Mast Cell Activation Syndrome in a nutshell…

Symptoms reported in the literature for MCAS:

***I would argue that the vast array of symptoms experienced with these patients often stem from elevated toxic burden as opposed to one single cell type driving a dynamic response. Nonetheless, patients can experience very debilitating symptoms when the root causes of inflammation have not been addressed.***

Symptoms vary widely between patients. Typically, patients will exhibit:

• a history of waxing and waning, often “migratory” symptoms
• multi-systemic problems, often with multiple true co-morbidities and/or mis-diagnoses
• dermatographism of the skin due to the high concentration of mast cells located there
• a combination of acute episodes and chronic ongoing debilitating symptoms

Acute episodes that involve degranulation or release of certain chemicals from mast cells may include:

• an individual and unique spectrum, from a mild reaction to a full-blown anaphylactic response that requires epinephrine and other drugs alongside an emergency room visit.
• flushing or redness of the face, itching with or without hives on the skin, blood pressure drops, difficulty breathing, abdominal cramping, nausea, vomiting or diarrhea, nasal and eye symptoms, throat tightness or soreness, and headaches.

Common symptom triggers include:

• emotional stress, exposure to extreme temperatures, and exposure to certain environmental factors, medications or foods. Many patients are sensitive to things like (hidden) mold in buildings, perfumes, chemical odors and cleaning supplies, and shampoo and other hygiene products. Direct sunlight, exercise and mechanical vibration (like those experienced while sitting on a bus) are other common triggers. “Typical” allergens like pets, dust, and seasonal allergens may be frequent triggers. Many patients experience reactions to caffeine, alcohol, and food (often food that they’ve considered “safe” will suddenly trigger a reaction). Foods that are high in histamine, oxalates, dyes, additives or salicylates can also be problematic. There’s a subgroup of patients who are also highly sensitive to insect stings and bites.

Patients often have dozens of the following symptoms:

Cardiovascular signs: tachycardia (high heart rate), blood pressure irregularity (both high and low blood pressure), flushing (especially of the face), syncope (fainting) or pre-syncope (near-fainting), heart racing and blood pressure responses to positional changes, heart disease, intermittent chest pain

Respiratory signs: asthma-like symptoms, sinus inflammation, shortness of breath, cough, rhinitis (nose mucous inflammation), frequent upper respiratory infections and/or pneumonia, shallow breathing patterns/impaired use of diaphragm muscle for breathing

Gastrointestinal signs: bloating, diarrhea and/or constipation, nausea, vomiting, abdominal pain, intestinal cramping, abdominal distention, heartburn, malabsorption of nutrients, delayed gastric (stomach) emptying, H. pylori-negative gastritis (stomach lining inflammation), oropharyngeal burning pain (in middle part of the throat), aphthae (ulcers on the mouth or tongue), ilieocecal valve dysfunction (valve separating small and large intestine), non-cardiac chest pain, food sensitivities, Median Arcuate Ligament Syndrome “MALS” (structural compression of the celiac artery and possible neural structures resulting in abdominal ischemia and pain), microbiome bacterial issues including SIBO (small intestinal bacterial overgrowth)

Neuropsychiatric signs: difficulty with memory and concentration, anxiety, depression, insomnia (difficulty sleeping), lightheadedness, vertigo (sensation of the room spinning), headache and/or migraine, neuropathic pain (abnormal nerve-related pain sensations), polyneuropathy (degeneration of peripheral nerves), lower attention span, organic brain syndrome (decreased brain function due to a medical disease), tinnitus (ringing in the ears)

Ophthalmologic signs: conjunctivitis (pink eye), difficulty in focusing with vision, increased “floaters” in eye, intermittent blurred vision, general eye irritation and redness, decreased oxygen to optic nerve resulting in decreased ability to differentiate between contrasting shades

Organ Signs: hepatic splenomegaly (enlargement of both liver and spleen), hyperbilirubinemia (elevated bilirubin in the blood), elevation of liver transaminases, hypercholesterolemia (high cholesterol in the blood), Splenomegaly (enlarged spleen), Lymphadenopathy (lymph nodes enlarged, abnormal consistency or abnormal number)

Cutaneous Signs: urticaria pigmentosa (rash and itchy skin), flushing, hives, efflorescences (spots on skin) with/ without pruritus (itching), telangiectasia (red lines on skin from small blood vessels), flushing, angioedema (swelling of the lower layer of the skin), abnormal bleeding, frequent bruising, delayed skin healing from injury, abnormal sweating, abnormal body odor, hair loss

Musculoskeletal Signs: muscle pain and aches, osteoporosis/osteopenia (decreased bone mineral density), bone pain, migratory arthritis, fibromyalgia

Other Signs: fatigue, asthenia (feeling weak), fever, environmental sensitivities (odors, chemicals, vibration, animals, etc.), Interstitial cystitis (bladder pain and increased urinary frequency), unexplained weight loss or gain, poor tolerance to exercise, idiopathic anaphylaxis, sensitivity to sunlight and/or extreme cold and heat, odd reactions to insect stings, difficult menses (females), thyroid and adrenal issues, poor tolerance to medications or anesthesia, poor tolerance to alcohol, fermented foods, processed foods, and foods high in histamine

THE HOLISTIC WAY:

See “Look Upstream” for why I do not recommend patients devote too much time or resources to diagnosing MCAS. MCAS is a label, but if you use that time to uncover the root issues, you will get better faster.

In some cases, patients pursue an MCAS diagnosis to feel validated for their suffering (which is not a bad thing!) or to have documented evidence for a disability hearing. Every case is different, but in my experience, the sooner the patient begins to look upstream, the quicker they can reverse this condition.

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THE MAINSTREAM WAY:

There are two general mainstream schools of thought for the diagnosis of MCAS, presented below.

ONE PERSPECTIVE

One group of researchers first published diagnostic criteria for MCAS in 2011, and their recommendations have traditionally involved a combination of certain symptoms, results from extracutaneous tissue and/or bone marrow biopsies, elevated levels of certain mast cell mediators in the blood and urine, and (eventually) symptomatic response to mast cell-targeting treatments. Their diagnostic criteria have been modified various times over the years to the following set of most recent guidelines: (Weinstock et al. 2020)

Major Criterion:
After excluding of mimickers or alternative explanations of symptoms (differential diagnosis), the patient meets the major criterion of characteristics of mast cell activation in two or more systems:

• Constitutional: Fatigue, fevers, weight loss or gain
• Dermatological: Flushing, pruritus, urticaria, rashes
• Esophageal: Heartburn, dysphagia, globus, chest pain
• Eyes, ears, nose, throat: Conjunctivitis, tinnitus, hearing loss, rhinitis, sinusitis, sore throat
• Hepatic: Elevated transaminases, hepatomegaly
• Lymphatic: Lymphadenopathy
• Musculoskeletal: Myalgia, arthralgia, edema
• Neurological: Headaches, migraines, brain fog, anxiety, flushing, nausea
• Salivary Glands: Swelling
• Small & Large Intestine: Abdominal pain/discomfort, diarrhea, constipation
• Stomach: Dyspepsia
• Urogenital: Frequency, urgency, dysuria

Minor Criteria:

1. Elevation in the blood and/or urine of mediators relatively specific to the mast cell: (1) plasma prostaglandin D2 and histamine, (2) serum tryptase and chromogranin A, and (3) 24-h and/or random urine N-methylhistamine, leukotriene E4, and 2,3-dinor-11-ß-prostaglandin-F2-α.
2. Clinical improvement using mast cell-directed medical therapy.
3. Greater than or equal to 20 mast cells per high powered field in extracutaneous tissue (luminal gastrointestinal tract or bladder) biopsies.

Diagnosis of MCAS is made by the major criterion plus any one of the minor criteria.

The above diagnostic criteria suggestions have been revised multiple times over the years, and are based off a 2020 publication by Weinstock, Pace, Rezaie, Afrin and Molderings. Some of these authors previously advocated for the inclusion of additional minor criteria relating to KIT mutations, spindle-shaped mast cells and CD25 expression, but the authors state that these characteristics are no longer advised, as they are generally specific to systemic mastocytosis and not MCAS. These authors also note that most of their patients do not experience anaphylaxis, so it is not considered part of the diagnostic criteria. These authors support the use of the validated Mast Cell Mediator Release Syndrome (MCMRS) questionnaire that factors in the medical history, symptoms, laboratory assessment, biopsy results, and radiographic changes. They recommend that the mediator testing occur at baseline (when the patient is not experiencing an acute mast cell reaction) and be repeated within 1-6 hours of an acute attack if the original testing is negative and the suspicion of MCAS remains high. At current, negative mediator test results do not necessarily exclude the diagnosis.The approach of this criteria is sometimes criticized because diagnosis can be made based off subjective information (symptoms and response to mast cell-targeting treatment) alone.

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ANOTHER PERSPECTIVE

Another group has traditionally focused on the presence of typical clinical symptoms, a response to mast cell mediator-targeting drugs, the absence of another disorder that could account for symptoms, and either an increase in tryptase levels or (more recently) another established mast cell mediator for diagnosis. In October of 2019, many of these same authors published an article summarizing their perspective on the latest approach to the diagnosis of MCAS. Their clinical decision-making was outlined as the following: (Weiler 2019)

• If patients meet the following criteria,
• Recurrent symptoms consistent with mast cell activation with involvement of two organs, AND
• Elevation of 1 or more validated mast cell mediators (urine or blood testing), AND
• Response to targeted therapeutic interventions

then the patient should be evaluated for:
a genetic mutation in KIT* or TPSAB1 alpha-tryptase* (via blood test or buccal swab; bone marrow biopsy may be last resort in certain scenarios). If the patient tests positive for these tests, they should be classified to have Primary MCAS with a somatic or germ line genetic mutation. If the genetic testing is negative, the patients would be classified to have MCAS without a known mutation.

*TPSAB1 alpha-tryptase is a test for hereditary alpha tryptasemia. KIT mutations are part of the diagnostic criteria for systemic mastocytosis.

These recommendations were published in a 2019 article by Weiler, Austin, Akin, Barkoff, Bernstein, Bonadonna, Butterfield, Carter, Fox, Maitland, Pongdee, Mustafa, Ravi, Tobin, Vliagoftis, and Schwartz as part of a working group AAAAI (American Academy of Allergy, Asthma & Immunology) committee report. According to these authors, symptoms consistent with mast cell activation include different cardiovascular, dermatologic, respiratory and gastrointestinal signs. Mast cell mediators accepted by these authors as diagnostic include: serum tryptase, urinary n-methyl histamine, urinary 11 beta-prostaglandin F2 alpha (prostaglandin metabolite), and urinary leukotriene E4. These authors do not support using other mediators like heparin and chromogranin A.

The perspective of these authors clashes with additional suggestions published by the other group. For example, they assert that an increase in mast cell numbers in the gastrointestinal tract or elsewhere, by itself, should not be considered diagnostic of mast cell activation. Part of their explained rationale for determining whether a genetic mutation is present includes the notion that this information could improve the diagnostic tools and treatment options in the form of new therapeutic interventions that could target the mutated gene product or associated molecular pathway in the future for patients with MCAD. The authors stated that they believe this algorithm will help prevent over-diagnosis of patients with MCAS, and they voiced concern that some patients are being misdiagnosed with MCAS which misses a treatable condition unrelated to mast cells. They also expressed concern about the trend of other disorders (such as EDS, POTS, and may more) being used to diagnose MCAS “without scientific basis for being associated with mast cell activation.” (Weiler 2019)

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Keep in mind that…

1. Tests performed while flared or symptomatic are more likely to be positive.
2. Certain medications can influence the results of the tests. (see chart below)
3. If urine is not continuously chilled, the tests could provide a false negative.
4. Many patients require several rounds of testing before seeing a positive result.
5. The above criteria are only specific to MCAS. (The Mastocytosis diagnostic criteria are clearly outlined in the World Health Organization’s classification that was updated in 2016).

There are few centers in the U.S. that specialize in MCAS, and they often have long wait times. Patients are encouraged to seek a provider who is willing to work with them in this process, even if that person does not have a background in the disease. (Certain MCAS specialists may be willing to provide phone consults for other providers to assist). It often takes a ruthless search for that one practitioner who is willing to take a thorough history and get on board at finding the root issue. Many recent graduates in naturopathy and functional medicine are becoming well-versed in MCAS. Allergists and hematologists may also be a good resource, although some will only test tryptase in order to rule out Mastocytosis and won’t order the tests for MCAS.

Common Chemical Mediators Tested in Patients with Suspected MCAD:

Mediators should be measured at baseline and during an acute attack. One of the major drawbacks to mediator testing is that some labs do not recognize the importance of keeping the plasma and urine samples continuously chilled, potentially resulting in false negatives. For example, urine collection containers should be kept on ice or in a refrigerator, transported the the laboratory on ice, and frozen before it is shipped out.

Some authors assert that chromogranin A is a problematic marker as it resides in neuroendocrine cells. Heparin was previously mentioned by some researchers as a potentially useful mediator for MCAS testing, but limitations in commercial laboratory procedures in the United States currently prevent it from making the diagnostic cut. Further research is warranted to investigate whether platelet activating factor, heparin, chymase, or carboxypeptidase A3 are suitable mediators to include in future MCAS testing.

A thorough differential diagnosis process is also a very important part of the diagnosis of MCAS.

References:

1. Weinstock LB, Pace LA, Rezaie A, Afrin LB, Molderings GJ. Mast Cell Activation Syndrome: A Primer for the Gastroenterologist. Dig Dis Sci. April 2020:1-18. doi:10.1007/s10620-020-06264-9

2. Weiler CR, Austen KF, Akin C, et al. AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management. J Allergy Clin Immunol. 2019;144(4):883-896. doi:10.1016/j.jaci.2019.08.023

This condition is 100% reversible with the right approach. See “Look Upstream” for more info!

 The following information is not intended to be medical advice, and it is not all-inclusive. If you think you have MCAS, please consult your medical care team to come up with an individualized treatment plan.

Mainstream medical approach to MCAS treatment:

A patient may be prescribed a combination of the following types of medications:

• Emergency Medications for use in anaphylaxis
  • Ie) Auto-injectable Epinephrine, inhaled medications for airway, and diphenhydramine
• Medications that block the action of released mast cell mediators
  • Ie) Antihistamines (H1 and H2 blockers, diphenhydramine), leukotriene antagonists, TNF antagonists, IL-1 antagonists
  • Medications to address osteoporosis/osteopenia if present
• Medications that inhibit the release of mast cell mediators
  • Ie) Cromolyn (oral or inhaled), tyrosine kinase inhibitors, Omalizumab, benzodiazepines, cannabidiol
• Medications that inhibit the production of mast cell mediators
  • Ie) NSAIDS (with caution), steroids, Vitamin C
• Cellular therapy and stem cell transplants are very rarely used, and always in the case of aggressive MCAD.

***Holistic Approach to MCAS treatment:***

Holistic care aims to address the root cause(s) and trigger(s) of the mast cell activation, and strives to foster lifestyle modifications for long-term thriving. There are many herbal supplements that patients find helpful to prevent and reduce flares, such as Vitamin C and quercetin. Most patients benefit from a detoxification and drainage plan to help lower inflammation gently, and this can involve utilizing a toxin binder, minerals, bile flow and kidney and liver support, mitochondrial support, and much more.

Put some thought into who you want on your team. Patients may work with a combination of natural medicine practitioners, energy healers, physical therapists, allergists, acupuncturists, mental health specialists, craniosacral therapists, experts in visceral manipulation, sound healers, naturopathic doctors, oral myofunctional therapists, visual experts, vestibular specialists, etc. 

It is strongly recommended to pursue care with a foundational medicine practitioner who can look upstream to help evaluate additional underlying causes. (See: “Look Upstream” tab.)

Additional Tips:

• Avoid keeping meticulous logs about symptoms, nutrition, etc. This can feed into more hypervigilance.
• Assess environment for hidden contaminants and do your best to reduce exposure to everyday toxins (ie-mold in the walls of a building, radon, asbestos, chemicals in skin products and cleaning supplies, etc.)
• Evaluate your lifestyle/schedule and reduce as many daily stressors as possible.
• Ensure adequate sleep, clean drinking water, organic food, and HEPA-filtered air for maximal success.
• Consider non-supplement ways to assist your body in detoxification. Some patients do well with modalities like foot soaks and Epsom salt baths, mud and clay baths, castor oil packs, saunas, etc. 
• Tap into resources for emotional trauma and the autonomic nervous system with the help of a professional.

 Be cautious of the low-histamine diet!

When patients are diagnosed with MCAS, they are often limited in the number of foods they can tolerate. Many experts recommend elimination of processed foods, refined sugar, caffeine, grains/gluten, alcohol, and dairy.

Typically, a “low histamine diet” is very restrictive in addition to avoidance of food allergies in patients with MCAS. An elimination diet may be helpful in the first few weeks to determine exact triggers, but it’s unhealthy to make massive long-term unnecessary dietary restrictions. Identify what foods may trigger a true allergic reaction – and of course eliminate anything that triggers anaphylaxis.

There are many different types of eating plans for patients with chronic illness, and it’s important to remember that there is no single cookie-cutter approach that works best. Food decisions MUST be individualized.

Over time, when patients address TOXINS and PARASITES, food reactions stop occurring, and “allergies” and sensitivities tend to resolve.

When patients are first diagnosed, they often get bogged down with a list of high-histamine foods to avoid. It’s important to keep in mind that:

1. Histamine is one of the hundreds of mediators released by mast cells.
2. The website resources that cite histamine levels are very variable. There are a number of factors that influence how much histamine is present in different food sources.
3. Eliminating foods on the “high histamine list” blindly (without factoring in individual response to such foods) can eliminate healthy options that the body may need for healing, and often leads to a short and restrictive list of “safe foods”
4. It’s possible that our mast cells react to certain healthy foods sporadically because they are reacting to toxins (such as pesticides or preservatives) added to the food, or the way it was processed, and not necessarily the food itself.

Similarly, patients often avoid salicylates – oxalates – FODMAPS – night shades – lectins (etc. etc.) because they read about them online or had a practitioner tell them to cut them out. That can also be a slippery slope that limits options and may lead to disordered eating. It’s best to avoid what you know causes issues in your own body as opposed to following a list blindly. 

Also, the FEAR of a food may be more inflammatory to the body than the food itself… Something to think about!

Take-home message: be wary of a strict low histamine diet or the elimination of foods based on internet findings vs. your own body’s individual response. A diet rich in fruits and vegetables and minimal in inflammatory foods like grains, processed foods, dairy, alcohol, preservatives, and refined sugar should be encouraged for patients with MCAS. Just as you’re giving attention to what you’re putting in the body, make sure you’re maximizing efforts to help with elimination of triggers and detoxification in order to reduce the collective “bucket” of things that could trigger mast cell activation. Working with a holistic practitioner to identify all of the puzzle pieces is strongly encouraged.

Often, patients spend years testing for MCAS, then trialing antihistamines and medications slowly one by one to try and find something to reduce symptoms. However, over-the-counter and prescriptions often have side effects and only mask the symptoms. 

I often see patients in my practice who have been working with an MCAS specialist for 2-4 years on “stabilizing the mast cell,” but they are still very symptomatic. This can waste time and ultimately is a Band-Aid approach. (That being said, things that help patients stabilize initially in order to tolerate other activities or treatments or avoid severe reactions are not necessarily a bad thing. Where this becomes problematic is when that is the only thing they are doing.)

To free yourself from this condition once and for all, look upstream.

And I am NOT talking about working on SIBO, candida, cortisol, other hormones, Lyme and coinfections, gut dysbiosis, chronic viral concerns, etc. These are all opportunistic infections that clear up on their own with a root issue approach. Nutritional deficiencies are caused by toxins. Bacterial infections and overgrowth are the body’s way of trying to decompose toxins (a concept known as pleomorphism.) Look upstream beyond functional medicine! 

The 4 things I see have the biggest impact on clients who have been labeled with MCAS are:

1) Detoxification/Drainage support. (Working on constipation alone can dramatically reduce people’s symptoms!) There’s a fine art to helping the body  gently clear toxins, and this is the biggest common denominator in this patient community (and with all of chronic illness, for that matter.) It’s crucial to find a practitioner who has finesse in working with this condition, so that treatment is low and slow at first.

2) Help the body clear parasites, because parasites feed on and harbor toxins, so parasite work is a necessary extension of detox. Most people’s food sensitivities stop once we do this step. Again, make sure you are being guided by someone who knows how to do this the right way.

3) Work on the autonomic nervous system with a trauma-informed practitioner in a customized manner.

4) Work on emotional release and emotional healing. Let’s face it, we all need this. 

 It’s really that “simple.” 

MCAS (and so many other diagnoses) are reversible. This approach also tends to completely resolve POTS symptoms, and has a dramatic impact on collagen & connective tissue concerns in patients who have hypermobility spectrum disorders.