Expert Recap: Mast Cell Activation Syndrome (MCAS) and CIRS

Mast cells are immune cells that are concentrated in your gut lining, sinuses, lungs, skin, and urinary tract. When they detect a threat, they release a cascade of chemical signals to sound the alarm. Normally this works well: threat detected, alarm raised, immune system responds, threat resolved, alarm quiets down.

But in MCAS, the mast cells become hypersensitive and trigger-happy, responding to things that shouldn’t provoke a reaction at all. Every trigger sends another wave of histamine and inflammatory mediators through the body.

CIRS and MCAS are not separate, unrelated conditions that happen to share some symptoms. In many patients, CIRS is the upstream driver that keeps mast cells in a perpetual state of activation.

MCAS and Fatigue: Could Mold Be the Hidden Trigger?

Most patients bring their test results. Laura brought a handwritten log of everything she’d eaten in the past six months. Everything. Including a colour-coded scale that illustrated her reaction severity:

• Green: Good day
• Red: Most of the day in bed
• Yellow: Somewhere between the two.

In her six month diary, there was almost no green…

She’d been to an allergist, no significant allergies found. She’d done elimination diets with two different naturopaths. She’d cut out gluten, dairy, eggs, nightshades, and high-histamine foods in various combinations, and her symptoms still made no sense to her. Before it got really bad, on some days Laura could eat tomatoes without issue. Other days, a small amount would send her into a spiral of brain fog, joint pain, flushing, and exhaustion that lasted until the next morning.

“My reactions are completely random,” she told me. “Nobody can explain it.”

When I met her, Laura was eating only lamb. And it had to be cooked from frozen. No left overs. Ever. That was the only food she could tolerate.

When reactivity is this severe, it almost always points to MCAS. And in Laura’s case, as in so many patients I see, they pointed even further: to mold and the chronic inflammatory response that is generated from an exposure to biotoxins.

What Are Mast Cells, and What Do They Have to Do with Fatigue?

Mast cells are immune cells that live at the borders between your body and the outside world. They’re concentrated in your gut lining, sinuses, lungs, skin, and urinary tract. They are your body’s first alarm system. When they detect a threat, they release a cascade of chemical signals to sound the alert. Histamine is the one most people know, but mast cells also release tryptase, leukotrienes, cytokines, and over 200 other mediators.

Under normal circumstances, this is a beautiful system. Threat detected, alarm raised, immune system responds, threat resolved, alarm quiets down.

But in mast cell activation syndrome, the alarm system gets stuck in the on position. Mast cells become hypersensitive and trigger-happy, responding to things that shouldn’t provoke a reaction at all. Things like foods, scents, temperature changes, light, stress, minor chemical exposures. Every trigger sends another wave of histamine and inflammatory mediators through the body. And because the gut, brain, skin, joints, and nervous system are all involved, the symptom picture becomes almost impossible to untangle through conventional medicine’s organ-by-organ lens.

The fatigue piece is particularly significant. Histamine acts as a neurotransmitter as well as an inflammatory signal. When mast cells are chronically activated, that constant histamine load on the nervous system contributes to exhaustion that no amount of sleep touches. It is not motivational. It is biochemical.

Confusing MCAS Symptoms That Don’t Make Sense… Until They Do

The symptom pattern in MCAS is one of the most varied I see in my clinical practice. No two patients present identically. But when I look at the constellation, there is a recognizable shape to it.

Patients commonly describe:

• Fatigue that is disproportionate to activity, often with a post-exertional crash.
• Anxiety and depression that seem to come from nowhere and shift without explanation.
• Pain that moves — joints, muscles, bones — and doesn’t respond consistently to anything.
• Strange neurological symptoms including numbness, tingling, brain fog, and difficulty concentrating.
• Headaches.
• Ringing in the ears.
• Sensitivity to light, touch, food, smells, EMFs, and chemicals that is far beyond what seems reasonable.
• Skin reactions including flushing, hives, and rashes.
• Gut symptoms including bloating, cramping, diarrhea, and constipation.
• Sleep disturbance.
• Balance issues.

The breadth of that list is exactly why these patients have often been told their symptoms are psychosomatic. And it is exactly why a framework that explains the mechanism matters so much. Not for me as a clinician, but for the person sitting across from me who needs to know their experience is real.

A 2023 PMC study examining 544 MCAS patients found extensive overlap between MCAS and chemical intolerance, with mold, volatile organic compounds, and pesticides documented as common initiating exposures. This is not fringe research. It is published, peer-reviewed confirmation of what I see every week in clinic.

MCAS and Food Sensitivities

I want to come back to Laura’s journal for a moment, because it illustrates something I think is worth naming clearly. Food allergies and sensitivities are reproducible. If you have a genuine sensitivity to gluten, gluten will cause a reaction consistently. You can build a reliable mental map: eat this, feel bad. Avoid it, feel better.

MCAS doesn’t work that way.

With MCAS, the problem is not the food. The problem is the baseline state of the mast cells. On a low-stress day when the mast cells are relatively calm, a food high in histamine might cause no problem. On a day when the mast cells are primed by a poor night’s sleep, or mold exposure after visiting a friend in a heritage apartment building, or a stressful event, that same food tips the bucket over and you’re in bed for the afternoon.

This is why I always say that chasing food sensitivities in MCAS patients is like trying to bail out a boat without finding the hole. The food is not the root cause. The root cause is whatever is keeping the mast cells in a state of chronic activation.

And in a significant number of my patients, that root cause is mold.

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The CIRS and MCAS Connection: What Most Practitioners Miss

Here is where I want to be direct with you about something that I think is genuinely under-recognized, even among practitioners who know about both CIRS and MCAS.

Chronic Inflammatory Response Syndrome and mast cell activation syndrome are not separate, unrelated conditions that happen to share some symptoms. In many patients, CIRS is the upstream driver that keeps mast cells in a perpetual state of activation.

This is how it works.

CIRS is a dysregulation of the innate immune system triggered by exposure to biotoxins (things like molds, endotoxins, beta glucans, and actinomycetes).  In the approximately 24% of the population with susceptible HLA-DR gene variants, the body cannot properly clear these toxins. Instead, the biotoxins recirculate. The innate immune system stays activated. And one of the consequences of that chronic innate immune activation is ongoing stimulation of mast cells.

Dr. Theoharis Theoharides at Tufts University, who has published nearly 400 peer-reviewed papers and is among the most cited researchers in pharmacology and immunology. He has written extensively on the link between mold exposure and mast cell activation. His work helps explain why mold patients so consistently develop the histamine and chemical sensitivity picture that characterizes MCAS.

The clinical implication is important: if a patient has MCAS that was triggered or sustained by mold exposure and CIRS, treating only the MCAS is like treating only the smoke while the fire burns on. The mast cells will not fully stabilize until the underlying inflammation (CIRS) is addressed.

I watched this play out with Laura. First, we identified the source of mold in her apartment, which was a slow leak inside the wall behind her refrigerator that had been there for at least three years. Next, she moved out, started the Shoemaker Protocol, and worked on stabilizing her mast cells. For the first time, her food reactions became consistent. Not gone overnight, but patterned. Traceable. Manageable.

That is what treating the root cause does.

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How MCAS Is Diagnosed?

Diagnosis is genuinely difficult, and I want to be honest about why.

Mast cells release over 200 different mediators. Many of them,  including histamine, degrade within minutes of being released into the bloodstream. Catching elevated levels requires samples to be collected and handled precisely, and timing matters enormously. This is why patients can have textbook MCAS symptoms and still receive normal lab results.

I start with clinical picture. The symptom pattern described above, combined with the hallmark inconsistency of food reactions, already tells a significant story. If a patient fits the MCAS picture, I then investigate the following labs:

• Serum tryptase
  • The most stable mast cell mediator, and the one most likely to be detectable even with the handling limitations. Elevated total tryptase is one of the more reliable laboratory indicators.
• Urinary N-methylhistamine
  • A histamine metabolite measured in a timed urine collection. More stable than serum histamine and a better indicator of mast cell activity over time.
• Chromogranin A
  • a non-specific but useful marker elevated in mast cell disorders.
• Urinary leukotriene E4
  • Elevated in MCAS and helps confirm mast cell involvement in the inflammatory picture.

None of these tests in isolation confirms the diagnosis. The clinical picture, symptom response to mast cell-directed treatment, and identification and treatment of upstream triggers like mold exposure all contribute to a full diagnostic picture.

If MCAS is present alongside a history of building exposure, neurological symptoms, multi-system involvement, and the characteristic Shoemaker symptom clusters, CIRS biomarker testing,  including VCS testing, MMP-9, C4a, TGF-β1, MSH, and HLA-DR genetics,  is essential. Missing CIRS in an MCAS patient means missing the engine that is driving the whole process.

Why Food Alone Won’t Fix MCAS

I see a lot of patients who have spent years on low-histamine diets and felt marginally better but never well.

Diet matters. A low-histamine approach, or more practically, a lower-carbohydrate, higher-fat diet that naturally tends to be lower in fermented and aged foods, can reduce symptom load and take some pressure off the mast cells. It is a reasonable supportive measure.

But it will not treat the root cause.

If your mast cells are chronically activated because you are living in a water-damaged building, or because your innate immune system has been dysregulated by years of biotoxin exposure, dietary changes will produce partial improvement at best. The mast cells are not overreacting to your food. They are overreacting to everything because something more fundamental has knocked them into a state of chronic alarm.

Find the root cause. Then use diet to reduce the load while you treat it.

What Actually Helps: A Layered Approach

Treatment for MCAS works in layers. The first and most important layer is root cause identification. If mold is involved, and in my practice, it frequently is, removing the patient from the water-damaged environment and beginning the Shoemaker Protocol is non-negotiable. Mast cells cannot fully stabilize while the biotoxin exposure continues.

Beyond that, there are specific interventions that help calm mast cell reactivity while we get to work on the Shoemaker Protocol.

• Quercetin
  • This is the supplement I reach for first. A 2012 study published in PLoS ONE compared quercetin directly against cromolyn (a prescription mast cell stabilizer).  Quercetin outperformed cromolyn in blocking the release of IL-8 and TNF, and unlike cromolyn, quercetin works prophylactically rather than requiring co-administration with a trigger. It must be taken before meals to be effective.
  • 500mg thirty minutes before eating is where I typically start, working up gradually toward 2000mg per meal if tolerated.
  • The key thing to know about quercetin: it needs to be taken before the trigger, not after symptoms have started.
• Diamine oxidase (DAO)
  • DAO is the enzyme your body uses to break down histamine in the gut. In many MCAS patients, DAO activity is low which means dietary histamine accumulates instead of being cleared.
  • DAO enzyme supplements taken before meals can help bridge this gap while the root cause is being addressed.
• Addressing gut infections
  • Bacterial overgrowth (SIBO), intestinal fungal overgrowth, and parasitic infections all stimulate mast cells in the gut lining and amplify histamine reactivity. These are worth investigating via breath testing and comprehensive stool analysis if the gut symptom picture is prominent.
  • Just remember that sequencing is ever so important. Be sure to read this article on CIRS and gut health to find out exactly when and how to address gut infections.

A practical note on sequencing: for some patients, mast cell reactivity is so severe that every treatment attempt triggers a flare. If this is the case, I often work on calming the mast cells first before starting the deeper Shoemaker Protocol work. The mast cells need to be stable enough for the body to tolerate treatment. This is not delaying the real work; it is creating the conditions for the real work to be effective.

Just remember to ALWAYS start by checking your environment for biotoxins. If you’re living in a place that is causing ongoing exposure, there aren’t any remedies that are going to offer relief.

What I Want You to Take Away

If you have been sick for a long time with symptoms that don’t fit neatly into any diagnosis. If your food reactions make no sense. If you have been told you’re anxious or stressed or that your labs are normal, please hear this:

There is likely a mechanism behind your suffering. It may be MCAS. It may be CIRS driving MCAS. It may be both, with a biotoxin exposure at the root of the whole picture.

You do not have to keep chasing individual symptoms or trying increasingly restrictive diets in hopes that one combination will finally work. The answer is not the diet. The answer is upstream.

If you want to know whether mold might be involved in what you’re experiencing, start with our free mold illness quiz. If the picture fits, book a discovery call with our team. We take the time to work through your story; not just the symptoms in front of us, but everything that might have set them in motion.

You’ve been managing this long enough. Let’s find out what’s actually driving it.

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Mark Volmer, FMP, is a certified Shoemaker Protocol practitioner and Clinical Director of Flourish Clinic in Cochrane, Alberta, specializing in CIRS, mast cell activation syndrome, chronic fatigue, and complex chronic illness.