Reviewing “Mast Cell Activation Syndrome: A Primer for the Gastroenterologist”

By Christopher H — October 15, 2025

It hurts my heart every time my partner gets sent to doctors who have had little experience with EDS, POTS, MCAS, and CSF leaks because more often than not, she is dismissed or treated as if she is seeking attention, as if she has concocted a slew of unlikely symptoms for some reason or another. And there are times when she is heard, but the medical complexity is so great that the doctor has no chance of seeing the forest through the trees. Misdiagnoses occur, and we are passed from one doctor to the next and the next, and so on. Each time, we repeat the process.

I know in my heart and my mind that if we had the correct team behind us, we could get a handle on things. A case manager would connect each of the experts on our team, making sure everyone was conscious ahead of time, of the role being played by EDS, POTS, MCAS, and the CSF leaks. Sometimes the discussion might occur where the case manager actually has to explain to the hernia specialist exactly why anesthetics and mesh can’t be used for this particular person with severe mast cell reactions. And then our team would innovate and get creative to find a fitting and adequate solution. For most of us, that is not reality.

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The Paper Reviewed

Mast Cell Activation Syndrome: A Primer for the Gastroenterologist

Leonard B. Weinstock, Laura A. Pace, Ali Rezaie, Lawrence B. Afrin, Gerhard J. Molderings

Digestive Diseases and Sciences (2020)

Before even making it past the introduction of the paper, the authors addressed the fact that many people with MCAS have symptoms that can seem to be “...inexplicable or even bizarre to a practitioner new to MCAS.” They immediately describe the challenges and how, indeed, a multidisciplinary approach is best for the diagnosis and management of MCAS. The paper was written to increase awareness among other medical professionals. What I like is that it primes the gastroenterologist for what to expect and explains some of the reasons behind the factors that might cause a doctor to cringe at the sight of a patient’s medical records.

Mast cell activation syndrome is a disease that affects one or more—usually more—of the systems in our body. Because it affects so many systems and in so many ways, people with MCAS are sometimes written off as being “difficult GI patients.” Many of the symptoms a patient might have throughout the systems are highlighted using tables. Specifically, the gastrointestinal symptoms include:

• Nausea and/or vomiting

• Heartburn

• Abdominal pain

• Atypical chest pain

• Alternating diarrhea and constipation

• Diarrhea

• Constipation

• Trouble swallowing due to the esophagus

• Oral symptoms or sores

My own partner’s whole diet has been affected by MCAS, and she is now restricted to a very plain diet with almost no variety. In the other systems, MCAS symptoms can appear as:

Summary of organ systems and related symptoms in mast cell activation syndrome (MCAS).

Adapted from Weinstock, L. B., Pace, L. A., Rezaie, A., Afrin, L. B., & Molderings, G. J. (2020). Mast cell activation syndrome: A primer for the gastroenterologist. Digestive Diseases and Sciences, 65(12), 3509–3520. Springer. DOI: 10.1007/s10620-020-06259-9.

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Mast Cell Activation Disease

The section titled Mast Cell Activation Disease touches on a topic of interest among some of the ZebrasAndSpoons community. The authors point out a controversy around diagnosing MCAS. Basically, there are two schools of thought, and in one, there is a misunderstanding that:

1. There is an increase in the serum tryptase level.

2. Anaphylaxis, as well as an increase of tryptase from its baseline, is necessary in making a diagnosis of MCAS.

But this is not the case! The absence of an anaphylactic reaction does not mean that you do not have MCAS. And if you would like to explore this particular tidbit more, see the following research:

P. Valent, C. Akin, P. Bonadonna, et al.

Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome.

J Allergy Club Immunol Pract 7 (2019) 1125–1133

L. Afrin, M. Ackerley, L. Bluestein, et al.

Diagnosis of mast cell activation syndrome: A global “consensus–2.”

Diagnosis (2020)

The authors go on to discuss mast cell function, pathophysiology, and pathology. These sections describe the roles mast cells play as well as the effects caused by the mediators released as part of their function. Mast cell mediators are released in reaction to allergens, tissue trauma, and infection—but when mast cells abnormally activate, these mediators can cause symptoms like tachycardia, and so on.

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Part 2 — Mast Cells, Comorbidities, and the EDS–POTS Connection

This leads me to ask so many questions! Does MCAS cause POTS? And why do MCAS, EDS, and POTS always seem to accompany each other as comorbidities? We can go over the math in another Research Review (we definitely will), but to sum it up—no pun intended—POTS and EDS seem to occur roughly in about 25% of the people with MCAS. The three occurred together in about 15% of the people with MCAS. Crazy, right? But here is why people with Stealth Syndrome (the EDS trifecta) can feel like their previous lives are completely unattainable.

Let’s talk about comorbidities.

The authors describe an evil version of rock–paper–scissors (these are my own words). Postural Orthostatic Tachycardia Syndrome (POTS) is a disorder of the autonomic nervous system (ANS). People with POTS can experience an abnormal increase in their heart rate when sitting upright without the appropriate corresponding decrease in blood pressure. Now, POTS has been known to affect people with nausea, heartburn, abdominal pain, bloating, constipation, and diarrhea. Hmmm... Where have I just seen these symptoms? Yep! These are gastrointestinal symptoms in MCAS.

As well, when mast cell mediators are released near the nerves of the autonomic nervous system, POTS flares can happen. Conversely, POTS, being a dysfunction of the autonomic nervous system, can alter your gastrointestinal permeability as well as vascular permeability, and either of these by themselves can lead to abnormal mast cell activation. So it seems that POTS and MCAS have the ability to feed off one another!

Next, Ehlers–Danlos Syndrome is basically a group of connective tissue disorders, and when the mast cells release chymases, excess extracellular matrix remodeling can happen. This isn’t such a big deal until you consider the fact that it might increase tissue laxity (tissue “looseness”) in people with EDS for whom this is already a problem. The authors note that this vicious cycle “...is difficult to break without aggressive intervention which addresses all comorbidities conditions simultaneously.”

So what does a diagnosis look like? The authors explain the criteria as follows. You must have:

1. (Major criteria)

Mast cell activation symptoms in two or more of the systems given in the symptoms table.

2. (Minor criteria) One or more of:

a. Elevation in the blood and/or urine of mediators specific to the mast cells.

b. Clinical improvement using mast cell-directed medical therapy.

c. At least 20 mast cells per high-power field in extra cutaneous tissue.

Item c refers to luminal gastrointestinal tract or bladder biopsies, and it seems like a CD–117 stain is performed on the biopsies to detect the increased levels of mast cells. However, one of the wonderful things about this paper is that it includes the validated Mast Cell Mediator Release Syndrome (MCMRS) questionnaire, which greatly helps in leading to a diagnosis of MCAS.

I can only speak for myself in saying that, if it were me, I would get my doctors to read this paper, fill out the questionnaire in hopes of receiving a mast cell directed medical therapy. …But that would be my own preference. The wonderful thing is that many people don’t know what the options actually are, and when we do know, then we have the luxury of picking what works best for our needs!

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Part 3 — Managing MCAS and Advocating for Hope

The authors then talk about managing MCAS. Basically, treatment involves a whole lot of identifying MCAS triggers so that you can avoid them, and on top of that, mast cell mediator production is controlled. Since the avoidance of triggers is so important, “elimination diets” can play a big role. See the paper:

G. Molderings, B. Haenisch, S. Brettner, et al.

Pharmacological treatment options for mast cell activation disease.

Naunyn–Schmiedeberg’s Arch Pharmacol. 389 (2016) 671–694

Histamine-, gluten-, and dairy-protein-free diets have also been recommended based on clinical experience.

Here are the pharmacological therapies, listed in a number of steps:

• First-line therapy: A non-sedating H1 histamine receptor antagonist once to twice daily, and an H2 histamine receptor antagonist once to twice daily. These histamine receptor antagonists block receptors to mast cells and other cells throughout the body, which cause symptoms.

• Second-line therapy: This can include montelukast, which is a leukotriene receptor antagonist. This can be taken by itself or with oral cromolyn sodium, which is a mast cell stabilizer. It’s not uncommon for symptoms to worsen in the first few days of taking cromolyn, which is consistent with what happened when my partner began her cromolyn treatment.

• Third-line therapy: This might include ketotifen, which is a second-generation H1 antagonist with anti-inflammatory effects, though I’m not 100% sure it’s even approved yet by the U.S. FDA for oral use.

• Fourth-line therapy: This can include omalizumab, which should be administered by allergists and other doctors familiar with MCAS.

This article can be a powerful ally in your own journey. The authors really did a great job in advocating in a way that promotes awareness to the doctors which we must inevitably visit.

So here are my afterthoughts: This article was excellent, because it can save us years of searching for the doctor that is willing to face overwhelming medical complexity. Imagine what it might look like if you were to purchase a copy of this paper from Springer (the publisher) and bring it with you on your medical trips. The questionnaire alone is priceless, because together with this article the two can serve as a means for achieving mast cell-directed medical therapy, or at the least, it might inspire your doctor to learn what you need them to know the most.

To any of you on a quest for a better quality of life, whether for yourself or for your partner, this paper can signify a step in the right direction. I am my partner’s advocate, and my greatest aspiration is to live in a way that brings light into her world. I see the way she struggles with things I can sometimes take for granted, like getting dressed and grocery shopping. Our life is a careful balance of care and progress… The two do not always have an intersection, but our progress is always in pursuit of a better quality of life.

I hope that this review will inspire some of you to advocate for the ones you love—the ones who might have a struggle of their own. We can’t just sit and watch as an invisible illness takes precious years from the ones we love.

So I will say this: If you are the spouse of a person with chronic illnesses, then be their strength when theirs is gone. Show honor in the face of adversity and give them hope by finding answers. But most importantly, stand at their side during the pain and give them consistency, compassion, and your love.