histamine, which is the breakdown product for about 30% of the histamine, or MIAA meth acidized with another 60%. And both I and Dr. Battlefield and others believe that one measurement is not enough because these are episodic histamine is release episodically as you know, you know, you might have a reaction and, you know, tomorrow might not have a reaction.

So I usually measure it, you know, at least [00:46:00] twice within three months. Uh, and, and, and that, you know, if it's not high, it's not high. 

Dr. Linda Bluestein: And, and when you're doing the urine tests, are these spot urines or are these, is this a 24 hour urine collection? We, 

Dr. Theoharis Theoharides: it used to be 24 hour urine, but Dr. Potterfield, the May Clinic, said that first morning void might be sufficient unless someone's in interstitial cystitis, uh, or they have an EIS and they're up all night, you know, urinating.

And I think it's, it's, it's fair, you know, first morning void. 

Dr. Pradeep Chopra: Does it matter that the patient is on mast cell stabilizers or, okay, you, you 

Dr. Theoharis Theoharides: asked that earlier and it's a very good point. So antihistamines block the action of histamine after it's being released 

Dr. Pradeep Chopra: after, so it's 

Dr. Theoharis Theoharides: not gonna make any difference to the amount of histamine.

Now there's some antihistamines, like ine, which is available in Canada and Europe is that also blocks the muscles to some extent. So if you were to tell me someone should be on ine, they'll say no. But if someone is on ZEC or you know, one of those [00:47:00] doesn't make a difference. The same way will not make a difference with singular, because it blocks the action, not necessarily the production thereof.

Definitely they should be off steroids because steroids will block a production of everything. So that's one. And number two, they should not be on any foods that contain, of course, high amounts of histamine. And that takes us to another topic, which is histamine intolerance. Uh, okay. Uh, because foods, as you know, like fermented foods, his, uh, you know, cheese, tomato, spices, avocado, pineapple, have a lot of histamine, cumin, uh, curcumin.

So, and sometimes colleagues will give actually flavonoid, uh, because it's anti inflammatory antiallergic. But unless it's 98% pure, it's gonna have a lot of histamine. Coum has histamine, cumin has histamine, cinnamon is histamine. So, and I see all these, you know, dietary supplements, [00:48:00] you know, immune support.

They have about 10 different things in there. And you know, unless they're pure, I say, my God, who knows what they do. 

Dr. Pradeep Chopra: So you said pineapple has a lot of histamine in it. Mm-hmm. So curse itin, I thought was made from pineapple, right? Well, that's why it depends how pure it is. Oh. 

Dr. Theoharis Theoharides: And unfortunately, what you see out in the market, uh, give you an example.

You can either try to buy quercetin or luol, 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 said bullshit. Excuse the expression, I know how much it costs to buy a kilogram of this in 98% purity. There's no way on earth that someone can be selling 60 capsules with 500 milligrams per capsule at $20.

They're just lying. That's it, period. So, you know, cost, cost alone should not be the determinant factor for, you know, either patients or physicians. And I've got [00:49:00] many colleagues who call me, well, why should we get Neuro Protect It costs, I dunno, $35 and not sat. And what I do, I send them the analysis because I send both for analysis to fins and one comes 50% purity and the other comes to 98% purity.

And if it's not pure, what the hell does does it have in it like histamine? 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 bins. 20% of Mediterraneans have G six PD deficiency. If the fava bins got hemolytic anemia, who tells you that?

On, on the label of the stupid dietary supplement. Okay, so don't get me going on the supplements. It's like, it's insane because, you know, it's like billions of dollars are spent all over the world for supplements and maybe 10% of them are worth anything. So, but it is what it is. As you probably [00:50:00] know, Amazon announced that as of May 1st, I dunno how strongly, uh, they will actually implement this.

Anything, any dietary supplement, uh, sold moving forward on, uh, Amazon will have to be analyzed by three laboratories that they actually selected, one of which is Fins. So they will send it to Fins, they'll 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 long time ago.

They haven't. They're not likely to do it either. So. Alright, back to Alpha Semia. 

Dr. Linda Bluestein: Yeah, because we definitely wanna talk about treatment and which, which you kind of were talking about when you were talking about supplements. So Alpha, alpha Emia. 

Dr. Theoharis Theoharides: So as I said earlier in the study that was published, and the first report was by Dr.

Ly at NIH, they found out it's a genetic condition where you actually make the alpha type of tryptase. And let me explain what that means. Inside the secretory grans of the mast cell, you have a [00:51:00] beta tetramer, beta tryptase, tetramer. It's inactive inside the granules because it's bound to sulfate, a heparin sulfate.

The moment the ground is released that gets disloved and our tryptase is active. We still don't have a drug to block the action of tryptase, but it's active now in this condition, it's alpha two, it's a dimer, not a tetramer, and alpha two is inactive. And it is not inside the granules. So question number one, where is it coming from?

If it's not in the granules? Question number two, if it's inactive, why on earth do these patients have almost all the symptoms of muscle activation patients? I have no clue, and I don't think anybody has for that matter. So if in fact someone has tryptase elevation without necessarily having all the symptoms, which is very hard to discern, then you might think.

Or if [00:52:00] someone is telling you as you take the medical history, or you know what, Myan has similar problems, my daughter has similar problems, then it's worth doing a genetic analysis for the, for the gene. Okay? How we 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, I. Alpha Trip case is not in the granules, and I don't know how it's coming from. So it's wishful thinking, uh, if you wish, but it's becoming much more common. Now, according Dr. Alliance, about 8% of the population has hereditary Alpha emia. That's a very high number, 

Dr. Pradeep Chopra: very high number.

So the symptoms of Alpha Emia is almost the same as MCAD 

Dr. Theoharis Theoharides: almost. Um, so there are a number of tables, uh, that you can, you know, we can look at, but they do have aging and they have a lot of GI problems. Not so much flashing, not so much the [00:53:00] 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 Semia, um, might be like 5%.

Uh, but skin is about 70%, GI is about 70%. Uh, and clearly trip days. Protease activate receptors pars. So it might be that the alpha two binds to a different par receptor and causes these problems, uh, and tryptase binds to different receptor. But we don't have a way of blocking either the release or these receptors, at least not for the time being.

Dr. Pradeep Chopra: So can we go to, can we go to treat treatment? Sure. So 

Dr. Theoharis Theoharides: invariably we start with an antihistamine and invariably we like the non-sedating or second generation antihistamines. And invariably we can go four times up the recommended [00:54:00] dose. So let's say situ in 10 milligrams, we can kind of slowly bring it up to 40 milligrams.

But the moment you start going upwards, you're likely to get sedation. So that's one. Second point is that about 15 1 5 15% of patients don't get sedated by get wired. So they get very anxious and they don't like it. And I don't know why they get wired. I mean I don't understand the pathophysiology, but they get wired.

Third point is that all of the antihistamines in the first generation, like Benadryl, like hydroxyzine, are more of what I'm about to say, are also anticholinergic. So they block acetylcholine receptors and therefore if you start pushing the dose, you might put someone in retention. They might not be able to urinate because they're anticholinergic or they might not sweat as much anymore.

Or they might have dry eyes and dry mouth and you might start thinking Sjogren's syndrome because of that. So keep that in [00:55:00] mind. Also at very high levels, like over a hundred milligrams. Uh, I would never give them on people that have a history of scissors because they increase scissor activity as well.

And even though what I'm about to say was true for the early. First generation antihistamines, it's been creeping up for cetirizine or hydroxyzine. The may actually increase the QTE interval. So cardiologists, you know, worry. And if we have someone that has actually QT elevation, then I might go very slow on the dosing there.

So that's for H one. Now, anytime you have a chronic problem, whether it's itching, gut problems, et cetera, you're gonna be stressed. And of course we're swimming in stress, whether it's political, financial, and what have you these days. So your histamine is going to be stimulating the parietal cells in the stomach to make acid.

So we've those, so invariably give histamine [00:56:00] blocker, and of course with some of block, which I'll mention in a second, there's another reason why. Which is not very well known. The MA cells have H two receptors on their surface, and histamine activates the MA cells through the H two receptor. So by giving an H two blocker, not only we reduce the amount of fast produced, but mildly keep the muscles cells from over firing other issues.

As you know, the first drugs Cimetidine, which was very popular in its over the counter, of course, it inhibits the P four 50 system in the liver. And because all of us, and I mean males have a little estrogen, if you book the P four 50 system, you build up the estrogen and you get gynecomastia and loss of lipid and loss of erection.

So we've gotta tell patients if they're going tug it, you've gotta watch out. Likely it's reversible. Now the others like famotidine ine a little better, even though it was a little [00:57:00] scare about, you know, some other side effects. But they're still on the market. Now individuals who have chronic gastritis or chronic gerd, I would worry about h pylori.

Uh, and as I said earlier, h pylori likes acid environment. Um, it is very difficult to eradicate. Uh, so if someone has chronic gerd, you've got to actually think about even doing an endoscopy or breathing test for, you know, it Pylori. And the treatment is two antibiotics and two antacids, uh, for about, you know, two weeks.

However, there's GERD that is eosinophilic of and eosinophilic of titis. We're looking eosinophils. I always urge my colleagues to look for MAs cells because I said earlier they go together. Same thing as your eosinophilic gastroenteritis. Again, I worry about mast cells in both of those conditions. So those are kind of the beginning.

So then if you've got a lot of itching before, you know, we talk about chronic spontaneous [00:58:00] TIC area, you know, you've got to give, you know, over and beyond. What the antihistamine can cover. You might give a steroid cream if it's localized, or you can give a cream that I help develop called Gentle Derm, that has actually tetra methol, which kind of, it's very well tolerated.

There are a couple of publications and you can use it together with an antihistamine. If you've got GI problems, then you do the food intolerance, of course, testing that we spoke about, or the food allergy testing. Then you might consider Dao that we spoke about last, uh, episode diamond oxidase. Just keep in mind that diamond oxidase will be destroyed in the stomach.

Uh, the stomach has a acidity of one. Enzymes work at an acidity of seven. It's like our blood. So I like one or two, uh, that are actually acid resistant or inter coded. And I think I sent you that 

Dr. Linda Bluestein: list, Linda. Yeah, you send it to me and I'll, I'll put it in the show notes so people have it. Yep. Okay. 

Dr. Theoharis Theoharides: So [00:59:00] now what do we do then?

Then it's where I look for natural molecules that might block the MA cells. And you know, quer can block the MA cells. Lutein is a little better. And we published the both qu and lutein are better than rolin. The only drug that is sold is a mast cell blocker. And the issues with rolin, number one, the new preparation in the United States is horrible.

It causes all kind of problems. Hardly antibody can tolerate it. I what on cannot tolerated.

Rapid phyla, the body gets used to it. So we started about a hundred milligrams, you know, once, twice a day, you know, by three, four months or 400 milligrams four times a day, stops working after that. And then you start getting about 15% diarrhea, about 10% alopecia. And Dr. Church in England published two papers that if you push the bi fascia curve, you start stimulating the muscles to release histamine.

So if I don't get any results by 400 milligrams four [01:00:00] times a day, that's it. You know, go cold Turkey, stop it. It's not gonna do anything more. So then what do we do after that? Well, we measure the mediators. If you go try this, high singular, if prostoglandin are high, some kind of NSAIDs, if it's tolerated, and then symptoms.

Now they're the so-called biologics, of course, are injectable, but Dupixent blocks, for instance, you know, some of the cytokines that stimulate also mast cells. Uh, now there's an L 31, uh, inhibitor, and L 31 is more progenic than histamine. So that's now available in the market. Um, and of course there are three, four new biologics that block the receptor for interleukin five, which stimulates the eosinophils.

So for, you know, chronic asthma, eosinophilic, you know, sitis, et cetera, those drugs might be good. But you see how we're now [01:01:00] limiting ourselves to specific symptoms, not the overall. So the overall is not gonna be helped by these drugs, but the itching would be. And then we have those patients that we mentioned earlier that might have autoimmune, chronic spontaneous urticaria because of antibodies.

What do we do for those? But very little in those.

God knows why it works. Immune IG IVIG or subq iv, which seems to work, but I dunno why it works. Or we use low dose naltrexone, which also works and I dunno why it works. So by LDN we mean 0.1 milligram, which incrementally is increased over like two weeks to no more than four milligrams a day and by four milligrams.

If it doesn't work, it's not gonna work. And patients experience kind of nightmares and all kind of, you know, uh, uh, other such symptoms. 

Dr. Pradeep Chopra: That's it. We forgot keto. Ah, [01:02:00] 

Dr. Theoharis Theoharides: I thought you'd ask. Well, keto is a misnomer. Keto is a very good antihistamine. It's not a Mars cell blogger. The only publication that ever showed that keto even blocks anything was in Conjunctival Must Cells, single publication.

But ever since that time, everybody calls it a muscle blocker and it is not. 

Yeah. 

RU is a, is a, is a muscle blocker. There are five publications. Now, having said what we said about antihistamines, some antihistamines work better than others. So I would not give up. And keto would definitely be up my sleeve, not because it's a muscle blocker, because it's a different antihistamine and some people tolerate it and do well, but it's very sedating and cause increasing appetite.

Just like the Tris antidepressants, you know, back then. So sure we, we would use it, but it's not a panacea. Uh, so, you know, I would put it probably in the [01:03:00] category along with the cetin and then the lutein, you know, et cetera. But before we give, leave the topic, I do wanna mention that all flavonoids are not necessarily good.

And lutein, Cetin of course is flavonoids, so is resveratrol, so it's cocum, et cetera. So you see soy flavonoids, for instance. Well, God forbid if someone has estrogen independent breast cancer, uh, they will actually increase the cancer because soys are, you know, estrogenic. So we've gotta, you know, be a little smart about what, of course patients cannot, you know, make out the difference.

But I'm so saying, 

Dr. Pradeep Chopra: so. So the mast cell stabilizers are only chromin. Chromin is not a mast cell stabilizer. 

Dr. Theoharis Theoharides: I published the first paper on Chromin in the Journal of Science as an undergraduate at Yale, and I'll brag about it, but it worked like a charming rat. Dr. Galley was chief of pathology. At University of Stanford.

He used to be, you may remember him, [01:04:00] uh, at, at Beth Israel. Actually before he moved to Stanford, he published that he doesn't even inhibit mouse MA cells. And as I said earlier, we showed that Chromin lutein are much better inhibitors, uh, than Chromin. Now give credit to Chromin though. 'cause as a student at Yale, I used one of the first programs NIH had for comparing basically molecules.

And why did I find actually LOL Aquity? 'cause rolin looks like a butterfly with two wings, and the flavonoids are butterfly with one wind with 90% accuracy. I see. So when I was looking at natural molecules and I saw the structure, I was stunned by the fact they're very similar. But to this day, no one has identified a receptor either on the surface or inside the cells.

For chromoly, we have no idea. 

Dr. Pradeep Chopra: Just to clarify. Sure. If I'm going to treat a patient with mcad, yes, I start with H one blocker, H two [01:05:00] blocker. Correct. What would be my third drug? 

Dr. Theoharis Theoharides: So as I said, if leukotrienes are high in the, in the urine, you'll Right. If you know prostaglandins are high, you'll give them a little of, you know, NSAIDs.

And then either at that point or from the very beginning, you give them liposomal lol or liposomal lutein. Enidine enidine together. Got it. Because they will block the mu cells, but it takes weeks before the muscles really calm down. It doesn't work like an antihistamine like overnight. You know, your, your hives will disappear, right?

Uh, and then you start tolerating foods. You start tolerating exposure to some, you know, other triggers, et cetera. I wish we had better drugs. We published a paper just a couple of weeks ago where two newer flavonoids are even better, or we tested them so far in microglia. Not on mass cells. We are in the process of doing that.

Uh, so those might be even better. And one of them is partially water soluble, uh, which makes it, [01:06:00] uh, better. 

Dr. Linda Bluestein: Yeah. Oh my gosh. We, we could talk about this for really a long time. This is such an incredible conversation and indeed that there's a 

Dr. Theoharis Theoharides: condition that we should touch upon, or maybe Lin, uh, should do it.

There's periodontitis now in a subgroup of patients with EDS, and we've published a lot of papers about muscle cell periodontitis, so maybe we should talk about that some other time. It's it'ss an incredible new entity now that I don't quite understand as of yet. 

Dr. Linda Bluestein: I, I have discussed that with her, but not during a recording.

So we'll have to figure out, uh, how to have that conversation. So maybe should bring 

Dr. Theoharis Theoharides: Ann and Anna and myself back. 

Dr. Pradeep Chopra: Yeah. Ed, Dr. Chopper, I have, uh, I have a question, which is a little bit out of the box. Sure. Now in MCA, we know that there is extensive metabolism going on and there's a lot of free radicals that are in the cyst in our bodies.

Dr. Theoharis Theoharides: Okay. 

Dr. Pradeep Chopra: Is it worth, but I are [01:07:00] there free radicals first I wanna ask you that question. 

Dr. Theoharis Theoharides: Well, any, anytime we, anytime we have inflammation, we have oxidative stress, we have free radicals. Right. So, so that goes without, so, so 

Dr. Pradeep Chopra: would, would, would like antioxidants or free radical scavengers be a good idea for add?

Sure, sure. It would 

Dr. Theoharis Theoharides: to this, it, it would be no harm done. And besides both car and lutein, our antioxidant. Oh, okay. In fact, they were identify anything that's color, like, you know, uh, up, up in the New England where the leaves change color, it's all flavonoids that do the color and they protect the tree eventually.

Um, so. What it is is the more phenolic the flavonoid is, the more antioxidant it is. So Pycnogenol has 15 hydroxys, so it's much better antioxidant. The qu that has five, the lute has four, but the more mesylated they are, the more anti-inflammatory they are. So tetra [01:08:00] methol that is present in the gentle derm that I mentioned earlier, is actually a better anti-inflammatory molecule.

And it's an antioxidant as well, uh, but doesn't have color because doesn have the hydroxy groups. Uh, so it's a yin yang. But there are many, if I have individuals, especially children with a lot of neuropsychiatric problems, there might be autism, there might be the A DH, adhd, not that I see the children myself.

Usually the parents bring them because they have a problem and then they tell me about, you know, the children kind of as well and says, you know, it happens. But then am I measured glutathione levels because. Has the only antioxidant that it has, it's glutathione. Now, some laboratories don't measure glutathione, but they measure glutathione peroxidase, which kind of the same idea.

If that is low, then I'll give them glutathione and it's you, you can give them, of course, herbal supplements, like the ones we spoke about. Uh, and vitamin C is an antioxidant, you [01:09:00] know, as well, et cetera, et cetera. Uh, but I might give them glutathione. It's says spray, it's sublingual, and it's, you know, by, by mouth and injectable as well.

So that's another kind of approach. But that would be, again, a subclass of individuals that have more neuropsychiatric uh, problems. 

Dr. Pradeep Chopra: Got it. Now, 

Dr. Theoharis Theoharides: before we leave, there are publications. The berberine also blocks mast cells. So Berberine, as you know, is, is an antioxidant. It's antibacterial, is antifungal. Uh, it's actually as good as Ozempic stimulating GMP one, by the way.

So if anybody wants, you know, pic, just take one gram a day of berberine, you'll do better. Um, so it blocks MA cells and if you have a lot of GI problems and you suspect MA cells, beauty rate also inhibits MA cells. But it acts primarily the gut doesn't get absorbed pretty much. So if I have patients that don't do well at all with anything that we spoke about, [01:10:00] am I yet some perine?

Am I yet some beauty rate? Uh, especially there's some people that just cannot tolerate flavonoids because they have phenol intolerance. So, you know, the same way we measure diamond oxidase as an enzyme, we can measure the enzymes, the breakdown phenols, one of which is ethyl transferase, COMT, of course. So if they've got polymorphs there, they cannot tolerate the Fluor node.

So you've gotta come up with something else. So in that case, berberine, you know, butyrate would be possible choices. 

Dr. Linda Bluestein: It's so interesting that you brought up about the berberine. 'cause when I interviewed Dr. Karen Herbst, she talked about, she talked about berberine as a, she called it a baby GLP one. And then we know now there's been good studies looking at GLP ones with mast cell activation.

And I, I wanted to ask you about that, but in the interest of time, um, because I feel like people are already gonna be overwhelmed and you have such an incredible wealth of knowledge. So we may have to do a, another, another part of this convers course conversation. I wish, I wish we had time to cover all of it.

Matt Leisure. I, I love our [01:11:00] conversations. Yeah. Yeah. So, um, it was just so, so great to to chat with you again and Of course, so great to have Dr. Chopra here this time. 

Dr. Pradeep Chopra: Thank you 

Dr. Linda Bluestein: very much. Um, yeah, thank you so much for sharing this incredible amount of information. I feel like, you know, people are gonna, I've, I've already listened to more than once, which I don't always do.

And uh, so I, I think a lot of people are gonna probably have to listen a few times, 

Dr. Theoharis Theoharides: but seriously, uh, and I think Linda, I had told you that before. I'd love us to work on, on a more practical. Uh, you know, mini review or mini whatever about muscle activation disorders, maybe for general family practice or something else that is likely to be seen by a lot of physicians and not necessarily the specialist.

Dr. Linda Bluestein: Yeah, I think that would be great. Yeah. I like a, like a review article. 

Dr. Theoharis Theoharides: Yeah. Mini review, you know, not a review to cover all the literature, which, which, you know, we can do, uh, more like along the lines of what we were discussing, you know, what are the confusing aspects, you know, what are these [01:12:00] questions, you know, why are, you know, so maybe Dr.

Chopra or Linda, you can make a little skeleton, you know, the kind of questions that came up today. Put you together in the sense, okay, here's an introduction about the mast cell in general with not too many references, just some very basic references. And then, you know, why is it confusing? You know, what does it mean if you have one and not the other?

Uh, is the treatment the same or is it really, you know, different, uh, you know, et cetera, et cetera. It might not amount to anything eventually, but I think if we kick it around a few times, it'll probably be decent. I think we should do, said. 

Dr. Pradeep Chopra: I like that idea. Yeah. Worst 

Dr. Theoharis Theoharides: comes to wars. We'll put it on on your websites or whatever.

Dr. Linda Bluestein: Okay. Yeah, I think, I think we should shoot for something more than a, than a blo because then we could do blog posts, you know, about the article. So I, I think that's a great idea. I would love to do it. And I know we, we, uh, shared last time and I want people to go back and check out that episode so they can [01:13:00] find out more about Dr The, and also I will put in the show notes, you know, all the relevant links so that you can have all that information.

And just, I wanna thank you so much for coming on the show again and sharing your knowledge with us. Thank you. I really, really appreciate it. 

Dr. Theoharis Theoharides: I, by the way, if someone is desperate to see me, they can reach out basically to Nova Southeastern at the Institute of Neuro Immune Medicine. I do see patients once a month.

Uh, that's it. Just, just five, six, however many they can fit in. And I, there are two wonderful nerve practitioners that help me out. Uh, but you know, I didn't use to do that, but there were so many requests that. I slowly started saying, okay. Uh, type of thing. Um, so, and, and as I said, you know, if anybody's interested in some of the supplements I mentioned, either Amazon or algon.com, they can find all of 

Dr. Linda Bluestein: those.

Yeah, we'll have all that in the show notes so that they can easily find that. So, yeah. And, uh, wonderful. Uh, and 

Dr. Theoharis Theoharides: I don't, I didn't [01:14:00] have anybody, Dr. Chopra, you are part of the woods anymore, uh, seeing this patient, so I don't wanna kind of start sending a lot of patients your way unless you tell me so, and I've got a lot from New England that they're desperate, especially because Dr.

Maria Costell said Brigham is leaving if hasn't already left. And she's shifted basically, from what I understand, her patients to some allergist who don't even believe that M exists. So these patients are desperate. Now. 

Dr. Pradeep Chopra: There's no one in New England who. Believe the damn cat. 

Dr. Theoharis Theoharides: I know. Yeah. Same thing with interstitial cystitis.

Same thing with same thing. Chronic fatigue syndrome. Same thing with fibromyalgia. You know, it's like, uh, I, I don't know why, but, um, we're just so. 

Dr. Pradeep Chopra: I'll, I'll be happy. I'll you, I'll let 

Dr. Theoharis Theoharides: you know ahead of time. Uh, but there are some up there that I used to send to Mariana. Uh, but you know, Mariana had shifted to seeing only mastocytosis patients and then as, as I'm [01:15:00] hearing, she's leaving if she hasn't left already, I think she has already 

Dr. Pradeep Chopra: left.

Yeah, she may have. It's a tremendous factor. She was gonna do research right now. Yeah. 

Dr. Linda Bluestein: Yes, absolutely. Thank you so much.

Well, there is so much to unpack from this conversation with Dr. Thea hedis. I think I'm going to create some newsletters specific to this topic, so be sure to sign up for my substack newsletter@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 leaving a review and sharing the podcast.

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