Tyrosine kinase inhibitors in the treatment of mast cell diseases

Author’s note: The following post is my personal opinion and is based upon publicly available information and not upon any confidential information I have obtained as a result of my job. The ideas described below are directly attributable to me and not to my employer. I am not a medical doctor and this is not medical advice. This information should be used only to better inform yourself prior to speaking with your provider.

Tyrosine kinase inhibitors have been described in literature for over thirty years. The first tyrosine kinase inhibitor, imatinib, was approved by the FDA in 2001. Because it was the first effective therapy known for a fatal disease, chronic myelogenous leukemia, it was fast tracked through the FDA approval process and approved in two and a half months. In the years that followed, newer tyrosine kinase inhibitors were developed by various pharma organizations. The indications for these therapies expanded from CML to include several other diseases, including certain forms of systemic mastocytosis.

Tyrosine kinase inhibitors were developed with the intention of reducing the toxicity seen in older chemotherapy medications. They do this by targeting specific structures on diseased cells. For example, patients with chronic myelogenous leukemia have a genetic abnormality called the Philadelphia chromosome. This is the result of pieces of DNA getting switched around so that genes that aren’t normally next to each other end up stuck together. This forms a gene called BCRABL that tells cells to continually make new cells even when they aren’t needed. Imatinib targets BCRABL. The idea is that only the cancer cells have BCRABL so healthy cells wouldn’t be damaged.

In reality, it’s a lot more complicated than that. The biggest reason for this is that even though healthy cells don’t have BCRABL, they have other things that look like BCRABL. This is actually why imatinib can treat some cases of systemic mastocytosis: CKIT looks like BCRABL. And there are plenty of other proteins on plenty of other cells, some healthy cells, some diseased cells, that look like BCRABL or CKIT. This means that while tyrosine kinase inhibitors are much more targeted than older forms of chemotherapy, they aren’t so targeted that healthy cells don’t incur any damage at all. Sometimes that damage is serious. Sometimes it is irreversible.

In the mast cell sphere, imatinib was originally used for cases of aggressive systemic mastocytosis that did not have the CKIT D816V mutation. Over time, it was also used for other forms of systemic mastocytosis, including mast cell leukemia, systemic mastocytosis with associated hematologic neoplasm, and smoldering systemic mastocytosis. While imatinib was approved for use in people without the CKIT D816V mutation, there were trials on SM patients who did have the mutation. Published reports found it was less effective but did give benefit to some patients with the mutation. To be clear, the published data strongly points to imatinib being more effective in people without the CKIT mutation than in those that do. But there is some evidence that imatinib might have benefit even if you have the mutation.

I sometimes see people telling other patients that it is dangerous to use imatinib if you have the CKIT mutation. The danger for these people is that it might not work well for them. There’s no special risk beyond that. In fact, the current FDA licensing for imatinib is for patients without the CKIT D816V mutation OR patients in whom CKIT status is unknown. This means that sometimes people are put on it without genetic testing so it’s possible that some of the patients have the mutation.

I want to be so, so super clear about the next thing I say because it is so important that people know this. Imatinib, and other tyrosine kinase inhibitors, are chemotherapies. They are licensed as antineoplastic therapies, also known as chemotherapies. When it’s shipped to your house, it arrives there with the label “contains chemotherapy drugs” on the package. Patients taking it are supposed to be consented for chemotherapy so that they fully understand the risks. TKIs are, for sure, kinder, gentler, more targeted chemo drugs. But they are chemo. And they carry a lot of risks associated with chemotherapy.

I have seen patients describe these drugs as “extremely safe”, “harmless”, “unable to damage other cells”, or even “unable to kill cells.” Those ideas are patently false. These medications are not benign. They are serious. They can cause organ damage, especially liver damage. They can suppress bone marrow, resulting in low blood cell counts. They can cause clotting issues. They most certainly can damage other cells and kill cells, targeted and otherwise. There are hundreds of references describing the ways TKIs can do this, mostly by inducing apoptosis, making a cell kill itself. All of this information is publicly available.

The very fact that TKIs are chemo agents and can cause many of the associated issues is the reason why use of TKIs is controversial in the mast cell community. A lot of people believe that use of TKIs is only warranted in the aggressive forms of systemic mastocytosis that can cause organ damage and death. But there is another school of thought that posits that TKIs are appropriate for indolent SM and MCAS, specifically for cases where anaphylaxis is frequent and severe. They argue that these cases present enough risk to life that the benefits outweigh the risks. Still another group feels that TKIs are safe enough to use for control of non life threatening symptoms in patients with indolent SM and MCAS.

It is my personal opinion that there is benefit to trialing TKIs in patients with indolent SM and MCAS for whom disability or risk to life is significant. I think that you have a right to try unproven therapies when your life is at stake. But I also think that because of the risks, they should only be used when more conservative therapies have failed. The sole fact that they are chemo drugs shouldn’t preclude TKIs from consideration for severe cases of MCAS and ISM. Chemo drugs are prescribed in low doses to treat dozens of conditions, especially immune mediated disorders like autoimmune diseases. But I do think they should be a last resort. I do not personally feel that TKIs are appropriate for general symptom management in non life threatening cases.

My opinion can be summed up pretty cleanly as this: these drugs are serious and they should be reserved for serious cases until such time as we have actual data on how TKIs affect these patients. We need studies, not a handful of case reports, to really understand the risks for MCAS and ISM patients using these therapies. But when other treatments fail and there is risk to life, I think it is appropriate to consider TKIs in these populations.

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 83

96. Why are cancer drugs used to treat mast cell disease?

Disclaimer: The following post was written by me in my capacity as a subject matter expert in mast cell disease and author of MastAttack. This is not work product of my position as a Senior Scientist for a large research organization. All below statements are attributable directly to me in my role as author of MastAttack and are in no way attributable to my employer. Information presented here is publicly available and includes no confidential information learned in my capacity as a Senior Scientist for my employer.

  • There are a number of medications used to treat cancers that are also used to treat mast cell disease. Some of those medications are old school chemotherapies, some are newer, targeted chemotherapies, and some help to control the immune system.
  • In mastocytosis, the body makes too many mast cells. If the bone marrow makes way, way too many mast cells, and those mast cells don’t function correctly, the mast cells can act like cancer cells. This can cause the mastocytosis to behave like cancer.
  • Systemic mastocytosis has several subtypes. The least serious forms do not act like cancer.
  • Indolent systemic mastocytosis (ISM) is the least severe form of systemic mastocytosis. ISM has a normal lifespan. While patients with ISM are at risk of dying for anaphylaxis, an important distinction is that patients with ISM do not die because the mast cell disease acts like a cancer. ISM does not act like cancer.
  • Smoldering systemic mastocytosis (SSM) is a moderately serious form of systemic mastocytosis. SSM can shorten lifespan. In SSM, the body is starting to make lots more mast cells than it should. Those mast cells can affect how organs function. SSM acts like an early cancer.
  • SSM requires treatment to stop it from becoming a more serious form of mastocytosis called aggressive systemic mastocytosis (ASM) that acts like a serious cancer. The treatments used to manage SSM are also used in some cancer patients to help fight cancer. These include meds that affect your immune system, like interferon; newer targeted therapies and chemos, like tyrosine kinase inhibitors; and older chemo drugs, like cladribine.
  • Aggressive systemic mastocytosis (ASM) is a serious form of systemic mastocytosis. ASM shortens lifespan significantly. In ASM, the body makes way too many mast cells. The bone marrow churns out so many mast cells into the bloodstream and then the abnormal mast cells get stuffed into various organs. The mast cells cause organ damage and can cause organ failure. ASM is often referred to as being malignant because it behaves just like a cancer. It is also treated like a cancer.
  • As mentioned above, interferon is a therapy that can affect how the immune system works. Interferon is sometimes used for ASM but it is less commonly used in ASM than in SSM. ASM patients need more aggressive treatment. Newer targeted therapies like tyrosine kinase inhibitors and multitarget kinase inhibitors are frequently used in ASM. Some of these newer therapies are FDA approved for treating some ASM patients. Cladribine and hydroxyurea are still common treatments for ASM.
  • Mast cell leukemia (MCL) is the most serious form of systemic mastocytosis. MCL greatly reduces lifespan. MCL causes production of an unbelievable number of mast cells. There are so many mast cells that they cannot all get stuffed into organs like ASM. This means that while there are lots of mast cells in the organs in MCL patients, there are so many mast cells like that there are still tons of them in the bloodstream. This leads to rapid organ failure, leading to death. Mast cell leukemia is cancer. It is treated like cancer with newer therapies like tyrosine kinase inhibitors and multitarget kinase inhibitors, as well as hydroxyurea or cladribine in some cases. As in ASM, some of the newer therapies are FDA approved to treat mast cell leukemia.
  • Sometimes patients with systemic mastocytosis develop a second blood disorder. This is called systemic mastocytosis with associated hematologic disease. Sometimes this second blood disorder is a form of cancer, like chronic myeloid leukemia. In these instances, the other blood disorder would be treated using cancer medications.
  • Mast cell sarcoma (MCS) is a cancerous form of systemic mastocytosis. Patients with MCS rapidly develop MCL and are treated as described above.
  • None of the therapies I mentioned here are indicated for cutaneous mastocytosis. Cutaneous mastocytosis does not behave like a cancer and is not treated like one.
  • In recent years, two other forms of mast cell disease have been described: mast cell activation syndrome and monoclonal mast cell activation syndrome.
  • Monoclonal mast cell activation syndrome (MMAS) is often considered to be a “pre-SM”. It is treated like indolent systemic mastocytosis and does not behave like a cancer.
  • Mast cell activation syndrome (MCAS) is not know to be an early form of SM. Many people live with MCAS for decades without ever developing SM.
  • Despite the fact that mast cell activation syndrome, monoclonal mast cell activation syndrome, and indolent systemic mastocytosis do not behave like cancer, cancer therapies are sometimes used in these patients. They are used when other therapies have failed and their symptoms are still poorly controlled. Generally, they are used when persistent mast cell activation becomes life threatening. In some instances, they may be used when a patient’s symptoms are not life threatening but are very disabling and cause a poor quality of life. In these cases, the patient and their provider make the assessment that they are able to assume the risk of using these medications.
  • There is very little data on the use of chemo and targeted therapies in patients with MCAS, MMAS and ISM, and no cancer therapies are FDA approved for these conditions. However, use of cancer meds for nonmalignant conditions is not that unusual. It is pretty common in autoimmune disease where lower doses of chemotherapy drugs can be effective in controlling the disease. Basically, the idea is that if we know that these therapies help forms of mast cell disease that behave like cancers then it might help those forms that don’t act like cancer.
  • On a number of occasions, I have seen patients discussing the dangers around certain cancer meds that are sometimes used to treat mast cell disease. In particular, I have seen comments that newer targeted therapies “do not kill cells”, “cannot cause organ damage”, and are “harmless.” This is completely untrue. There are thousands of articles on the side effects and complications of all of the meds I have described here. None of them are harmless. Patients need to understand the risks associated with these therapies.
  • I would like to add a note about something sort of related. Xolair is an anti-IgE medication that is used by many mast cell patients. It is a subcutaneous injection and is administered in a healthcare setting. Patients are required to stay in the office for a little while after the shots are given to be sure that they don’t have a bad reaction. Because the patient is monitored in the office after the shot, the provider’s office will bill insurance for the observation period. The old billing code for this often comes up as “chemotherapy observation” because the same code was used for patients who needed monitoring after chemo. This means that patients may see “chemo” on the explanation of benefits from their insurance company. This does not mean that they received chemo. Xolair is NOT chemotherapy. It’s just a quirk of the medical billing. There is now a new code for post injection observation for meds that are not chemo but not everyone has caught up to it. Just figured I would mention this as people ask about it from time to time.

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 66

80. When is chemotherapy necessary for mast cell disease?

  • For mastocytosis patients, chemotherapy is used for patients with systemic mastocytosis in whom the disease is malignant (aggressive systemic mastocytosis or mast cell leukemia) or seems to be progressing towards a cancerous form of the disease (smoldering systemic mastocytosis). There are very clear cut guidelines for this. Interferon and chemotherapy are used when a patient has smoldering mastocytosis with increasing mast cell counts; aggressive systemic mastocytosis; or mast cell leukemia, in order to kill off mast cells to slow disease progression and extend a patient’s lifespan.
  • A patient who already meets the criteria for systemic mastocytosis, who has two or more B findings, is considered to have smoldering systemic mastocytosis. SSM is a transition state between indolent SM, which has a normal lifespan, and malignant forms of mast cell disease, including ASM and MCL.
  • Having two or more of the following gets you a diagnosis of SSM: mast cell aggregates that take up 30% or more of cells in a bone marrow biopsy, and/or serum tryptase over 200 ng/mL; bone marrow with too many cells in it overall, without evidence of MDS or a myeloproliferative neoplastic disease; or organ swelling that has not yet affected organ function (swelling of the liver without ascites, spleen swelling enough that it can felt by palpation, lymph nodes swollen to 2 cm or larger).
  • Patients with SSM are watched to see if their body is making lots of mast cells quickly, or if their organs are feeling the strain of too many mast cells. One of the way they check this is to see how quickly their tryptase level increases. If their provider feels that their disease is progressing, they receive chemo or interferon to try and knock the disease down enough that they don’t reach the criteria for ASM.
  • Patients are diagnosed with ASM if they meet the criteria for SM and any of the following criteria: the body not making enough blood cells, cytopenia (absolute neutrophil count below 1000/ul, hemoglobin below 10g/dl, or platelets below 100000/ul); swelling of the liver along with free fluid in the abdomen (ascites), elevated liver enzymes, or portal hypertension; swelling of the spleen along with decreased blood cells due to damage in the spleen, excessive production of blood cells by the bone marrow to compensate, and likely resolution if the spleen is removed; malabsorption in the GI tract causing low protein in the blood (albumin) and weight loss; and severe bone dysfunction, causing a series of bone breaks and large osteolytic lesions from mastocytosis.
  • ASM patients are put on chemotherapy or interferon, usually continuously, unless there is evidence that they have killed off enough mast cells to have a less dangerous disease category.
  • Mast cell leukemia patients are on chemotherapy continuously.
  • There is no described use for chemo in cutaneous mastocytosis.
  • There are situations where patients with other disease categories (ISM, MMAS, MCAS) are put on chemo drugs to try and manage symptoms or shock episodes after all other therapies have failed. While this has been mentioned in literature, there have been no studies on it.
  • Chemo drugs should be used as a last resort. They can have significant side effects and complications that cannot always be remedied by stopping the treatment.
  • Please note that while newer, targeted chemos have become more common, they are in fact chemotherapy and carry significant risks despite being more tailored, including the potential for organ damage or failure.

For additional reading, please visit the following 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, MCS 

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

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 59

73. Can mast cell disease cause organ damage?

  • Yes.
  • The term organ damage is tricky because people use it to mean a lot of things while providers and researchers often use it to mean one very specific thing. For providers and researchers, the term “organ damage” usually means a change in the organ that affects its structure, like it becomes misshapen or deformed in some way. Structural changes like this are often irreversible. This damage to the organ’s shape and structure usually affects how the organ works, called organ function.
  • When patients and laypeople talk about organ damage, they usually mean a change in the way the organ functions, even if the structure is not changed at all. This is different in a very important way: changes in an organ that do not affect its permanent structure can sometimes be reversible.
  • Both cutaneous and systemic mastocytosis cause organ damage in a way that damages the organ’s structure. When too many mast cells burrow into the tissue of an organ, it has to push other things out of the way. When you have mastocytosis, the mast cells like to stick together and form a big clump in the tissue. This punches holes in the tissue, affecting the organ’s structure and shape. This is called dense infiltration. It is one of the criteria for systemic mastocytosis and also happens in cutaneous mastocytosis.
  • In patients with mastocytosis, those mast cells clumping together cause a lot of the organ damage. This means that people who have the most mast cells usually have the worst organ damage. Patients with malignant forms of mast cell disease, like mast cell leukemia or aggressive systemic mastocytosis, often have organs that are riddled with TONS of mast cells.
  • Mast cells don’t live in the blood so when your body makes way too many mast cells, those mast cells will dive into whatever organ they can to get out of the bloodstream. This causes damage to the structure that you can see with scans or in biopsies.  People with mast cell leukemia and aggressive systemic mastocytosis suffer so much damage to the shape and function of their organs that the organs can totally stop working, called organ failure.
  • One of the key differences researchers and providers see between mastocytosis and mast cell activation syndrome is that mast cells don’t cause THIS TYPE of structural damage in mast cell activation syndrome patients.
  • We know this because in biopsies, they do not have mast cells clumped together to punch holes in the tissue. Sometimes they have lots of mast cells, but it is much less damaging to the tissue if they aren’t clumped together. Think of it like poking something with finger versus punching with your fist.
  • In MCAS, mast cells do not cause structural damage to organs IN THIS WAY. However, many people with MCAS do have structural damage to their organs. Many of them also have organs that do not function correctly even if the organs look normal.
  • Even if you don’t have mast cells punching holes in all your organs, they can still do a lot of damage. This is because mast cells cause lots of inflammation, which can stress out your organs. Over time, your organs can be damaged by the mast cells releasing too many mediators. While this is not always dangerous, it is certainly painful and frustrating.
  • Many MCAS and mastocytosis patients have a lot of damage to their GI tracts from years of vomiting, obstructions, diarrhea or constipation. Hives and mastocytosis spots can damage your skin, causing discoloration, scarring or sensitivity. Muscles can become weaker over time because of mast cell inflammation. Swelling can stretch out your skin and connective tissues. Nerves can be damaged significantly, affecting organ function. Bones can become brittle and break, or can become too dense because the body is making new bone when it shouldn’t.
  • All of these effects on organ function can be caused by mast cells. Major changes in organ function can also cause secondary conditions to arise.
  • Mast cell patients are also at an increased risk for anaphylaxis which can cause changes in organ function or organ damage.
  • Patients who have trouble breathing or low blood pressure may not be getting enough oxygen to their whole body. That can cause lasting damage if it goes on long enough.

For more detailed reading, please visit the following posts:

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)

MastAttack position on Mast Cell Activation Syndrome

In the unlikely event that it is unclear where MastAttack stands on mast cell activation syndrome:

MCAS is a serious, debilitating disease that directly causes an array of symptoms that often interfere with the daily living activities of patients who have it.

MCAS increases the risk of anaphylaxis, a potentially fatal, severe allergic reaction.

MCAS patients require careful management of their condition to stay healthy and safe. Overwhelmingly, this requires medication. There is nothing wrong with needing medical management of MCAS. You are not doing anything wrong by taking medications prescribed by a knowledgeable provider.

MCAS patients are more likely to have other disabling conditions, such as gastroparesis, Ehlers Danlos Syndrome, Postural Orthostatic Tachycardia Syndrome, and various autoimmune disorders and immunodeficiencies, among others.

Patients with MCAS sometimes need an extraordinary level of nutritional intervention to prevent malnutrition, starvation, and complications thereof.

Patients with MCAS sometimes require central intravenous lines to facilitate nutrition, use of IV fluids, and IV medications.

Patients with MCAS sometimes require GI tubes to facilitate nutrition and medication use in patients who are not able to take foods and medications orally.

Patients with MCAS often live complicated, stressful lives. Their experiences do not deserve to be mocked or minimized. They should under no circumstances attempt to manage their disease on their own without medical supervision without detailed conversations with their own care teams.

Patients with MCAS often repeatedly suffer the indignity of having their very state of health questioned and belittled by providers, family members, coworkers, and the public. This is especially an issue where it concerns medically complex children as unfamiliar providers may incorrectly assume that these children are receiving unnecessary medical interventions, sometimes resulting in removing the child. All of these situations can discourage MCAS patients from seeking care and can endanger them.

The idea that MCAS patients cannot die of complications of their mast cell disease and other diagnoses is ridiculous. I know MCAS patients who have died from anaphylaxis or from the inability to receive needed therapies without anaphylaxis and shock. We are fortunate as a community that these deaths are rare, but to insinuate that they do not happen is both incorrect and disrespectful.

The recent “controversy” about whether or not MCAS can be serious and disabling is shocking and has been difficult to watch. I do not often find myself truly stunned. While many patients are fortunate to be able to live safely while managing MCAS, we all know a number of MCAS patients who are not able to achieve stability, and who require aggressive medical and surgical management to stay alive. I cannot believe I have to say this.

MCAS patients are an integral part of the mast cell community. Please support them now.

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 45

54. How does mast cell disease affect clotting?

Heparin is a very potent blood thinner and inhibits the body’s ability to form clots.  Mast cells are full of heparin. Mast cells stores chemicals like heparin in little pouches inside them called granules. In the granules, histamine is stuck to heparin. This means that when mast cells open their granules and release histamine, heparin comes out with it. This can contribute to things like bruising or bleeding more than expected.

Mast cells release other chemicals that can affect clotting. Platelet activation factor and thromboxane A2 both encourage the body to make clots. Some chemicals that help to regulate when to make a clot can activate mast cells, like complement C3a and C5a.

55. How many people have mast cell disease?

It is hard to know exactly how many people have a rare disease because they are not reported if they are recognized and correctly diagnosed. As recognition and diagnosis improves, rare diseases are often found to be more prevalent than previously thought. The numbers below are current estimates.

Systemic mastocytosis is thought to affect around 0.3-13/100000 people. In one large study, indolent systemic mastocytosis (ISM) makes up 47% of cases. Aggressive systemic mastocytosis (ASM) has been described in various places as comprising 3-10%. Systemic mastocytosis with associated hematologic disease could count for as many of 40% of cases of SM. Mast cell leukemia is extremely rare and accounts for less than 1% of SM cases.

Systemic mastocytosis accounts for about 10% of total mastocytosis cases. This means that total mastocytosis cases come in at around 3-130/100000 people. The remaining 90% of mastocytosis cases are cutaneous with incidence roughly around 2.7-117/100000 people.

We do not have yet have a great grasp upon how many people have mast cell activation syndrome (MCAS) but from where I am sitting, it’s a lot and that number is likely to grow. We know that genetic studies have found mutations that might be linked to MCAS in up to 9% of the people in some groups. However, having a mutation is not the same thing as having a disease. As we learn more about MCAS, we will gain some clarity around how many people have it.

For more detailed reading, please visit the following posts:

Progression of mast cell diseases: Part 2

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 Provider Primer Series: Cutaneous mastocytosis/Mastocytosis in the skin

 

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 42

51. What is the difference between mast cell activation syndrome and histamine intolerance?

Histamine intolerance is not widely accepted by the mainstream medical establishment. I haven’t been able to find much about it in the way of peer reviewed literature. That said, it doesn’t seem ridiculous to me. It feels plausible, I just haven’t seen convincing evidence of that yet.

Histamine intolerance is when a patient has symptoms from ingesting something that has a lot of histamine in it, that causes the body to release histamine, or that interferes with the body’s ability to break down histamine. In histamine intolerance, the problem is what is being put into your body rather your body itself. The problem is external, not internal.

Mast cell activation syndrome is when a patient’s mast cells are fundamentally dysfunctional. The problem is internal, not external. There is no evidence at this point that patients with MCAS can’t break down histamine normally with enough time, there’s just so much of it that it takes longer.

Many patients with MCAS (and other mast cell diseases) often have symptoms when they ingest something that has a lot of histamine in it or that causes the body to release histamine. There are two theoretical ways in which ingestion of histamine can cause symptoms: either the histamine released/ingested makes it way to other parts of the body and causes symptoms there directly; or, the histamine released/ingested makes mast cells release more histamine.

Regardless of exactly what is happening, patients with MCAS and histamine intolerance can have identical symptoms to ingesting a trigger. Importantly, MCAS patients may have histamine symptoms from lots of other things, not just ingesting something.

Histamine intolerance is much more commonly discussed in holistic and alternative medicine groups, which is definitely not where my expertise is. If you are aware of some recent data on histamine intolerance, or if I have made a mistake in this post, please let me know so that I can correct it.

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 40

49. What is the relationship between FPIES and MCAS?

FPIES is food protein induced enterocolitis syndrome, a severe type of food allergy. It causes continuous vomiting and diarrhea upon ingestion of a trigger. FPIES reactions can cause dehydration and dangerous drop in blood pressure. I cannot emphasize enough that FPIES can be extremely serious and that the reactions can be life threatening if they are not managed properly.

FPIES almost exclusively affects children starting in infancy and resolves around the age of 5. The reasons for this are unknown. FPIES is a diagnosis of exclusion. There are no tests to identify FPIES.

An important point is that trigger avoidance is generally sufficient for management in children with FPIES. When the child is not being exposed to a trigger, they should not have lingering symptoms.

If a child with FPIES continues to have symptoms, the conventional thinking is often that there must be a trigger that has not yet been eliminated from their diet. In children with continuing symptoms, they frequently have more traditional allergy type symptoms than the profuse GI issues seen with FPIES exposures. This is where FPIES starts to overlap with MCAS. MCAS can cause the same reactions to foods seen in FPIES. MCAS can also cause daily symptoms even if food triggers are avoided. Increasingly, children who were initially diagnosed with FPIES are later diagnosed with MCAS.

There are a few possible scenarios here. Firstly, it is possible that the child has FPIES and has MCAS secondarily to the FPIES. It is also possible that the child was misdiagnosed with FPIES and had MCAS all along. It may also be that FPIES is some form of MCAS. They have a lot in common.

Because there is no test for FPIES, and it is very difficult to accurately perform mediator testing to look for mast cell disease in infants, it is hard to be definitive at that age anyway. In some cases, investigation of MCAS as a possible diagnosis for these children only occurs when they fail to “grow out of” FPIES around age 5. Having anaphylaxis also provides a clue towards MCAS as a potential diagnosis.

For more detailed reading, please visit these posts:

Food allergy series: FPIES (Part 1)

Food allergy series: FPIES (Part 2)

Food allergy series: Mast cell food reactions and the low histamine diet

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