The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 55

69. What routine monitoring should mast cell patients receive?

There are not yet routine testing recommendations for MCAS patients, but there are some for mastocytosis patients. Many doctors use the mastocytosis recommendations to monitor their MCAS patients in the absence of specific MCAS guidelines.

Mastocytosis patients should monitor tryptase level annually. In mastocytosis patients, tryptase level is often a good marker for how many mast cells are in the body (although this is not always true.) If a patient’s tryptase is increasing over time, the provider will need to check other things to see if their disease is moving to a more serious disease category.

DEXA scans measure bone density. Osteoporosis is a common complication of systemic mastocytosis. Patients should receive regular osteoporosis screening, even if they are young.

Mastocytosis patients usually receive routine bloodwork annually that includes a complete blood count (CBC), which counts the amount of blood cells a person has; and a metabolic panel, which looks at how well the liver and kidneys are working.

Repeat biopsies are usually only done if the result will change treatment in some way. Most patients with systemic mastocytosis are diagnosed based upon bone marrow biopsies. These don’t usually need to be repeated unless tryptase level increases sharply or there are unusual results in routine blood count testing. Increasing tryptase can indicate that the body is making more mast cells much faster, which is sometimes linked to a more serious disease category. Unusual blood cell counts can indicate not just too many abnormal mast cells, but also other bone marrow conditions sometimes seen in mast cell patients, like myelofibrosis and essential thrombocythemia.

Patients with cutaneous mastocytosis are diagnosed by skin biopsy. There is not usually a need to repeat a skin biopsy for patients with CM.

Patients with systemic mastocytosis are usually diagnosed by bone marrow biopsy but can also be diagnosed as a result of a positive biopsy in any organ that is not the skin. A person can be diagnosed with SM via a GI biopsy.

GI biopsies are a little different than bone marrow biopsies in that there are sometimes reasons to repeat them. GI biopsies may be repeated to see if the general inflammation in the GI tract is improved or worsened. The provider may also be interested in whether or not the amount of mast cells in the GI tract has decreased. The result of GI biopsies often change treatment options so it is not unusual to repeat them. However, unlike bone marrow biopsies, repeated GI biopsies do not tell the provider if the mastocytosis is moving toward a more serious disease category or not.

MCAS patients are diagnosed based upon positive tests for molecules that indicate mast cells are overly active, like n-methylhistamine, and D2- or 9a,11b-F2 prostaglandins. Once the patient is diagnosed, there’s not a clear rationale for repeating these tests, although some providers do for their own information. Some providers like to check prostaglandin levels to see if treatment to stop mast cells from making prostaglandins (like use of aspirin or other NSAIDs) is helping.

However, it is important to understand that the level of mast cell mediators is not associated with symptoms. A person who has a normal level of 9a,11b-F2 prostaglandin may have the same symptoms as a person above the normal level, who may have the same symptoms as a person who has three times the normal level. For this reason, many providers consider these mediator tests to be less about the numerical value of the test and more about whether it’s normal or high, period.

For more detailed reading, please visit the following post:
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 5
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 6
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 7
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 8
The Provider Primer Series: Diagnostic criteria of systemic mastocytosis and all sub variants
The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)
The Provider Primer Series: Mediator testing
The Provider Primer Series: Mast cell activation syndrome (MCAS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, part 49

60. Is anaphylaxis the same as anaphylactic shock?

No. Anaphylaxis can result in anaphylactic shock but it often doesn’t. When talking about anaphylactic shock, people are referring to circulatory shock that was caused by anaphylaxis. Circulatory shock occurs when there is not enough blood to carry oxygen to all the tissues that need it. When the tissues don’t get enough oxygen, your organs stop working correctly.

Circulatory shock is usually caused by low blood pressure. Anaphylaxis commonly causes low blood pressure and that can cause shock. However, anaphylaxis does not always cause low blood pressure, and it does not always cause shock.

61. If a tryptase level over 10.9 ng/mL is high, why is one of the criteria for systemic mastocytosis a tryptase level of 20.0 ng/mL or higher?

Tryptase level is used in two ways in assessing mast cell patients: as a marker for activation, and as a marker for how many mast cells are in the body.

There are two primary methods of using tryptase to indicate mast cell activation.

The first way is to compare a tryptase level when a patient is reacting to a tryptase level when they are not reacting (baseline). Mast cells release more tryptase when they are activated. For mast cell patients, an increase of 20% + 2 ng/mL is considered evidence of mast cell activation. So if a patient has a baseline tryptase of 5 ng/mL when they are not reacting, anything 8 ng/mL (20% of 5 ng/mL is 1 ng/mL, then add 2 ng/mL = 8 ng/mL) or higher is considered evidence of activation.

The second way is to count anything over 10.9 ng/mL as evidence of activation.

When you are using tryptase as a measure of how many mast cells are in the body, the patient should not be reacting beyond their normal day to day symptoms. This is because you don’t want an increase in tryptase from activation to make the baseline level look higher than it is. Tryptase is used to measure how many mast cells are present because mast cells release some tryptase all the time, even when they aren’t activated.

Anything over 10.9 ng/mL is considered an elevation of tryptase. The reason that 20 ng/mL is the cutoff for the SM criterion is that patients are likely to have a positive bone marrow biopsy when the tryptase level is twice normal (21.8 ng/mL). They round the number down to 20 ng/mL because all tests have a margin of error. By rounding down to 20 ng/mL, they catch patients that might not have made the cutoff before because of an error in the test. This means that a patient who has a tryptase level of 20 ng/mL or higher is likely to have a bone marrow biopsy that will be positive for systemic mastocytosis.

For more detailed reading, please visit these posts:

Anaphylaxis and mast cell reactions

The Provider Primer Series: Mediator Testing

Patient questions: Everything you wanted to know about tryptase

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

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 48

59. Is systemic mastocytosis a form of cancer? Why do some papers say the life expectancy for systemic mastocytosis patients is much shorter?

Systemic mastocytosis is a term that different people use in different ways, often without defining them for the audience. This can lead to some confusion.

In its broadest sense, systemic mastocytosis is actually a disease category rather than one specific diagnosis. The subtypes of systemic mastocytosis are indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), systemic mastocytosis with associated hematologic disease (SM-AHD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL).

When patients talk about systemic mastocytosis without specifying which diagnosis, they almost always mean indolent systemic mastocytosis (ISM), the most common form of SM. ISM is benign and has a normal life expectancy. But when providers and researchers talk about systemic mastocytosis, they usually mean the disease category that includes all of these diagnoses.

I just recently explained in another post what a neoplasm is. It is essentially when the body grows something that doesn’t belong there, like extra cells or a tumor. Cancers are neoplasms but not all neoplasms are cancerous. Indolent systemic mastocytosis is not cancerous. Even without taking drugs to kill off lots of mast cells, the prognosis is excellent with a normal life span. However, aggressive systemic mastocytosis and mast cell leukemia are considered cancerous. Without taking drugs to kill off mast cells, the body would be unable to cope with the huge number of mast cells and the damage they cause. Smoldering systemic mastocytosis is sort of a bridge between ISM, which is benign, and ASM, which is not.

If you are not aware that research papers usually use the term systemic mastocytosis to mean all forms of systemic mastocytosis and not just indolent systemic mastocytosis (ISM), it is easy to get confused and misunderstand what is being said. There was a paper published in 2009 that discussed expected survival for the various forms of systemic mastocytosis. It provides a very jarring statistic for patients who may not understand the context. This study found that many patients with systemic mastocytosis died 3-5 years after diagnosis.

Let’s pull this apart. We know there are five forms of SM: indolent SM, the most common form, which usually has a normal life span; smoldering SM, which usually has a shortened life span; aggressive SM, which can have a very shortened life span; mast cell leukemia, which has a very shortened life span; and SM with an associated hematologic disorder, which may have a shortened life span. When you average the life expectancies for a mixed group of patients with these various diagnoses, it shows that overall, SM patients are more likely to die 3-5 years after diagnosis when compared to healthy people of the same age.

Additionally, a lot of the patients in this study group were older and died of causes unrelated to systemic mastocytosis. However, because they were part of the study, their deaths of unrelated causes were still included in this data.

Let’s recap: in a research paper, the term systemic mastocytosis includes forms of SM that are malignant and can really shorten your life expectancy as well as forms that are benign and do not shorten your life expectancy. When you average the life expectancies of all of these forms together, it looks like patients are more likely to die 3-5 years after diagnosis. A bunch of other papers then used the data from this study in 2009 without explaining the details behind it. However, most patients with SM have normal life spans.

For more detailed information, please visit these posts:

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

The Provider Primer Series: Natural history of SM-AHD, MCL and MCS

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 47

  1. 58. What is mastocytic enterocolitis?

A high powered field (hpf) is what you see through a microscope when you use powerful magnifying lenses. With very few exceptions, high powered fields using the same lenses are the same size. Since they are the same size, you can directly compare results from various groups all over the world.

In 2006, a paper was published that coined the term “mastocytic enterocolitis”. The author described mastocytic enterocolitis as more than 20 mast cells per high powered field. This paper was about people with severe chronic diarrhea that did not improve with treatment. The author found that healthy people had about 13 mast cells/hpf while people with severe chronic diarrhea had about 20 mast cells/hpf. The author felt that the extra mast cells were responsible for the diarrhea and inflammation so they called the extra mast cells in the colon and the small intestine “mastocytic enterocolitis”. Enterocolitis is the term for inflammation in the small intestine and colon.

The author felt that 20 mast cells/hpf was the cutoff between a normal amount of mast cells in the GI tract and an abnormal amount. Under 20 was considered normal while 20 and above was considered abnormal. However, there have been a number of papers since that look at how many mast cells are present in the GI tract for patients with different conditions as well as healthy people. There are several conditions that can cause you to have 20 or more mast cells/hpf. (I wrote an exhaustive series on this in 2015-2016. Links are below.)

Additionally, in some situations, people have over 20 mast cells/hpf without having any symptoms. Sometimes healthy people without any GI conditions have over 20 mast cells/hpf. For this reason, there is not agreement about how many mast cells in the GI tract is too many. (If you’re looking for my opinion, I think the number for what is too many is around 25-30/hpf. This is just my opinion.)

In the last several years, some doctors have begun linking mastocytic enterocolitis to mast cell disease. This makes sense because we know that in those people, mast cell inflammation drives GI symptoms and damage. Mast cell patients certainly have a lot of inflammation in the GI tract so having extra mast cells there makes sense. Some experts think that mastocytic enterocolitis is a sign of mast cell activation syndrome and that patients with mastocytic enterocolitis all have mast cell activation syndrome.

Mastocytic enterocolitis is absolutely a real phenomenon. In these people, mast cells cause a lot of GI symptoms and damage the GI tract. Experts have not all agreed upon whether or not everyone with mastocytic enterocolitis has mast cell disease. Also, there are some researchers that feel that mastocytic enterocolitis is actually its own mast cell disease rather than just a feature of another mast cell disease like mast cell activation syndrome.

Currently, mastocytic enterocolitis is not recognized by the WHO as its own disorder. However, that could certainly change. It was only last year that MCAS was recognized by the CDC even though it was routinely recognized by researchers and providers. (Author’s note: This was initially published stating that the WHO recognized MCAS, rather than the CDC. MCAS has not yet been recognized by the WHO. This is a whopper mistake on my part. Many thanks to the reader who saw this. Sorry!) I personally expect this to change in the next few years as more mast cell patients are diagnosed and mastocytic enterocolitis is better recognized. I think it is suggestive of mast cell disease but I also think providers need to eliminate other possible causes for the extra mast cells in the GI tract.

For more detailed information, please visit these posts:

Mast cells in the GI tract: How many is too many? (Part One)

Mast cells in the GI tract: How many is too many? (Part Two)

Mast cells in the GI tract: How many is too many? (Part Three)

Mast cells in the GI tract: How many is too many? (Part Four)

Mast cells in the GI tract: How many is too many? (Part Five)

Mast cells in the GI tract: How many is too many? (Part Six)

Mast cells in the GI tract: How many is too many? (Part Seven)

Mast cells in the GI tract: How many is too many? (Part Eight)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 43

52. Is it true that it can take up to six bone marrow biopsies to diagnose systemic mastocytosis?

Sort of. This has become sort of an urban legend in the mast cell community. I am partly to blame for this as I have offered this information up several times without explaining it, which is lazy on my part.

Systemic mastocytosis is diagnosed by biopsy. While a positive biopsy in any organ that’s not skin can be used to diagnose SM, bone marrow biopsies are overwhelmingly what is used to diagnose.

In 2004, a paper was published that discussed how well bone marrow biopsies worked for diagnosing SM in a group of 23 patients. These patients had bilateral bone marrow biopsies taken, so each patient had one on each side. In 19 of those patients, both of the biopsies showed mastocytosis. In 4 of those patients, only one of their two biopsies was positive. 4/23 is 17%, which is roughly 1/6. Based upon this figure, it means that theoretically, in a patient who has SM, they could have five negative biopsies before getting a positive biopsy.

It’s important to two things in mind when you think about this 1/6 thing. Firstly, this is a very small patient group. Things that you see in a small group don’t always translate to what really happens in larger groups. Another thing is that the criteria they used in 2004 to diagnose SM are not the same as the criteria we use now. It’s possible that with changes in diagnostic criteria that this 1/6 number is no longer accurate.

In reality, I have never met a person who needed six bone marrow biopsies to get a positive biopsy for SM. But I do know a few who needed two or three. It’s not impossible that it could take six to get a positive biopsy but it’s unlikely.

However, it’s also important to realize that every expert acknowledges that you can have a negative biopsy while having SM. The reason for this is that you can’t tell by looking whether or not a biopsy site will give you a positive biopsy for SM. You have to just hope that the mast cells are clustered where they stick the needle. Mast cells don’t cluster evenly throughout your bone marrow when you have SM. If you get a biopsy site where the mast cells didn’t happen to cluster, you are out of luck. For this reason, some doctors advocate getting bilateral bone marrow biopsies (two at once) to increase the chances of catching a positive biopsy.

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)