mast cell activation syndrome

MCAS: GI Symptoms and Liver Abnormalities

MCAS patients suffer a variety of GI ailments, which are largely in common with SM.

Aerophagia, excessive swallowing of air, is very common. It is not entirely obvious why this occurs. In other patient populations, aerophagia is usually due to poor coordination between swallowing and respiration. Severe cases can lead to abdominal distention, aspiration of stomach contents into the lungs and esophageal rupture.

Chest discomfort is common in MCAS. Cardiac issues should be ruled out, but in most people, it is due to esophagitis. Some patients have a previous diagnosis of reflux but it is refractory to all relevant treatments.

Diarrhea and constipation, sometimes alternative, are very common. In one study, 89% of MCAS patients studied had frequent nausea, 100% had abdominal pain of some nature, and 69% had noncardiac chest pain. Partial bowel obstructions are uncommon, but do occur in MCAS. They are thought to be due to focal dysmotility or focal edema.

IBS is a frequent previous diagnosis in MCAS. The GI tract often looks normal by eye and typical H&E staining shows mild inflammation. Staining for mast cells often shows they are increased. Of note, there is not a universal consensus on what is considered “increased mast cells” in GI samples. Generally, above 20 cells per hpf is marked as high by pathologists. Presence of the D816V CKIT mutation is rare in GI biopsies of MCAS patients.

Selective malabsorption of certain nutrients is often seen in MCAS. Iron malabsorption is by far the most common. Copper and B vitamins are often poorly absorbed as well. Protein calorie malabsorption is rare, but leads to weight loss and wasting.

Pancreatic enzyme supplementation can be helpful in treatment of diarrhea, weight loss and malabsorption. The fact that this often works suggests that MCAS driven inflammation or fibrosis causes pancreatic exocrine deficiency, a condition in which the pancreas does not make enough digestive enzymes. Mast cells have a known link to painful chronic pancreatitis. In patients with painful vs painless chronic pancreatitis, mast cell density is 3.5X higher in pancreas biopsy.

About half of MCAS patients have some kind of liver abnormality. Fibrosis (obliterative portal venopathy) is the most common. However, fatty metamorphosis, sinusoidal dilatation, venoocclusive dilatation, nodular regenerative hyperplasia and cirrhosis have also been seen. Sterile (non-infectious) inflammation of the liver and portal trial infiltration by lymphocytes and eosinophils has also been identified in a number of patients. In particular, these patients often have a 2-3X elevation in transaminases and/or alkaline phosphatase, determinants of liver function. Impeded flow of bile from the liver is usually absent. Portal hypertension is unusual but has occurred, causing swelling of the spleen and varices in the esophagus. Rarely, free fluid in the abdomen (ascites) has occurred in MCAS patients.

One study found that 75% of MCAS patients tested had high cholesterol levels. Importantly, 79% of patients had “normal” BMI or were underweight, so the high cholesterol was not correlated to weight. 44% had a twofold or greater elevation of liver enzymes. 36% had increased bilirubin in the blood. 15% had fatty liver; 13% had swelling of the liver; 4% had cysts; 4% had adenomas; 2% had hemangiomas. 14% of patients had pancreatic involvement with elevated lipase or amylase.

 

References:

Kirsten Alfter, Ivar von Ku gelgen, Britta Haenisch, Thomas Frieling, Alexandra Hu lsdonk, Ulrike Haars, Arndt Rolfs, Gerhard Noe, Ulrich W. Kolck, Jurgen Homann and Gerhard J. Molderings. New aspects of liver abnormalities as part of the systemic mast cell activation syndrome. 2009 Liver International 29(2): 181-186.

Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome. 2011. Mast Cells.

MCAD: General information for public

Mast Cell Activation Disorders (MCAD): Frequently Asked Questions

What are mast cell activation disorders?

They are a group of conditions  in which the mast cells in the body do not function correctly.  MCAD includes systemic mastocytosis, urticaria pigmentosa and mast cell activation syndrome, among other conditions. Mast cells are responsible for allergic responses. In MCAD, patients can have allergic type reactions to things they are not allergic to. These reactions can be very severe and even life threatening.

What are mast cell reactions?

These are reactions caused by mast cells being improperly activated. These reactions vary from person to person. Symptoms can include, but are not limited to, nausea, vomiting, hives, rashes, itching, flushing (turning red), dizziness, confusion and irritability. Symptoms are caused by the chemicals released by the mast cells.

What causes mast cell reactions?

Triggers vary from person to person. More common triggers include heat, cold, friction (especially on the skin), sunlight, foodstuffs, physical exertion, stress, dyes and fragrances. Triggers can also change over time, with new triggers presenting.

Are mast cell reactions dangerous?

YES. Many MCAD patients will experience uncomfortable reactions throughout their lives. However, every reaction carries the risk of anaphylaxis, a life threatening, severe allergic reaction. Therefore, avoiding reactions as much as possible is very important for mast cell patients. Each patient has an individualized response plan. For many, it involves removal of trigger and administration of medication, such as antihistamines or inhalers.

What is anaphylaxis?

Anaphylaxis is a severe allergic reaction affecting multiple organ systems in the body. These are the kinds of reactions observed in patients with bee sting allergies. Anaphylaxis can be fatal. It is a medical emergency requiring immediate treatment, usually epinephrine (Epipen.) Please receive guidance from treating physician on when to use an Epipen.

How are mast cell anaphylaxis and mast cell reactions different from normal allergies (like food allergies?)

With allergies, your body reacts by a specific method that involves ingesting and recognizing the allergen. In MCAD patients, the mast cells incorrectly think many things are allergens. Since mast cells are so sensitive in these people, ingestion of an allergen is NOT necessary to cause mast cell reactions or anaphylaxis. Smelling a perfume or breathing in very hot, humid air is enough to cause a reaction in many MCAD patients.

What causes MCAD?

Genetic mutations cause different kinds of MCAD. Recent studies have shown that mast cell disease can affect multiple members of the same family.

Why do some MCAD patients have spots?

These spots occur in locations where there are more mast cells than usual in the skin. These are NOT contagious rashes. In addition, MCAD patients who do not have permanent spots often have very sensitive skin, which may cause temporary marks or rashes.

How can I help an MCAD patient be safe?

By not being afraid of their disease. Respect their triggers and help them work around these limitations. Reactions can be painful and very scary, especially for kids. Learn the symptoms associated with reactions and be ready to help with a response plan.

 

Is there more information you feel should be included here?  Let me know in the comments and I can add it in.

MCAD, MCAS and the hierarchy of mast cell disease classifications

I have seen several posts recently expressing confusion about various mast cell diagnoses so I figured I would put up a post to clear things up.
Mast cell activation disorder (MCAD) is a catch-all term for mast cell disease (MCD.)  MCAD and MCD can be used interchangeably.  So if you have any mast cell disease, you have MCAD.  If you have SM, you have MCAD, because SM is a type of MCAD.  If you have UP, you have MCAD, and so on.  MCAD is an umbrella term.  It is non-specific.  It is similar to being told that you have heart disease when you have mitral valve prolapse.  It is true, but it is not precise enough to give all information needed to treat effectively.
Mast cell activation syndrome (MCAS) is the diagnosis you get if you do not meet the criteria for any of the defined mast cell diseases, but have mast cell mediator related symptoms.  You cannot have MCAS and another mast cell disease because, by its definition, MCAS is ONLY diagnosed if you do NOT meet the criteria for any other mast cell disease.  You cannot have UP and MCAS.  You cannot have SM and MCAS.  I think some people think that MCAS means you have mediator related symptoms.  This is not the case.  You can have mediator related symptoms with pretty much any mast cell disease. 
A paper was published a few years ago by a doctor who considers mast cell activation symptoms to be due exclusively to proliferation (like in SM.)  He wrote a paper that says that MCAS is found in people with SM.  This paper sort of confused the issue for a lot of people.  However, the mast cell community (including researchers and prominent doctors) do not consider this to be the case.  They agree that you cannot have SM and MCAS.
Also confusing is the fact that mast cell activation (MCA) is NOT the same as MCAS.  MCA just means that your mast cells are activated, which occurs in any mast cell disease.  MCA is not a diagnosis, it is a symptom.  So you can have MCA in SM.  But you still can’t have MCAS in SM.
So if you have SM and have lots of mediator related symptoms, you have SM.  If you want to speak broadly, you have SM.
If you test negative for SM and have no CM, but have mast cell symptoms and elevated mast cell markers, you have MCAS. 
If you have UP and then later develop SM, you have SM with skin involvement, or SM with UP. 
If you have UP or TMEP and have lots of mediator related systemic symptoms, you do NOT have UP and MCAS.  You have UP.  UP and TMEP (forms of CM) can cause systemic symptoms.  But you cannot have MCAS because you can only have MCAS if you do not meet the criteria for another mast cell disease.
Let’s review.
If you have UP: you have UP, you have CM, you have MCAD.
If you have TMEP: you have TMEP, you have CM, you have MCAD.
If you have SM: you have SM, you have MCAD.
If you have SM with UP: you have SM with skin involvement, you have UP, you have MCAD.
If you have SM with TMEP: you have SM with skin involvement, you have TMEP, you have MCAD.
If you have SM-AHNMD: you have SM-AHNMD, you have MCAD.
If you have ASM: you have ASM, you have MCAD.
If you have MCL: you have MCL, you have MCAD.

If you have MCAS: you have MCAD.

Reference:
Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J. Hematol. Oncol.2011; 4:10-17.

Diagnosis of mast cell diseases

There seems to be a lot of confusion regarding diagnosis of mast cell diseases, so I figured I’d do a review.

Cutaneous mastocytosis (CM) is diagnosed by skin biopsy.  Urticaria pigmentosa (UP), also called maculopapullar cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM) and telangiectasia macularis eruptive perstans (TMEP) are types of cutaneous mastocytosis.  They each present with a rash and may have accompanying systemic symptoms. 
Mastocytoma of the skin is also diagnosed by skin biopsy.
Systemic mastocytosis (SM) has the following diagnostic criteria:
Major:
1.       Multifocal, dense infiltrates of mast cells (15 or more in an aggregate) detected in sections of bone marrow and/or extracutaneous organ. 
Minor:
1.       In biopsy sections, more than 25% of mast cells in infiltrated area are spindle-shaped or have atypical morphology; or, of all mast cells in bone marrow aspirate smears, more than 25% are immature of atypical. 
2.       Detection of Kit mutation at codon 816 in bone marrow, blood or other extracutaneous organ.
3.       Mast cells in bone marrow, blood or other extracutaneous organ that co-express CD117 with CD2 and/or CD25.
4.       Serum total tryptase persistently >20 ng/mL (if there is not a clonal myeloid disorder.)
SM is diagnosed if a patient has either one major and one minor criteria, or three minor criteria.  So let’s look at how this plays out.
A patient with mast cell symptoms gets a bone marrow biopsy.  It shows more than 25% abnormal mast cells in the section.  They are CKIT negative, have a serum tryptase of 2, and do not express CD2/CD25.  They are diagnosed with SM.
A patient has a biopsy that does not show dense infiltrates.  All their mast cells are shaped normally.  In blood tests, their mast cells are found to express CD2.  They are CKIT+, also from blood.  Their serum tryptase is 28.  They are diagnosed with SM.
A patient has a biopsy that shows dense infiltrates, but they have less than 25% abnormal mast cells and their mast cells do not express CD2/CD25.  They are CKIT- and have a serum tryptase of 18.  They are not diagnosed with SM.
A few things to keep in mind:
Most people with SM are diagnosed by bone marrow biopsy, but a biopsy from any non-skin organ showing mast cell infiltration as described above can be used.  This means if you have a positive lung biopsy, liver biopsy, whatever, you may not necessarily need a bone marrow biopsy. 
It can take up to six bone marrow biopsies to diagnose SM in a patient who has had it the entire time.  This is because there is no way to know where the mast cells will cluster.  A negative bone marrow biopsy does not necessarily mean that you do not have SM.  Hence the minor criteria.
The CKIT test looks for a specific mutation, the D816V mutation.  There are other mutations found in codon 816.  You may have a mutation but test CKIT- because you do not have the D816V mutation.  Also, the blood test for CKIT is not always reliable.  The test way to test this is from a bone marrow sample.  You could test CKIT- in blood and then test CKIT+ in bone marrow.
The serum tryptase criterion refers to persistent baseline level tryptase, not reaction level tryptase. 
So let’s say you have a negative bone marrow biopsy and a blood test that shows you are CKIT+ and have mast cells expressing CD2/CD25.  What do you have?  You have monoclonal mast cell activation syndrome (MMAS.)  MMAS is diagnosed in patients who have one or two of the minor criteria for systemic mastocytosis.
Let’s say you have a negative bone marrow biopsy and blood work that shows normal mast cells and tryptase below 20, but you have systemic symptoms.  What do you have?  You probably have MCAS (mast cell activation syndrome.)  There are some other tests for that.  24 hour urine tests are usually done to measure the levels of histamine metabolites and prostaglandin D2 metabolites.
The following are the diagnostic criteria for MCAS:
1.       Episodic symptoms consistent with mast cell mediator release affecting two or more organ systems: skin (urticarial, angioedema, flushing); GI (nausea, vomiting, diarrhea, cramping); cardiovascular (fainting or near fainting due to low blood pressure, rapid heartbeat); respiratory (wheezing); naso-ocular (itching, nasal stuffiness, red eyes.)
2.       A decrease in frequency or severity; or resolution of symptoms with antihistamines, leukotriene inhibitors or mast cell stabilizers.
3.       Evidence of elevation of urinary or serum marker of mast cell activation: Documentation of elevation of marker during a symptomatic period on at least two occasions, or if baseline tryptase is persistently above 15 ng.  This includes urinary histamine and prostaglandin D2.
4.       Clonal and secondary disorders of mast cell activation ruled out.
MCAS is a diagnosis of exclusion.  It is the diagnosis you receive if you have mast cell symptoms that are ameliorated with mast cell medications if you do not meet the criteria for any other mast cell disease.
Back to SM.  Let’s say you’re positive for SM.  Now what?
They will determine if you have other important markers of disease severity.  These are called B and C findings.  They are as follows:
B findings:
1.       Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/ml).
2.       Hypercellular marrow, signs of overproduction or abnormal development of blood cells, normal or slightly abnormal blood counts that are not abnormal enough to be considered an associated hematologic disorder.
3.       Swelling of the liver that can be felt manually, no free fluid or signs of dysfunction, persistently swollen glands, swelling of the spleen that can be felt manually without signs of dysfunction.
If you have two or more B findings, you have SSM (smoldering systemic mastocytosis.) 
C findings:
1.       Unusual blood counts (low ANC, low Hb, low platelets)
2.       Swelling of the liver that can be felt manually, with impaired liver function, free fluid and/or portal hypertension.
3.       Large osteolytic lesions and/or pathological fractures.
4.       Swelling of the spleen with impaired function.
5.       Malabsorption with weight loss and/or low albumin.
If you have one or more C finding, you have ASM (aggressive systemic mastocytosis.)
How are these B and C findings identified?  Bone marrow biopsy, blood tests and imaging (ultrasounds, MRI, etc.) 
If you have SM and one B finding, or no B findings, you have indolent systemic mastocytosis (ISM.) 
If your bone marrow biopsy shows significant overproduction or abnormal development of a cell type that is not a mast cell, you may be diagnosed with SM-AHNMD (systemic mastocytosis with associated hematologic non-mast cell lineage disease.)  People with this type of SM also have another blood disorder, such as chronic myelogenous leukemia, myelodysplasia, etc.  In these patients, serum tryptase is not reliable to assess mast cell burden.  
Mast cell leukemia (MCL) is extremely rare.  It is diagnosed by >20% mast cells on the bone marrow aspirate smear.   
Mast cell sarcoma is a very aggressive form of sarcoma.  It is diagnosed by biopsy of the tumor.  People with these tumors quickly developed mast cell leukemia.  There have only been three cases reported in literature.  To be clear, this is NOT the same as mastocytoma.  Mastocytomas are benign.
I think I got everything.  Any questions?  Ask in the comments.

Mast cell disease in families

Three types of MCAD are currently known: systemic mastocytosis (SM); mast cell activation syndrome (MCAS); and mast cell leukemia (MCL).  SM and MCL are thought to be rare, while MCAS is now believed to be much more common, and possibly even the underlying cause of various clinical presentations (such as IBS and fibromyalgia.)  Very little is known about the heritability of these conditions , but many patients report that they have family members with similar symptoms. 

A study examining the familiality of MCAD found that 74% of patients interviewed had at least one first degree relative (parents, siblings, children) with systemic MCAD, regardless of MCAD subtype or gender.  The prevalence of systemic MCAD among first-degree relatives was 46%, while the prevalence in the control group is about 17%.  The prevalence of MCAD among first-degree relatives of patients with MCAS was 60%; with SM was 44%. 


MCAD subtype and severity of symptoms varied between family members.  Variable genetic alterations in CKIT were detected.  Activating CKIT mutations were found in 65% of patients, compared to 15% of the control group. The genetic mutations detected in the three families included mutations at position 816 of CKIT (D816G, D816V, S1A).  This finding is remarkable in that it disproves the longstanding belief that the somatic nature of KIT and related exon 17 mutations means that it cannot be inherited.  It also supports the belief that other mutations in genes that regulate mast cells could be contributing to these diseases.  Multiple mutations were sometimes found in the same patient, including those found in other genes (JAK2, TET2, DNMT3A, ASLX1, CBL, U2AF1, SRSF2, MS4A2). 


There was also no obvious relation between the CKIT mutations and clinical severity of MCAD.  Although familial occurrence due to shared environmental factors cannot be ruled out, it is likely that there is a significant genetic contribution to this phenomenon.  More females than males were affected.  The prevalence of MCAS was expected to be at least within the single-figure percentage range in the population (1-9%.) 


Systemic MCAD family histories include more systemic MCAD cases than would be expected when compared to the prevalence in the general population. This study advocates that the different subtypes of MCAD (MCAS and SM) should be more accurately regarded as varying types of the same disease rather than distinct diseases of mast cell dysfunction.


Reference:

Molderings GJ, Haenisch B, Bogdanow M, Fimmers R, No¨ then MM (2013) Familial Occurrence of Systemic Mast Cell Activation Disease. PLoS ONE 8(9):e76241. doi:10.1371/journal.pone.0076241

On prognosis and dying from mast cell disease


There isn’t a lot of data on death from mast cell disease.  Not real data, with statistics and numbers.  People with SM and MCAS are frequently reassured that they will live a normal life span.  People with SM-AHNMD are quoted an average survival of about 8.5 years; ASM, 3.5 years; MCL, under a year. 
Of those groups, only the survival time for mast cell leukemia is convincing to me.  This is because mast cell leukemia has a pretty homogenous presentation, meaning that it affects most people in the same way.  When a disease is as rare as MCL, it is important that you remove as many variables as possible in order for the data to be sound.  And that’s the problem with the rest of the survival data, to my eyes – there’s just too much variability.  Throw in a patient population as small as ours and you’ve got a lot of uncertainty.
The effects of mast cell disease are highly individualized.  There are several B and C findings, meaning that combinations of symptoms and manifestations are very variable.  The SM-AHNMD group is a good example of this.  This category lumps together many different combinations of diseases, not to mention the stages of those diseases.  Someone with ASM-AML is going to have a very different prognosis than someone with SM-CEL.  Simply averaging the lifespans of these people and quoting this as a life expectancy does the mast cell community a disservice.  It is important to remember this when you are typing “mast cell disease death” in the middle of the night. 
Even though we know that most people with SM die from something else, or that for many people, it is a very manageable disease, there is always the possibility that it will be different for you.  It’s hard not to imagine that you will be in the unlucky percentage of people that have progressive disease, that develop ASM, that have leukemic transformation.  Admonishing people who bring up this concern as “negative” or “paranoid” doesn’t make it less terrifying.  It just makes people more afraid to talk about the fact that sometimes people die from mast cell disease and often they aren’t sure how best to minimize their chances of becoming one of them.
Due to the differences in presentation, it has been difficult to identify markers that definitively indicate prognosis.  A lot of effort was put into looking at various CKIT mutations, not just D816V, to see if this could be predictive.  There has not been statistically significant data that this is the case.
The closest things we have to prognostic markers don’t get a lot of play in the general mast cell consciousness.  We talk a lot about CKIT because it affects treatment, and symptoms because it affects diagnosis.  But beyond the initial workup, we don’t often hear much about the CD2 and CD25 markers.  However, a paper published in 2009, established a link between “immunophenotype,” in this case which markers the cells present, and prognosis. 
This study looked at bone marrow samples from 123 patients with different types of SM, including MCL.  Importantly, they also had a large control group of people who did not have SM.  A solid control group is key to determining that a finding is real.  They defined the patients as either good-prognosis (SM, well differentiated SM, and cMAD, clonal mast cell activation disorder (what we now call monoclonal mast cell activation syndrome, MMAS)), or poor-prognosis (ASM and MCL.) 
They determined that for patients whose mast cells expressed BOTH CD25 and CD2 (ISM/MMAS) or NEITHER CD25 and CD2 (WDSM), prognosis was good.  However, mixed expression (typically CD25+ and CD2-) indicated a poorer prognosis.  They compared it to current markers, like the D816V mutation and serum tryptase, as well as clinical findings, like swollen spleen, swollen liver, skin lesions and white blood cell count.  The expression of markers was found to be a sounder method for estimating life expectancy than any of these.
It’s okay to be scared.  We all know people who have died from mast cell disease.  It is scary to think that we could be next.  It is scary to live under the looming threat of anaphylaxis.  But the good news is that science is trying to catch up.  More people are being diagnosed with mast cell disease, and science is getting better at identifying the ways that we are alike and different.  There is every reason to think we will have comforting data in the future.  We just have to get there. 


Reference:
Teodosio, Cristina, et al.  2009.  Mast cells from different molecular and prognostic subtypes of systemic mastocytosis display distinct immunophenotypes.  Journal of Allergy and Clinical Immunology, 125: (3), 719-726.