The MastAttack 107: The Layperson’s Guide to Understand Mast Cell Diseases, Part 27

35. Why are there different sets of criteria for mast cell activation syndrome? What are the differences between them?

To answer this fully, we need to first discuss the history behind some terms.

Mast cell activation syndrome was first used to describe episodes of mast cell mediator release symptoms in a paper published in 2007 (Akin 2007). Specifically, the term was used to detail the experience of patients who had symptoms we commonly associated with mast cell activation, like flushing, hives, and low blood pressure.

However, the patients in this study were all found to have some features of systemic mastocytosis. While they had some of the criteria for an SM diagnosis, they didn’t meet all the criteria. These patients sort of looked like SM and quacked like SM but would not cleanly meet the diagnostic criteria. So the author of that paper made a separate diagnostic category for them. He called it monoclonal mast cell activation syndrome.

The use of the word “monoclonal” is VERY important here. Monoclonal is a medical term that is associated with the body making too many cells at once so that the cells that are made don’t work correctly. Systemic mastocytosis is a condition in which the body makes too many cells at once that don’t work right. It is a monoclonal disorder. So the author of that paper in 2007 is linking monoclonal mast cell activation syndrome to systemic mastocytosis. He thought of it as sort of a “pre-SM” or “early SM”.

Shortly after that 2007 paper was released, another school of thought was proposed by different groups about the nature of mast cell activation syndrome. These groups also linked the term mast cell activation syndrome to symptoms of mast cell activation, like flushing, hives, and all the rest. However, they did NOT link mast cell activation syndrome to monoclonality. This means that these researchers felt that mast cell activation syndrome could be present without a condition where you make too many sloppy cells like systemic mastocytosis. So patients with no evidence of systemic mastocytosis could still have mast cell activation syndrome according to these groups. The two major groups that believed MCAS was distinct from SM were led by Afrin/Molderings and Castells.

Let’s recap:

In 2007, Akin described mast cell activation syndrome as something that happened only in patients that had some evidence of systemic mastocytosis but not enough to be diagnosed with systemic mastocytosis. In order for this group to diagnose you with mast cell activation syndrome, you had to have evidence of systemic mastocytosis. It was an add on diagnosis to SM, sort of like SM with really bad symptoms.

In the years that followed, two groups, led by Afrin/Molderings and Castells, described mast cell activation syndrome as something that was distinct from systemic mastocytosis and could be found in anyone, even if they had no evidence of systemic mastocytosis at all.

Okay. So these two groups agreed that MCAS could happen to anyone. But they differ greatly in how they think MCAS can be diagnosed. For these groups, MCAS is NOT an add on diagnosis to systemic mastocytosis. It is a standalone diagnosis and entity.

So if the term MCAS was already being used, why didn’t the other groups just call their diagnosis something different? There isn’t a good answer to this but it is super common. Things are much more fluidly changing in the time between coining a term and having the diagnosis accepted by a large organization like the CDC so that your insurance can bill for treatment for that diagnosis. It would be great if everyone just used different names for their variants but this just doesn’t always happen.

Castells feels that in order to be diagnosed with MCAS, you have to show mast cell mediator symptoms, response to medications to treat mast cell activation, and evidence of mast cell activation. You also have to rule out every other possible cause of mast cell activation. Keep in mind that your mast cells are normally activated for lots of reasons so this can really difficult to do.

Additionally, this school considers mast cell activation to be evidenced only by elevation of serum tryptase, 24 hour urinary n-methylhistamine or 24 hour urinary prostaglandin D2 or 9a,11b-prostaglandin F2. So if none of these mediators are high, the patient doesn’t meet the criteria for diagnosis.

Afrin’s criteria are harder to explain because he believes that you should provisionally be diagnosed with mast cell activation disease, which can be a few different things, and then it should be narrowed down to mast cell activation syndrome or another mast cell condition.

The key difference between Afrin’s criteria and Castells’ are that he accepts elevated levels of several other mast cell chemicals to prove mast cell activation. Afrin counts toward diagnosis elevation of serum tryptase, 24 hour urinary n-methylhistamine, serum or 24 hour urinary prostaglandin D2 or 9a,11b-prostaglandin F2, 24 hour urinary leukotriene E4, heparin in blood, and chromogranin A in blood. All of these are released by mast cells. But some of them are released by other cells too so it’s not as easy to say for sure that mast cells cause the elevations. Additionally, some of these mediators are REALLY difficult to measure accurately, like heparin. So some people feel that these tests are less reliable to indicate mast cell activation alone.

Let’s talk about puppies for a second because when things get tough, just find a puppy and things will be cool from there on out.

Let’s present these three schools of thought on MCAS as puppies.

Let’s say that Akin is saying that all dogs with 10 spots on them have SM. He’s saying that dogs with some spots, but less than 10, have MCAS. He is also saying that dogs with NO spots CANNOT have MCAS.

Castells is saying that it doesn’t matter how many spots the dog has but it has to have either blue or green eyes to have MCAS. She doesn’t think the MCAS is related to spots but that it is related to specific eye color.

Afrin is saying that it doesn’t matter how many spots the dog has, or what color eyes. He will accept eyes of many other colors if the dog has a lot of symptoms that look like mast cell activation or respond to medications to treat mast cell activation.

I have simplified this as much as possible so it’s easier to understand. For that reason, I have omitted a lot of things. I am in no way saying that what I described here represents everyone’s experience. I am not saying that at all.

If you want my opinion on what MCAS is, and I’m inclined to think you do because you’re on my website reading my thoughts about mast cell disease, I feel that the evidence points strongly towards a space that blends both Afrin’s and Castells’ points. I feel that we should use more mast cell mediators than just serum tryptase, 24 hour urinary n-methylhistamine, serum or 24 hour urinary prostaglandin D2 or 9a,11b-prostaglandin F2. But I personally find the reliability of tests for heparin level to be very problematic and elevations of chromogranin A can be from so many things. I am not AT ALL saying that people diagnosed with these elevated markers do not have MCAS. I professionally develop diagnostics and these tests are just not great.

I also don’t think there’s enough evidence yet to say that mast cell disease can be proven with a biopsy demonstrating a certain number of mast cells per hpf (high powered field, this is a measurement we use for counting things we see under a microscope). I think it is very suggestive of inflammation and mast cell activity. But there are MANY instances in which normal, healthy, asymptomatic patients have a bunch of mast cells/hpf in their biopsies when they are used in studies.

So I’m solidly in the MCAS is its own entity group but don’t fall evenly into one group or the other regarding diagnosis.

Regarding treatment, I land more squarely with Afrin. I believe that if you have tried all of the conventional treatments and continue to have life threatening episodes, you should be able to try more drastic treatments provided you are well supervised by a knowledgeable provider. This is my personal opinion and in no way reflects the views of my employer. I think that if you are constantly anaphylaxing, or have no safe foods, or have dystonic seizures, or can’t stand up, and you have gone through a long list of “reasonable treatments” that you have a right to try to preserve your life and the quality thereof with any means available.

So, yea. MCAS is a can of worms. But we owe it to MCAS patients to have these awkward discussions even though it’s, well, awkward. Patients are falling through the cracks and we owe it to them to identify what criteria would let us catch them so they can get diagnosed and treated sooner.

I’ve tried hard to explain this objectively but if I haven’t done great, let me know in the comments.

For more detailed reading, please visit these posts:
The Provider Primer Series: Mast cell activation syndrome (MCAS)
MCAS: Differing criteria among experts

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 14

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

22. Is MCAS an early form of SM?

MCAS is not viewed as an early form of SM but the diagnosis of MCAS may precede a later diagnosis of SM.
• In the last few years, we have learned a lot about the genetics associated with mast cell diseases and how it occurs in families. As a result, we are beginning to understand that mast cell diseases occur more along a spectrum than as distinct categories. This means that there is a lot of overlap between conditions.
• While it is certainly not a new disorder, MCAS is a pretty recent diagnostic entity. The last decade has seen a large increase in diagnosis as it has been more frequently described. Because of how new it is, and also the fact that there aren’t uniform criteria for what MCAS is, there will be a level of uncertainty about how this disease tends to progress for some time.
• That uncertainty aside, we know that at least some patients with a long history of MCAS have continued to have symptoms without developing markers of systemic mastocytosis.
• However, some patients with history of MCAS do develop markers of systemic mastocytosis.
• Many patients do not receive bone marrow biopsies when they are diagnosed with MCAS because there is not always a reason to have one. It often doesn’t affect treatment. If there is no sign of organ damage, the patient has a negative blood test for the CKIT D816V mutation, and their baseline tryptase is below 20 ng/mL, most doctors do not order a bone marrow biopsy. This means that some patients who are diagnosed with MCAS may have had SM all along but it wasn’t found until a biopsy was performed later.
• In 2007, monoclonal mast cell activation syndrome was described in scientific literature. This condition is diagnosed when a patient meets some criteria of systemic mastocytosis but not enough for a diagnosis of SM.
Monoclonal mast cell activation syndrome is more often viewed as a “pre-SM”. I personally view it this way. Before it had a name, researchers called it “pre-diagnostic SM.” Literally, SM before they could diagnose it as SM.

For more detailed reading, please visit these posts:

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 13

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

21. Why do people care so much about diagnostic criteria?
• Historically speaking, the medical establishment tends to draw very explicit borders around diagnoses. There are several reasons for this.
• It is partly to help diagnose things correctly. There are thousands and thousands of diseases and disease states. The most effective way of getting as many people as possible correctly diagnosed with a disease is to define what that disease is and how you diagnose it. That doesn’t mean that every person who has this disease will always be diagnosed correctly. It also doesn’t mean that every person who doesn’t have this disease will be diagnosed with something else. It just means that this is the best way to diagnose the largest point of people all over the place.
• It is also to strength any research done around these diagnoses. As a scientist, who has to operate within the trappings of specific diagnoses with specific criteria, it is 100% necessary for me to do my job well.
• We have to know that all the patients in a study meet the same criteria. It’s not enough for their doctor to give them a diagnosis because they think that’s what they have even if they don’t meet the criteria. Let’s look at this a little more closely below, under the heading “Blue Disease.”
• The bottom line is that diagnostic criteria is the foundational bedrock of the Western medicine establishment (and some Eastern traditions as well).
Diagnostic criteria also help determine what insurance companies will pay for. If you are a provider caught saying a bunch of patients have a diagnosis that they don’t have, you can be charged with insurance fraud. That can carry significant penalties including fines, loss of license and even prison time.
• Furthermore, if a doctor is caught misdocumenting diagnosis, insurance companies will crack down on patients with the same diagnosis in other places, making it harder for everyone to get treatment. There have been situations in recent history where patients getting a very expensive treatment were required to stop treatment to prove that they needed it since doctors were prescribing it for many other conditions without documenting it correctly.
• The last reasons why everyone cares about diagnostic criteria are related more to the experiences of patients within this community. Most of us have been misdiagnosed more than once. It can really complicate things and it can endanger people. It can also really scare people, too.
• Finally, most of us in this community have been lied to someone impersonating a rare patient at least once and usually more. It is exhausting and insulting.
• I want to be very clear that the reason a lot of people get stuck on diagnostic criteria is NOT because people who don’t meet one or the other set are not deserving of treatment or are not as sick. That is not the case at all.

Blue Disease:

• Let’s say that I am running a study on a disease called Blue Disease. Blue Disease is a condition that strikes people on their 25th birthday. On this day, people with this disease just wake up completely blue. They are never not blue again. I am interested in Blue Disease and so I design a study for it.
• In order to fund my study, I have to get grant funding. This money may be from a private foundation or a university or the government. I have to convince them to care about Blue Disease. More importantly, I have to convince them that the money they give me will be used intelligently and not wasted.
• Let’s say that I let in 100 people who all tell me they have Blue Disease. They are all blue. They all are older then 25. I let them in to my study to research a medicine to treat this disease.
• At the end of my study, I have found that if I give most of them a medicine called anti-Blue, their blue goes away. There is gladness and rejoicing. I find that 90 out of 100 respond to the medicine. Hooray! That’s a 90% success rate.
• Except then I find out that not all of those people actually had Blue Disease. Some of them turned blue before their 25th birthday. Some of them started purple, then became blue, then green. And so instead of having a 90% success rate for Blue Disease, we find that it’s much less effective than 90% for Blue Disease. We know that it has helped some other people not be blue but we don’t even know what disease they have. And I am in a hell of pickle as a researcher because I don’t know what these data mean.
• Because the medication seems not very effective for Blue Disease, it doesn’t get approved or prescribed to people who have Blue Disease.
• Because my study was not controlled enough, no one wants to give me any more money to research this disease. In certain situations, I could actually have to pay back the money, would almost certainly lose my job, and could be prosecuted because I have an ethical obligation to only research the disease I say I will research in a study.

For more detailed reading, please visit these posts:

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, part 8

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

14. Are there any special instructions for the tests to diagnose mast cell disease?
• There are a lot of tests used to diagnose mast cell disease. There are certainly people who slip through the cracks with the current diagnostic criteria.
• Remember this as you read the following: DO NOT, UNDER ANY CIRCUMSTANCES, EVER, DISCONTINUE MEDICATION FOR TESTING WITHOUT EXPLICIT INSTRUCTIONS TO DO FROM A DOCTOR THAT UNDERSTANDS MAST CELL DISEASE. Stopping medications for mast cell disease can be very dangerous.
• The biopsy forms the centerpiece of diagnosis of both cutaneous and systemic forms of mastocytosis.
You can increase your chance of positive skin biopsy by choosing either a permanent lesion or an area of skin that is frequently reactive.
• For internal organs, including bone marrow, you can’t always tell where to biopsy just by looking. The area may look normal but show inflammation when viewed with a microscope.
• If patients do not need to take daily corticosteroids because they do not make their own (adrenal insufficiency or Addison’s disease), they are often recommended to not use corticosteroids (prednisone or similar) for five days before a bone marrow biopsy. Taking corticosteroids can tell your body to make a lot of extra white blood cells which can make it harder to give a correct diagnosis.
• The CKIT D816V mutation test is often done on a blood sample. It is much more accurate when a bone marrow biopsy is tested because there are many more mast cells. Mast cells do not live in the blood so the blood test is less accurate. If the test is positive in blood, we assume that the patient is truly positive. If the test is negative in blood, we are not sure if the patient is truly negative.
• Serum tryptase is a test with a lot of caveats. It is influenced heavily by timing and patient factors like weight. Many people with mast cell disease have normal serum tryptase. It is good for tracking progression of disease in patients with systemic mastocytosis.
• About 85% of patients with systemic mastocytosis have a baseline tryptase value over 20 ng/mL. Patients with monoclonal mast cell activation syndrome may also have baseline tryptase value over 20 ng/mL. For these patients, they should have two different tests from days when they are not especially reactive, or have had anaphylaxis.
• For patients with mast cell activation syndrome, we are often looking for an increase in tryptase during a reaction or anaphylactic event. In these patients, experts recommend having blood drawn 15 minutes to 4 hours after onset of the event.
• Another sample should be drawn 1-2 days later so that you have a sample to compare with the tryptase level during the event. Many experts accept a level increased by 20% plus 2 ng/mL above the baseline to be indicative of mast cell activation. (I made a typo on this that said 20% to 2 – sorry!)
• As we have previously discussed, many mast cell mediators should be kept cold because they break down quickly. 24 hour urines for n-methylhistamine, prostaglandin D2, 9a,11b prostaglandin F2, and leukotriene E4 should be kept cold.
Performing a 24 hour urine when you are having a reaction event can increase the likelihood of mediator release.
COX inhibitors will interfere with prostaglandin production. Some patients stop these meds before giving 24 hour urines for prostaglandin testing. DO NOT STOP MEDS WITHOUT BEING ADVISED BY AN EXPERIENCED MAST CELL PROVIDER.
Lipoxygenase inhibitors will interfere with leukotriene production. Some patients stop these meds before giving 24 hour urines for leukotriene testing. DO NOT STOP MEDS WITHOUT BEING ADVISED BY AN EXPERIENCED MAST CELL PROVIDER.
• Heparin is very heat sensitive. Plasma heparin must be kept cold. One study reported that a tourniquet on the upper arm for ten minutes before drawing the sample increased the change of detecting mast cell activation with this test.
• Chromogranin A is influenced by many other conditions and medications. It is important that those other conditions be ruled out. This may require lengthy body scans and other tests. Chromogranin A is influenced by proton pump inhibitors, meds that are commonly taken by mast cell patients. DO NOT STOP MEDS WITHOUT BEING ADVISED BY AN EXPERIENCED MAST CELL PROVIDER.

For more detailed reading, please visit these posts:

The Provider Primer Series: Mediator testing

Patient questions: Everything you wanted to know about tryptase

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, part 7

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

 

13. What do these biopsy tests look for?
• They look for the shape, quantity, and distribution of mast cells.
• They also look for specific proteins on the outside of mast cells and tissue damage around mast cells.
• Systemic mastocytosis and cutaneous mastocytosis are generally diagnosed by biopsy. With very, very few exceptions, you cannot meet the criteria for systemic mastocytosis without having a positive biopsy. Sometimes people with monoclonal mast cell activation syndrome are diagnosed by having a biopsy that looks like a very early phase of systemic mastocytosis.
• The diagnostic criteria for mast cell activation syndrome are hotly contested. Most doctors do not use biopsies to diagnose MCAS because there are not uniform criteria. Some doctors feel that more than 20 mast cells in a field when you look through the microscope is a sign of MCAS.
• Cutaneous mastocytosis is having too many broken mast cells in your skin. For this condition, they are looking for either 20 mast cells to be present in the microscope field (hpf) when looking at the skin, or for there to be at least one cluster of at least fifteen mast cells.
• Clustering is a very important feature of mastocytosis. When mast cells bunch together in a cluster, it is easier to damage the tissue. They are essentially punching holes in the tissue by clustering.
• Systemic mastocytosis is having too many broken mast cells made by the bone marrow. Systemic mastocytosis is usually diagnosed by a positive bone marrow biopsy. However, sometimes people are diagnosed by biopsies of other organs. Skin biopsy is NOT enough to diagnose systemic mastocytosis.
• For systemic mastocytosis, there are three key things they are looking for in the biopsy.
• They are looking for at least one cluster of at least fifteen mast cells.
• They are looking for some of the mast cells to be shaped like spindles, sort of smushed at the ends and round in the middle. You see this shape a lot when cells are trying to stick together in a cluster.
• They are looking for special proteins that are only found when a patient has systemic mastocytosis or monoclonal mast cell activation syndrome. They are called CD25 and CD2. These are like flags that the mast cells fly to tell us they are broken. One of them, CD25, actually helps mast cells cluster together.
• In biopsies, they usually also look for the protein CD117. This is a normal flag for mast cells to fly and just allows us to know that we are looking at mast cells.

For more detailed reading, please visit these posts:

The Provider Primer Series: Management of mast cell mediator symptoms and release

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 6

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

12. What do these blood and urine tests look for?

• There are a lot of tests ordered for mast cell disease. How they are interpreted can depend upon a lot of factors. Some of the tests are unreliable, a fact that will be addressed in detail later in this series. (And has been addressed in detail elsewhere on this blog). Please keep in mind when reading this post that I am being VERY general and assumed the test was performed correctly on a correctly stored sample.
• The most common test ordered for mast cell disease is serum tryptase. Tryptase is a molecule that mast cells release. While it has lots of functions in the body, and is especially important in healing wounds and tissue growth, the amount present in your body at a given moment should be low.
• Tryptase is special because mast cells release it in two ways. Firstly, they make and release a little bit steadily. This is not related to activation. Mast cells just normally release a little tryptase as they go about their work. So the idea is that if you have more mast cells than you should, and each of those mast cells releases a little tryptase all the time, that you will have a higher than normal serum tryptase.
• Patients with a clonal mast cell disease, in which they have too many broken mast cells, usually have elevated baseline tryptase. This means tryptase that is elevated at least two times when you are NOT having a big reaction or anaphylaxis.
• Mast cells also store lots of tryptase in their pockets. When the mast cell is activated and it empties out its pockets, lots of tryptase comes out at once. This is why tryptase can be higher after a reaction or anaphylaxis, because mast cells release a bunch at once.
• Patients with mast cell activation syndrome or cutaneous mastocytosis do not always have elevated tryptase even with a big reaction or anaphylaxis.
• Mast cells have huge amounts of histamine stored in their pockets inside their cells. Histamine has lots of functions inside the body and is required for normal body functions. In particular, it is important to our nervous system. Smaller amounts are released as a normal function of the body.
• A lot of histamine is released when mast cells are activated. The idea is that if your mast cells are more activated than they should be that your histamine level will be higher. However, the test recommended for us to consider the histamine level in mast cell patients is not for histamine. It is for n-methylhistamine. This is a molecule that is formed when the body breaks down histamine, which happens very quickly (within minutes of release). n-methylhistamine is more stable, which is why we look at it.
• The test for n-methylhistamine is most reliable when performed in a 24 hour urine sample. This is because the level in urine can fluctuate throughout the day.
• Mast cells make a lot of prostaglandin D2 (abbreviated PGD2). PGD2 is very important for cell communicating. It can carry a message from one cell to another, allowing cells to work together. Unlike histamine and tryptase, mast cells do not keep PGD2 stored in their pockets. They make it only when they need it and then release it.
• PGD2 is released in large amounts when mast cells are activated. However, because it is not stored in the pockets, it is not always elevated right away when you have a big activation event or anaphylaxis. Prostaglandin D2 is broken down quickly. While we do test directly for PGD2 for mast cell disease, we also test for 9a,11-PGF2, a molecule formed when PGD2 breaks down.
• The tests for PGD2 and 9a,11b-PGF2 are most reliable when performed in 24 hour urine samples. This is because the levels in urine can fluctuate throughout the day.
• Heparin is a blood thinning molecule that is stored in pockets inside mast cells. Mast cells are the only cells that release significant amounts of histamine. When the mast cell is activated and it releases histamine, the histamine comes out stuck to heparin. Heparin is broken down very quickly so it is hard to measure accurately.
• The test to assess heparin level actually looks for a molecule called anti-factor Xa that can interact with heparin. This test is performed in serum.
• Chromogranin A is released by mast cells. It is also released by a lot of other cells. The level of this molecule can be affected by many things, including common medications. It is sometimes tested for and considered a sign of mast cell disease if elevated when all other possible reasons can be excluded.
• Chromogranin A levels are most reliable in serum.

 

For more detailed reading, please visit these posts:

The Provider Primer Series: Management of mast cell mediator symptoms and release

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 5

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

10. How is mast cell disease diagnosed?
• There are several tests you need to definitively determine if you have mast cell disease and what kind you have.
The most well known test for mast cell disease is serum tryptase. This is a blood test. This is the test doctors are most likely to have heard of. Doctors may think that you can’t have mast cell disease if tryptase is normal. This is not true.
• If a patient has a tryptase over 20 ng/mL, the next step is usually a bone marrow biopsy. A tryptase over 20 ng/mL increases the likelihood that a patient has systemic mastocytosis. SM is most commonly confirmed by a bone marrow biopsy.
• You need a special stain in order to see mast cells in any biopsy. Stains that show mast cells include Giemsa Wright stain and toluidine blue. Your doctor should specify these stains.
• Several tests must be run on the bone marrow biopsy to look for clonal mast cell disease. Remember that in clonal diseases, the body makes too many broken cells.
• The shape of the mast cells in the biopsy is very important. If the mast cells are not shaped right, this can be a sign of mast cell disease.
• The number of mast cells grouped together in the body is also important. If 15 or more mast cells are all stuck together, this is called a cluster. When mast cells are clustered together like this, they can punch holes in the tissue and damage it a lot. This prevents the tissue from working right.
• Immunohistochemistry (IHC) is a way to find specific proteins that allow us to know what cells we are looking at in the biopsy. Often, these proteins are on the outside of the cells. Think of these are flags that a cell can wave. IHC can look for the specific flags a cell is waving so that we know for sure which cell is which. For mast cell disease, they want to look for CD117, CD25, and CD2. The CD117 flag is flown normally by all mast cells. CD25 and CD2 are special flags flown by mast cells if you have clonal mast cell disease.
• PCR is a way to look for genetic mutations. They need to look for a mutation in the mast cells in the bone marrow. The mutation is found at a specific place in the CKIT gene. This mutation is found in 80-90% of patients with systemic mastocytosis. It may also be found if patients have monoclonal mast cell activation syndrome.
• If a patient does not have a tryptase over 20 ng/mL, a bone marrow biopsy is often not ordered. There are other tests that can indicate mast cell disease.
• Urine collected over 24 hours can be tested for specific chemicals. In the case of mast cell disease, they are looking for chemicals that can be high if you have mast cell disease. These chemicals have very long, complicated names. I will explain in a later post exactly what they are and what they do. The most common ones are called n-methylhistamine, prostaglandin D2, 9a,11b-prostaglandin F2, and leukotriene E4. Anti-heparin Xa and chromogranin A are sometimes tested. They are much less reliable as indicators of mast cell disease than the others mentioned here.
• If a patient is suspected to have cutaneous mastocytosis, a skin biopsy is needed to confirm. As with bone marrow biopsies, your doctor should specify that they need to use toluidine blue or Giemsa Wright stain to be sure they see the mast cells.
• The skin biopsy should also receive the other tests I described above for bone marrow biopsy: the counting of mast cells and looking at the shape; looking for CD117, CD2, and CD25; and looking for the same mutation with PCR.
11. What kind of doctor diagnoses mast cell disease? Can any doctor order these tests?
Doctors from all different specialties may diagnose and manage mast cell disease. It depends upon the individual provider and where you are located. It could be a dermatologist, allergist, hematologist, pulmonologist, gastroenterologist, or another specialist.
• The serum tryptase is the easier to order and the most well known test. Many labs can run this test.
• The 24 hour urine tests are specialized. Some of them are run in only a few places and samples are usually shipped there. Most often, these samples are run at the Mayo Clinic. Many outpatient labs have no way to run those tests. You will need to speak with your doctor about how to get these tests. It is often easiest if they are run by a hospital lab but again, this depends upon the hospital.
• The PCR genetic test for this specific gene is run in more places than the urine tests but is still not very common. Again, it is often easiest if they are run by a hospital lab.
• A bone marrow biopsy is usually ordered by a hematologist or by another specialist that works commonly with hematologists. They are usually performed by hematology providers. Some testing can usually be performed in house (the counting of the cells and looking at the shape) while others may need to be sent out (the IHC testing).
• A skin biopsy is usually ordered by a dermatologist. Some testing can usually be performed in house (the counting of the cells and looking at the shape) while others may need to be sent out (the IHC testing).
For more detailed reading, please visit these posts:

The Provider Primer Series: Management of mast cell mediator symptoms and release

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

Chromogranin A

Chromogranin A is a protein secreted in several environments. While it is primarily released in the adrenal medulla with catecholamines (norepinephrine, epinephrine, dopamine, and others), CgA is often found stored in the granules of endocrine cells in the GI tract. CgA is the precursor molecule for several active molecules. Vasostatin-1 and -2 are involved in regulation of various effects of the cardiovascular system, including blood pressure and stroke volume, by opposing the action of catecholamines. Catestatin decreases release of catecholamines. Pancreastatin decreases insulin secretion. A number of other molecules are also derived from CgA.

Chromogranin A and its derivatives are biomarkers for several conditions. 60-80% of neuroendocrine tumor patients demonstrated elevated chromogranin A. A connection with Alzheimer’s disease has recently been reported. Rheumatoid arthritis and lupus patients may have elevated CgA as a result of increased tumor necrosis factor. Various forms of cancer, kidney disease, and elevated cortisol can also impact chromogranin A level.

Elevated CgA has also been linked to a number of inflammatory GI conditions. 30-50% of IBD patients with active disease have elevated serum CgA. In ulcerative colitis, fecal chromogranins were elevated but not correlated with disease activity. Conflicting results have been seen in patients with Crohn’s disease. Some studies have reported an increased amount of CgA containing cells in patients with IBS.

There are a number of methods for quantifying chromogranin A. Proton pump inhibitors and H2 antihistamines can yield false positive results. A study compared several commercial kits for measuring chromogranin A and found that the radioimmunoassay (RIA) kit was most likely to be accurate with a sensitivity of 93% and specificity of 85%. This means that 93% of the time, this kit properly identified patients with high CgA as having high CgA, while 85% of the time, it properly identified patients with normal CgA as having normal CgA. Currently, there are multiple test methods for quantifying serum and plasma CgA with no central standardization.

Chromogranin A is a constituent of granules in rat mast cells. Tumor necrosis factor is a mediator released by mast cells and may also influence the levels of chromogranin A in mast cell patients. One study found that 31.5% of patients with mast cell activation disease (in a cohort mostly composed of MCAS patients) demonstrated elevation of serum CgA. This same study concluded that plasma heparin and 24 urine testing for prostaglandin D2 and 9a,11b-prostaglandin F2 were the most sensitive markers for mast cell activation with other mediators being less effective.

References:

Gut P, et al. (2016) Chromogranin A – unspecific neuroendocrine marker. Clinical utility and potential diagnostic pitfalls. Arch Med Sci, 12(1): 1-9.

Wernersson S, Pejler G. (2014). Mast cell secretory granules: armed for battle. Nature Reviews Immunology, 14: 478-494.

D’Amico MA, et al. (2014) Biological function and clinical relevance of chromogranin A and derived peptides. Endocrin Connect, 3(2):R45-54.

Mazzawi T, et al. (2015) Increased chromogranin A cell density in large intestine of patients with irritable bowel syndrome after receiving dietary guidance. Gastroenterology Research and Practice, Article ID 823897.

Zenker N, Afrin LB. (2015) Utilities of various mast cell mediators in diagnosis mast cell activation syndrome. Blood, 126:5174.

Massironi S, et al. (2016). Chromogranin A and other enteroendocrine markers in inflammatory bowel disease. Neuropeptides, xxx, xxx-xxx.

The Provider Primer Series: Mast cell activation syndrome (MCAS)

Mast cell activation syndrome (MCAS), also called mast cell activation disorder (MCAD), is an immunologic condition in which mast cells are aberrantly activated, resulting in inappropriate mediator release.

Presentation

  • MCAS can be responsible for chronic symptoms in multiple organs that cannot be attributed to another cause[vi].
  • Patients frequently receive diagnosis for a number of idiopathic conditions prior to correct diagnosis with MCAS[vi].
  • Mast cell activation syndrome is overwhelmingly a secondary condition. MCAS can be secondary to a number of conditions, including autoimmune diseases, connective tissue diseases, and atopic conditions[i].
  • The term “primary MCAS” refers to mediator release symptoms associated with mastocytosis[xvii] . However, the term “mastocytosis” generally conveys the understanding that both proliferation and mediator release symptoms are possible.
  • In idiopathic MCAS, no cause for symptoms can be identified[xvii] .
  • The presence of multiple mast cell patients in one family is not uncommon. A heritable gene has not yet been identified. Epigenetic mechanisms are suspected for transmission of mast cell disease to another generation[iv].
  • Approximately 75% of mast cell patients have at least one first degree relative with mast cell disease and not always the same subtype[ii]. For example, a mother may have MCAS, while one of her children has SM and the other has CM.

Diagnostic criteria

  • MCAS is a recently described diagnosis. In the absence of large studies, several groups have developed their own, sometimes conflicting, diagnostic criteria.
  • Differential diagnoses with potential to cause similar symptoms should be considered and excluded[iii].
  • The criteria most frequently used include those by a 2010 paper by Akin, Valent and Metcalfe[iii]; a 2011 paper by Molderings, Afrin and colleagues[iv]; and a 2013 paper by Castells and colleagues[v].
  • The criteria described in the 2011 paper by Molderings, Afrin and colleagues have been updated to include response to medication[vi].
  • Of note, a 2012 consensus proposal[x] was authored by a number of mast cell experts including Valent, Escribano, Castells, Akin and Metcalfe. It sees little practical use and is not generally accepted in the community.
  • The major sets of criteria listed above all include the following features:
    • Recurrent or chronic symptoms of mast cell activation
    • Objective evidence of excessive mast cell mediator release
    • Positive response to medications that inhibit action of mast cell mediators
  • Valent warns that in some cases, patients may not fulfill all criteria but still warrant treatment: “In many cases, only two or even one of these three criteria can be documented. In the case of typical symptoms, the provisional diagnosis of ‘possibly MCA/MCAS’ can be established, and in acute cases, immediate treatment should be introduced.”[vii]

Evidence of mediator release

  • Mast cells produce a multitude of mediators including tryptase, histamine, prostaglandin D2, leukotrienes C4, D4 and E4, heparin and chromogranin A[viii].
  • Serum tryptase and 24 hour urine testing for n-methylhistamine, prostaglandin D2, prostaglandin 9a,11b-F2 are frequently included in testing guidelines in literature (Castells 2013)[ix], (Akin 2010)[x], (Valent 2012)[xi].
  • It can be helpful to test for other mast cell mediators including 24 hour urine testing for leukotriene E4[xii]; plasma heparin[xiii]; and serum chromogranin A[xiv].
  • In most instances, elevation of a mediator must be present on two occasions[ix]. This helps to exclude situations of appropriate mast cell activation, such as infection or wound healing.
  • For patients with baseline tryptase level >15 ng/mL, elevation of tryptase above this baseline is only required on one occasion[viii].

Symptoms associated with mast cell activation

  • Mediator release causes a wide array of symptoms, including hypertension[xv], hypotension, hypertension, wheezing, itching, flushing, tachycardia, nausea, vomiting, diarrhea, constipation, headache, angioedema, fatigue, and neurologic symptoms[iv].
  • In a small MCAS cohort (18 patients), 17% had a history of anaphylaxis[xvii] . A larger data set is desirable.
  • Patients with history of anaphylaxis should be prescribed epinephrine autoinjectors[v]. If patient must be on a beta blocker, they should be prescribed a glucagon injector for use in the event of anaphylaxis[v].

Response to medications that inhibit action of mast cell mediators

  • Treatment of MCAS is complex and may require a number of medications. Second generation H1 antihistamines; H2 antihistamines; and mast cell stabilizers are mainstays of treatment[xvi].
  • Additional options include aspirin; anti-IgE; leukotriene blocker; and corticosteroids[xiii] .
  • First generation H1 antihistamines may be used for breakthrough symptoms[xiii] .
  • “An important point is that many different mediators may be involved in MCA-related symptoms so that the final conclusion the patient is not responding to antimediator therapy should only be drawn after having applied several different antimediator-type drugs[xiii] .
  • Inactive ingredients are often to blame for reaction to mast cell mediator focused medications. Many mast cell patients see benefit from having medications compounded[xvii].

Natural history

  • In one MCAS cohort of 18 patients, 33% had a complete (no unmanaged symptoms) response and 33% had a major (only one serious symptom) response after one year of mast cell treatment[xviii].
  • In another MCAS cohort of 135 patients, 51% demonstrated significant improvement, 11% had no obvious change in symptom severity and 38% experienced worsening symptoms[v]. (Author’s note: While described in an Afrin 2016[v] paper, the data from this cohort has not yet been published. Molderings is the principle investigator.

 

References

[i] Frieri M, et al. (2013). Mast cell activation syndrome: a review. Current Allergy and Asthma Reports, 13(1), 27-32.

[ii] Molderings GJ, et al. (2013). Familial occurrence of systemic mast cell activation disease. PLoS One, 8, e76241-24098785

[iii] Akin C, et al. (2010). Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol, 126(6), 1099-1104.e4

[iv] Molderings GJ, et al. (2011). Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology, 4(10), 10.1186/1756-8722-4-10

[v] Castells M, et al. (2013). Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clin Ther, 35(5), 548-562.

[vi] Afrin LB, et al. (2016). Often seen, rarely recognized: mast cell activation disease – a guide to diagnosis and therapeutic options. Annals of Medicine, 48(3).

[vii] Valent P. (2013). Mast cell activation syndromes: definition and classification. European Journal of Allergy and Clinical Immunology, 68(4), 417-424.

[viii] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[ix] Picard M, et al. (2013). Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clinical Therapeutics, 35(5), 548-562.

[x] Akin C, et al. (2010). Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol, 126(6), 1099-1104.e4

[xi] Valent P, et al. (2012). Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol, 157(3), 215-225.

[xii] Lueke AJ, et al. (2016). Analytical and clinical validation of an LC-MS/MS method for urine leukotriene E4: a marker of systemic mastocytosis. Clin Biochem, 49(13-14), 979-982.

[xiii] Vysniauskaite M, et al. (2015). Determination of plasma heparin level improves identification of systemic mast cell activation disease. PLoS One, 10(4), e0124912

[xiv] Zenker N, Afrin LB. (2015). Utilities of various mast cell mediators in diagnosing mast cell activation syndrome. Blood, 126(5174).

[xv] Shibao C, et al. (2005). Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension, 45(3), 385-390.

[xvi] Cardet JC, et al. (2013). Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep, 13(1), 10-18.

[xvii] Afrin LB. “Presentation, diagnosis and management of mast cell activation syndrome.” In: Mast Cells. Edited by David B. Murray, Nova cience Publishers, Inc., 2013, 155-232.

[xviii] Hamilton MJ, et al. (2011). Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. Journal of Allergy and Clinical Immunology, 128(1), 147-152.e2

The Provider Primer Series: Mediator testing

Evidence of mediator release

  • Mast cells produce a multitude of mediators including tryptase, histamine, prostaglandin D2, leukotrienes C4, D4 and E4, heparin and chromogranin A[i].
  • Objective evidence of mast cell mediator release is required for diagnosis of MCAS (Castells 2013)[ii], (Akin 2010)[iii], (Valent 2012)[iv].
  • Serum tryptase and 24 hour urine testing for n-methylhistamine, prostaglandin D2, prostaglandin 9a,11b-F2 are frequently included in MCAS testing recommendations (Castells 2013)[ii], (Akin 2010)[iii], (Valent 2012)[iv].
  • It can be helpful to test for other mast cell mediators including 24 hour urine testing for leukotriene E4[v]; plasma heparin[ix]; serum chromogranin A[ix]; and leukotriene E4[ix].

Tryptase

  • Tryptase is extremely specific for mast cell activation in the absence of hematologic malignancy or advanced kidney disease. Of note, rheumatoid factor can cause false elevation of tryptase[ix].
  • Serum tryptase levels peak 15-120 minutes after release with an estimated half-life of two hours[vi].
  • Per key opinion leaders, tryptase levels should be drawn 15 minutes to 4 hours after onset of anaphylaxis or activation event (Castells 2013[ii]), (Akin 2010[iii]), (Valent 2012)[iv]). Phadia, the manufacturer of the ImmunoCap® test to quantify tryptase, recommends that blood be drawn 15 minutes to 3 hours after event onset[vii].
  • Serum tryptase >11.4 ng/mL is elevated[i]. In addition to measuring tryptase level during the event, another sample should be drawn 24-48 hours after the event, and a third sample drawn two weeks later. This allows comparison of event tryptase level to baseline[vi].
  • An increase in serum tryptase level during an event by 20% + 2 ng/mL above patient baseline is often accepted as evidence of mast cell activation[v],[i].
  • Absent elevation of tryptase level from baseline during an event does not exclude mast cell activation[viii].
  • Sensitivity for serum tryptase assay in MCAS patients was assessed as 10% in a 2014 paper[ix].
  • A recent retrospective study of almost 200 patients found serum was elevated in 8.8% of MCAS patients[x].
  • Baseline tryptase >20.0 ng/mL is a minor criterion for diagnosis of systemic mastocytosis. 77-85% of SM patients have baseline tryptase >20.0 ng/mL[ix].

Histamine and degradation product n-methylhistamine

  • N-methylhistamine is the breakdown product of histamine.
  • Histamine is degraded quickly. Samples should be drawn within 15 minutes of episode onset[vii].
  • Serum histamine levels peak 5 minutes after release and return to baseline in 15-30 minutes[vii].
  • Sample (urine or serum) must be kept chilled[xi].
  • In addition to mast cells, histamine is also released by basophils. Consumption of foods or liquids that contain histamine can also inflate the level when tested[ix].
  • A recent retrospective study of almost 200 patients found that n-methylhistamine was elevated in 7.4% of MCAS patients in random spot urine and 5.4% in 24-hour urine[xi].
  • Sensitivity of 24-hour n-methylhistamine for MCAS was assessed as 22% in 24-hour urine[ix].
  • Plasma histamine was elevated in 29.3% of MCAS patients[xi].
  • 50-81% of systemic mastocytosis patients demonstrate elevated n-methylhistamine in 24-hour urine[ix].

Prostaglandin D2 and degradation product prostaglandin 9a,11b-F2

  • 9a,11b-prostaglandin F2 is the breakdown product of prostaglandin D2.
  • Prostaglandin D2 is only produced in large quantities by mast cells. Basophils, eosinophils and other cells produce minute amounts[ix].
  • A recent retrospective study of almost 200 patients found that PGD2 was elevated in 9.8% of MCAS patients in random spot urines and 38.3% in 24-hour urine[xi].
  • PGD2 was elevated in 13.2% of MCAS patients in plasma[xi].
  • 9a,11b-PGF2 was elevated in 36.8% in 24-hour urine[xi].
  • 62-100% of systemic mastocytosis patients demonstrate elevated prostaglandin D2 or 9a,11b-PGF2 in urine[ix].
  • Prostaglandins are thermolabile and begin to break down in a minutes. This can contribute to false negative results[xi].
  • Medications that inhibit COX-1 and COX-2, such as NSAIDs, decrease prostaglandin production[xi].

Leukotriene E4

  • Leukotriene E4 is produced by mast cells and several other cell types[ix] including eosinophils, basophils and macrophages.
  • A recent retrospective study of almost 200 patients found that LTE4 was elevated in 4.4 % of MCAS patients in random spot urines and 8.3% in 24-hour urine[xi].
  • 44-50% of systemic mastocytosis patients demonstrate elevated leukotriene E4 in urine[ix].
  • Medications that inhibit 5-LO, such as lipoxygenase inhibitors, decrease leukotriene production[xii].

Chromogranin A

  • Chromogranin A is produced by mast cells and several other cell types including chromaffin cells and beta cells.
  • Proton pump inhibitors can cause increased values during testing[xi].
  • A 2014 paper reported chromogranin A was elevated in 12% of MCAS patients and 63% of systemic mastocytosis patients tested[ix].

Heparin

  • Heparin is a very specific mediator for mast cell activation[ix].
  • Heparin is extremely heat sensitive. The sample must be kept on ice or refrigerated at all times[ix].
  • Venous occlusion of upper arm for ten minutes has been successful in provoking mast cell activation leading to heparin release[ix].
  • A 2014 paper reported plasma heparin was elevated in 59% of MCAS patients and 47% of systemic mastocytosis patients tested[ix].
  • A recent retrospective study of almost 200 patients found that plasma heparin was elevated in 28.9% tested[ix].

 

References

[i] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[ii] Picard M, et al. (2013). Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clinical Therapeutics, 35(5), 548-562.

[iii] Akin C, et al. (2010). Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol, 126(6), 1099-1104.e4

[iv] Valent P, et al. (2012). Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol, 157(3), 215-225.

[v] Lueke AJ, et al. (2016). Analytical and clinical validation of an LC-MS/MS method for urine leukotriene E4: a marker of systemic mastocytosis. Clin Biochem, 49(13-14), 979-982.

[vi] Payne V, Kam PCA. (2004). Mast cell tryptase: a review of its physiology and clinical significance. Anaesthesia, 59(7), 695-703.

[vii] Phadia AB. ImmunoCAP® Tryptase in anaphylaxis. Retrieved from: http://www.phadia.com/Global/Market%20Companies/Sweden/Best%C3%A4ll%20information/Filer%20(pdf)/ImmunoCAP_Tryptase_anafylaxi.pdf

[viii] Sprung J, et al. (2015). Presence or absence of elevated acute total serum tryptase by itself is not a definitive marker for an allergic reaction. Anesthesiology, 122(3), 713-717.

[ix] Vysniauskaite M, et al. (2015). Determination of plasma heparin level improves identification of systemic mast cell activation disease. PLoS One, 10(4), e0124912

[x] Zenker N, Afrin LB. (2015). Utilities of various mast cell mediators in diagnosing mast cell activation syndrome. Blood, 126(5174).

[xi] Afrin LB. “Presentation, diagnosis and management of mast cell activation syndrome.”  Mast Cells, edited by David B. Murray, Nova Science Publishers, Inc., 2013, 155-231.

[xii] Hui KP, et al. (1991). Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax, 46, 184-189.