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In the latest episode of the “Allergy, Asthma & Immunology Innovations” podcast, we focus on how doctors diagnose mast cell diseases. This is the third episode of a 6-part podcast series on mast cell diseases. The series is sponsored by Blueprint Medicines.

The podcast is a collaboration between Allergy & Asthma Network and The Itch Podcast. It is once again hosted by The Itch Podcast’s Kortney Kwong Hing and allergist/immunologist Payel Gupta, MD. In this episode, Kortney and Dr. Gupta are joined by allergist/immunologist Joshua Milner, MD.

Dr. Milner, Dr. Gupta and Kortney focus on the complexities of mast cell disorders and cases of unexplained anaphylaxis. From family history to blood tests to bone marrow biopsies, they address the many tests needed to diagnose mast cell diseases.

You can listen to or download the podcast on ItchPodcast.com anytime, anywhere. The podcast can also be downloaded at:

Full Transcript of How to Diagnose Mast Cell Disease

Kortney Kwong Hing: Put on your detective hats, my friends, because we are about to uncover the intricate art of diagnosing mast cell disorders with Dr. Joshua Milner. He takes us through all of the steps and tests done to diagnose mast cell disease. And my friends, it is not an easy journey.

This episode is made in partnership with Allergy & Asthma Network and sponsored by Blueprint Medicines. You’re listening to The Itch, a podcast exploring all things allergy, asthma, and immunology.

Payel Gupta, MD: We’re really excited today to have Dr. Milner on with us. We are going to be discussing mast cell disease diagnosis, and we’re just going to get right into it. If somebody is worried and they’re coming to you because you’re the expert in mast cell disease, what is the first thing that you would sit down and say to them? Well, it sounds like you have these things going on. What does that look like for patients?

Joshua Milner, MD: The tricky part is the patient who shows up could have a wildly different story. Both have mastocytosis. It all depends on what the person came in with and what they googled.

Kortney: So I’m a patient and I have unexplained anaphylaxis, and I just don’t know when it’s happening. What’s happening? Why is it happening? ‘I’m at my wits end, so I’ve come to you.’ How do you decide whether it’s anaphylaxis to say a food allergen, and I’m just not putting two and two together, or it’s something related to mast cells?

Dr. Milner: Both of them could be related to mast cells. Just one of them would be because of food allergy or something else. But obviously, the first thing we want to know is, was it anaphylaxis? Unfortunately, anaphylaxis is misdiagnosed in both directions. It’s incorrectly diagnosed as anaphylaxis, and it’s incorrectly diagnosed as not anaphylaxis. Unfortunately, more often than it is correctly diagnosed as anaphylaxis or correctly diagnosed as not anaphylaxis. We really would want to get into exactly what it was that happened and objective signs and symptoms that ended up happening and what made it better, if anything, how long it lasted, and that a thing.

That’s one of the most important things to clarify, because I can tell you right now, I passed out when I was getting married, or I almost passed out, but I had a problem with my heart slowing down when things got very exciting. Had someone given me an EpiPen at that time, I would have snapped right up because my heart slowed down and EpiPens make your heart speed up. Would that have been anaphylaxis? The answer, of course, would have been absolutely not. But you’d be amazed at how often something like that ends up getting confused with anaphylaxis.

We really want to be able to dig in, Was it anaphylaxis? If it was anaphylaxis, then we could work on figuring out what the cause may or may not have been. But first, we need to know, was it anaphylaxis? But I would also ask about other symptoms that happen. Even if you don’t get all the way to anaphylaxis, do you get sudden and abrupt episodes of diarrhea? Do you get sudden and abrupt episodes of flushing or of itching and swelling? I would ask if you have a rash that’s around all the time because there are certain rashes associated with mastocytosis on the skin that are very, very different from hives or other things like that.

Then we would also ask about chronic symptoms that you might have, whether you have a propensity to passing out, which is what some people do, or getting palpitations out of nowhere. Are you feeling more fatigued or depressed after a certain point in time where beforehand you didn’t think that you were? Those would all help paint a picture as to whether or not to get an idea we should be worried that there is a mast cell disorder or an allergy that activates the mast cells that might be explaining the symptoms that are happening.

Of course, a lot of those other symptoms, like chronic belly pain or anxiety, depression, fatigue, chronic itching, those can have many, many, many common causes that may or may not have anything to do with a mast cell. You want something that points you towards it being a mast cell. Anaphylaxis – that’s the scariest thing, and that’s the thing that tends to get the most attention to then trying to make a diagnosis of a particular mast cell disorder.

If someone were to come in and say, I have these frequent episodes, the most valuable thing that we can do is to get a blood test or a urine test immediately after you’ve had one of these episodes. If you have chronic symptoms every day that aren’t episodes, the result is not going to be as helpful, whether it’s abnormal or normal, the result will not be as helpful.

The most important thing that we could do is to either get a tryptase drawn within four hours of the episode happening or to start collecting urine within hours of the episode starting to be sent for, in the case of the blood, to be sent for a tryptase test.

In the case of urine, there are three different metabolites, meaning that your body breaks down what the mast cell makes. That’s something that we can measure accurately. Those tend to hang around in the body longer, and you can see them in the urine. Whereas tryptase, when you measure that, that is actually what the mast cell is making. It’s not being broken down. It’s being made by the mast cell.

For years and years, the most commonly done thing is the blood thing because you can order it and there’s a test. The urine tests have not been available as long and haven’t been used as long, although in some ways they might be better because as long as you have a cup and you can aim, you actually can get that test done and you don’t have beg someone else to draw your blood, which is what we have to do all the time. We beg docs to draw the blood.

But in the end, the urine testing is actually quite sensitive and specific. If they were elevated after one of these episodes, then we would want to look at what they look like at baseline, because there are special cases where, and actually more common cases, where your tryptase is always elevated.

That’s hereditary alpha tryptasemia. If your tryptase were elevated after you had one of these episodes, and then your tryptase were still elevated at baseline, not much different than what it was when you had the episode may have nothing to do with the mast cell at all. It’s just you happen to be one of the many, many millions of people who have hereditary alpha tryptasemia.

The urine is probably a little bit different. We don’t know yet that it’s common for someone to have one of these abnormal mast cell mediator metabolites in their urine. And so if those were elevated at baseline as well, we probably would be concerned that there’s a mast cell disorder happening. But comparing the baseline to when you have one of these episodes is the most important thing that we can do, as opposed to just taking the value and saying this is the diagnosis, because it’s usually not.

Kortney: If this happens, how fast do they have to get to their doctor to give them a fresh sample of urine? Is it going to be 12 hours later or should they just pee in a cup and bring it with you?

Dr. Milner: When it comes to the blood test, it has to be done within 4 hours of the episode happening. In the case of the urine, it still should be within hours, but often you collect for 24 hours afterwards. But they are around in the urine for longer, but I wouldn’t wait till the next day. That would be too long.

Dr. Gupta: Josh, you mentioned that ideally you would get a 24-hour urine collection and not just one sample, correct?

Dr. Milner: Yeah, and that just has to do with the way that your body metabolizes things, and different people may have had more or less water intake at that point in time. The accuracy is the highest when you do a 24-hour urine collection, what’s called a spot urine collection. It could be correct. It’s just not as well validated as when you do the 24-hour urine collection.

The other thing is that there are three different metabolites tests to be done, and usually we do all three of them because it’s in combination that they become the most accurate than just doing one. You only have to collect once. When you send it for the test, they can then send the three different tests when it’s done.

None of those tests are histamine. We don’t look in the blood for histamine, we don’t look in the urine for histamine. It’s not as accurate. It’s not diagnostic. Most people metabolize histamine very, very quickly, so you won’t see it, even if something really bad has happened. If the histamine is higher, there may be another reason why it is. It’s not diagnostic.

Kortney:  I have a question, and this is just a curiosity thing. Imagine it’s like I can’t get to my doctor in 4 hours of my reaction to get my blood drawn. Is there ever a case where if I know what triggers that, I can sit in the office, do it, and then you can grab my blood?

Dr. Milner: That is something that sometimes people do. We call it a challenge. Usually, if I’m allergic to blank, am I really allergic? We’ll do the challenge in the office, and if there is a reaction, we would draw blood. But the truth is that I don’t think we usually would do that for someone who’s worried that maybe they have a mast cell disorder. I think there might be some rare cases where it’s really not been clear despite trying some other things. That is precisely, though, why it’s difficult, why using the blood test is just difficult because people can’t get to it.

Actually, what I tend to try to do is to send patients home with the urine collection kit. They have it, and then they’re empowered to go ahead and get it done whenever an episode happens, and then they don’t have to worry about getting the blood test done. I would love for this to become something that’s easy for any doctor to just set you up for. Then when the result comes back, if it happens to be abnormal, then you can be referred. It’s actually easier to already have that answer than it is to go and say, ‘Can you figure it out?’ It’s hard to figure it out without having one of those tests give us an idea beforehand.

Kortney: Okay, that makes total sense. That would be really cool. Then just one more thing that you don’t have to worry about.

So we’ve talked about the fluids that would be collected. What about skin biopsies? Because I know I’ve read a lot about skin biopsies and mast cell diseases. How does that look and when would you decide to biopsy skin?

Dr. Milner: The only time I would biopsy skin is if I saw a rash that I think might look like the rash that can happen in mastocytosis. That rash is called urticaria pigmentosa. Actually, one of the more common ways to diagnose it than doing the biopsy, believe it or not, is to simply scratch above that rash, which in adults often looks like freckles. In kids, it can look like all different kinds of things. The point is it doesn’t come and go. It stays. It can be all over the body, or in kids, it can be in one place. That’s called a mastocytoma. Often you’re born with or you have early. But those freckles or the different ways that that rash can look, if you scratch right above it, it makes like a hive. Then the hive goes away and then you still have the rash that’s there. If you scratch somewhere else on the body, you don’t get a hive.

There are some people, you can scratch anywhere, you get a hive. That’s not urticaria pigmentosa, and that’s not something you need to biopsy. It would just be if there was a rash that looked something like it was hives, that can be enough.

There definitely are people who never get a biopsy because it’s completely clear that it’s urticaria pigmentosa. You don’t need to do the biopsy because of the other diagnostic stuff that’s been done. But in cases where it’s not clear, you would just biopsy that spot. It looks like it could be urticaria pigmentosa. You would just biopsy that and you would look for abnormal normal-looking mast cells. It’s not the number of mast cells that matters at all. It’s that they’re abnormal-looking in the pathology.

The same is true in the gut. So very often I get asked, I’m getting an endoscopy, should we do special stains to count the number of mast cells? The answer is, ‘We don’t have normals.’ You can have tons and tons of mast cells. As long as they don’t look abnormal, they probably don’t have anything much to do with a mast cell disorder because mast cells can accompany all sorts of things happening in the gut normally. Then also with other kinds of inflammation, mast cells can come along. That doesn’t mean, just because you have more mast cells in your gut, that there’s a problem. It would be as if they are clumping up and having huge numbers and looking atypical under the microscope.

Then you would want to do other things to say, ‘Those are atypical mast cells.’ That’s what you need to worry about. That doesn’t take us anything special to do. But very often we get asked that question. There are other things that we count in an allergic patient, in a gut biopsy, like eosinophils, that don’t have to look abnormal for there to be issues by raw number. With mast cells, it’s a different story.

Kortney: Just quickly back to you, to urticaria pigmentosa, is that only ever found in patients with mastocytosis, or is that also found in other circumstances?

Dr. Milner: If it’s urticaria pigmentosa, it’s mastocytosis. The question is, is it only in the skin, in which case it’s called cutaneous mastocytosis, skin mastocytosis. Or is it a part of systemic mastocytosis, where the mast cells are somewhere else besides just the skin, and that’s called systemic mastocytosis. If your biopsy is positive in the skin, you still may only have cutaneous mastocytosis, and there’s no problem in your gut, and there’s no problem in your bone marrow or anywhere else.

Kortney: That’s very good. That’s also nice to hear the difference between cutaneous and systemic mastocytosis because we’ve talked about that a few times already. What about bone marrow testing?

Dr. Milner: The bone marrow biopsy is only being done if we think that you might have systemic mastocytosis. In terms of clinical symptoms, it would have to be unexplained or very severe anaphylaxis. That would be the clinical symptom that we would go with besides if you had urticaria pigmentosa, or if your liver and your spleen were enlarged, or if your blood count was low, and you had some symptom like severe recurrent allergic reactions of some sort, whether they even get all the way to anaphylaxis.

Having chronic symptoms, having chronic belly issues, those would not be symptoms alone to be looking in the bone marrow. The bone marrow would be because you had severe anaphylaxis and then, yes, if there was an elevation in the serum tryptase. Right now above 20 is what folks would want to see at baseline or with activation.

Again, if someone has hereditary alpha tryptasemia and their tryptase is 20 at baseline and they don’t have symptoms, there’s no reason to be doing the biopsy because their tryptase level is fully explained by that genetic trait. Even if they have a peanut allergy, it doesn’t matter. Even if they have a bad belly, it doesn’t matter. It’s not going to change anything from that point of view. Having the elevated tryptase would be one of the big reasons to go ahead and do that bone marrow biopsy.

The other thing that we would often do if we continued to suspect that it was mastocytosis and not some other either idiopathic, which means we couldn’t find something and not an allergic cause, would be to do a blood test for a KIT mutation, which is a mutation that happens later in life, not one you’re born with, that can drive mastocytosis. It happens in the mast cell in the kit. It’s one specific mutation that we checked for, even though there are others that can cause it.

But right now, the only test we have is for that one specific mutation. You might hear it. It’s called D816V. That would be the thing that someone would say. But that can be a blood test. If that blood test were positive, then we might consider doing the bone marrow biopsy. When the blood test is negative, it would all depend on the clinical scenario. But sometimes people can have mastocytosis, but the blood test is negative. In other words, you wouldn’t be doing anything different for that person. You might stop right there and not do the bone marrow biopsy because it’s not going to change what you’re going to do with your management for that particular person. But that blood kit test would be done as a last thing to do before deciding on doing the bone marrow biopsy.

Actually, in the end, those are the only lab tests that really have significant value – the serum tryptase and the urine metabolites. Not urine histamine, not serum histamine, not serum anything else. All the biomarkers that people have tried and hoped that they would help us be able to differentiate, they just haven’t panned out. Unfortunately, we wish we had better tests. The urines even still need more panning out in the general population as opposed to just people with mastocytosis, to be clear. But either way, those are really the only tests. Doing your blood count – because, again, some folks with mastocytosis, their blood count can go down, things are getting much more severe, you would be up no matter what, if your blood count started dropping for all sorts of different stuff. But specifically for a mast cell disorder, those are the only things that we’re going to be looking for to find a mast cell disorder.

If you find something in those, then there are other tests that we do to see, could it have been an allergy or could it have been something else?

Kortney: What happens when it’s idiopathic? You said idiopathic means you don’t know. Does that mean that you’ve done all these tests and you still can’t explain what’s happening with the patient?

Dr. Milner: Well, to be clear, you’ve done all these tests and either the urine showed that during these symptoms there was an elevation or the tryptase went up during the symptoms and there was an elevation. Now we’ve established that there were symptoms, that the urine mediators went up. Then actually, of course, the third criteria is that taking an antihistamine helps you. With that, an antihistamine or taking a mast cell stabilizing drug helps you. If it doesn’t help at all, then technically you don’t meet the criteria for mast cell activation syndrome.

But if we have someone where the lab test shows that there was an elevation during one of these symptoms, they had symptoms consistent with mast cell activation, and not that they’re cured, but if they take an antihistamine or cromolyn gastrocrom, or something like that, and it helps them even partially, then they have mast cell activation syndrome. If we do the workup to see, do we need to do more workup for mastocytosis? The D816v is negative, their liver and their spleen are not large, they may or may not have needed to get a bone marrow biopsy – if those are all negative, then it’s the idiopathic mast cell activation syndrome. That was for mastocytosis. Then also we’ve said this happens every time X happens or Y happens, you make sure that there isn’t an occult food allergy.

To be honest, in an adult, it’s so rare. It’s unbelievably rare for us to find something that the person who came in didn’t already tell me. Every time I do blank, this ends up happening. Sometimes, like with exercise, they did eat something and it was four hours before, and then they had to exercise, so it was harder to put together. But yeah, we would want to make sure there wasn’t some clear exposure that we could go and figure out that was causing the mast cell activation.

One of the other things is things that come along for the ride in medicines or foods, like certain preservatives or things that we put in all sorts of stuff, like polysorbate 80, or in those rare cases, there are people who can have those allergies that might have been an idiopathic mast cell activation syndrome until you put it together. Once those types of history taking and then testing has been done, then that’s when it’s idiopathic mast cell activation syndrome.

The other one, by the way, is the meat allergy, alpha-gal, which is delayed, and that can be a tricky one because that can start later in life, and it can be over a day, in some cases, before you actually have the reaction. It’s certainly been shown now that something in between one and five and one to 10 individuals who had idiopathic anaphylaxis or muscle activation syndrome, it was because of the allergy to the meat. If they were from the right region of the country, it’s possible that it could be alpha-gal. It would no longer be idiopathic mast cell activation. You’d say, Oh, it’s alpha-gal allergy, and that’s it. Then once you’re there, there’s not much more that gets done. It’s just managing symptoms until we do better research to figure out why some folks get it.

Although to be clear, and I think this is one of the most important messages, in clinics that are specialty clinics that look for idiopathic mast cell activation syndrome, so people are being sent to them because of a high level of suspicion, it’s usually fewer than one in 20 or one in 30 individuals who actually end up having it. When I speak to my colleagues all around, they can count on fewer than three hands the number of people who they’ve ever actually diagnosed with idiopathic mast cell activation syndrome. It’s really rare.

Dr. Gupta: Josh, essentially, if somebody has cramping abdominal pain, flushing, anaphylactic symptoms, within 4 hours, they should check the tryptase through the blood or check the 24-hour urine collection in order to look for the metabolites. The 24-hour urine collection – we also just recommend people put that in a special container. There are special containers that the doctor could give you so that you can collect it. It’s just basically a big gallon jug that you pee in. Maybe you need one or two, depending on how much you pee. That’s something that you want to keep in mind. You don’t want to just put your urine in any container because then there could be contaminants within that. You can’t just use a regular milk container to do that. Those are just things that we want to mention.

Then from there, if anything is abnormal, then we go into looking at getting a C-kit and seeing what that looks like. Then the skin biopsy, we would do, if necessary, but technically with the classic urticaria pigmentosa lesion, just rubbing above it or rubbing near the lesion should produce that classic urticarial reaction around that lesion. And so skin biopsy isn’t always necessary.

Dr. Milner: And certainly skin biopsy is not necessary if there is no lesion that’s there. Just because you happen to be itching, at least for diagnosing mast cell problems, you wouldn’t do it if there weren’t a rash there. That thing is called Darier’s sign, which is the medical term for when you scratch and you see that high.

Dr. Gupta: And then you do a bone marrow biopsy, if necessary, if it seems that their symptoms are more severe and more worrisome for a more progressive mastocytosis,

Dr. Milner: Yes.

Dr. Gupta: Great. Thank you. I learned so much.

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