Mast Cell Activation Syndrome in a nutshell…

• 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

There are two general 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

While there is no “cure” for MCAS, 2/3 of patients will experience significant symptom relief once they find the right treatment combination that works for them.

The prognosis for MCAS vs. other types of MCAD are different. With cases of Mastocytosis or Mast Cell Leukemia, life expectancy may be shorter than average. However, with MCAS it appears that life expectancy is normal.

“Symptoms often initially manifest during adolescence or even childhood or infancy but are recognized only in retrospect as MCAD-related. Clinical features and courses vary greatly and range from very indolent with normal life expectancy to highly aggressive with reduced survival times.”

(Molderings et al 2011)

That being said, quality of life is clearly dramatically impacted by any form of MCAD. Many patients with MCAS have limitations in their ability to work and face hurdles in terms of receiving quality affordable care options. Most patients report significant financial and relationship stressors and have to alter their lifestyle significantly in order to reduce triggers.

“The lifespan for those with MCAS appears to be normal, but the quality of life can range from mildly impaired to severe discomfort, often to the point where patients are home-bound and unable to work.”

(Afrin, 2014)

Mainstream medical approach to MCAS treatment:

Patients begin by working with their doctors to identify medications that may help stabilize their symptoms. The trial and error process can take months or even years to find the right combination, dosage and brand. Keep in mind that many patients react to fillers/additives and may need to trial many versions of the same active ingredient before ruling it in/out.

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 additions to MCAS treatment:

Holistic care aims to address the root cause(s) and trigger(s) of the mast cell activation, and also strives to foster lifestyle modifications for long-term management. It’s important to create a care team that incorporates multiple areas for healing success (ie- doctor who focuses on MCAS such as hematologist or primary care doctor, physical therapist, allergist, acupuncturist, mental health specialist, naturopath, etc.) Some patients find symptom relief with more natural/herbal approaches to treatment, such as Quercetin.

It is strongly recommended to pursue care with a functional medicine doctor or naturopath who can help evaluate additional underlying causes contributing to or flaring the symptoms. This professional can help evaluate whether the following factors are present that may impede progress:

Heavy metal toxicity, mold toxicity, Lyme disease and co-infections, Ehlers Danlos Syndrome, POTS, Epstein-Barr Virus, parasites, poor integrity of the gut’s bacterial microbiome, adrenal and hormonal imbalances, thyroid issues, celiac disease or gluten intolerance, additional bacterial infections/viruses, and so much more.

Additional Tips:

• Prepare yourself for acute episodes
  • Obtain medical alert ID bracelet or necklace.
  • Carry emergency medications at all times and stash them in car, gym bag, etc.
  • Carry card or paper that summarizes medical instructions for the event of an ER visit. Include past medical history, emergency contact, conditions, and medication list.
  • Consider purchasing a mask to wear if needed for contact with smokers, perfumes, cleaning supplies, etc.
• Complete a thorough assessment of any and all potential triggers
  • Environmental
  • Dietary
  • Medication-based
  • Physical
• Assess environment for stealthy hidden contaminants (ie-mold in the walls of a building, 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 ways to assist your body in detoxification. This may reduce overall reactivity.
  • Epsom salt baths, sweating, and colonics may be useful.
  • Focusing on certain foods and supplements may help this process.
• Focus on a positive mindset and make sure to address any unresolved emotional trauma. Therapy, meditation, prayer, yoga, affirmations, reading and podcasts can all be helpful with this.
• Consider a temporary symptom log as you are adjusting foods and medications, to be discontinued once you find a stable baseline.

On the role of diet:

When patients are diagnosed they are often limited in the number of foods they can tolerate. Working with a nutritionist can help to ensure adequate nutrients and calories in the diet. 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 and made while factoring in other diagnoses too (such as SIBO or other gastrointestinal ailments).

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 because they read about them online or tend to react to aspirin. However, blind avoidance of salicylates can also be faulty (unless warranted by true allergic reactions). Salicylates are present in highest quantities in medications and beauty products and in small quantities in certain vegetables and plants.

Research is highly supportive of a plant-based diet for healing and overall wellness. Read more about this perspective HERE.

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.

There are many challenges alongside the diagnosis of MCAS, a condition which has only been coined for the last decade or so. There’s debate about the etiology of MCAS and the role of genetics, and appropriate universal diagnostic criteria and patient classification. We are lacking clear universal clinical guidelines for this patient population. The research is still in it’s infancy and there’s a great need for continued research to connect the dots between MCAS and other conditions as well. We can speculate based on studies about the role of mast cells in certain tissues and in conjunction with certain diseases, but there are still many holes and gaps in our knowledge and understanding of the disease.

In general, there exists a very real discrepancy between the management of patients by allergists as opposed to true MCAD specialists, and yet there are so few specialists in the United States, each of whom have lengthy wait lists and have barriers in terms of insurance coverage if you’re traveling from another state (and sometimes even if you have good same-state coverage). And globally, there’s a huge void of knowledge and acceptance of the condition in mainstream medicine, similar to the struggles of other conditions that are difficult to diagnose, like Lyme disease.

We need better diagnostic testing options and reinforced protocols or training of lab technicians to increase testing accuracy. We need better clinical screening tools, and the development of clinical prediction rules that could be more based on history and physical exam to assist in raising suspicion of the disease. We need specialty centers that provide holistic care.

In the US, we are often lacking insurance coverage of this disease, making it difficult to find adequate treatment and access to prescriptions needed. Some medications are not available at all and others are available at outrageous amounts. This is true for many diseases and some of what we need as a MCAS community is unfortunately dictated by the much bigger medical system picture.

Despite all of these challenges, there are a growing number of resources for the disease (see Resources and Reading List sections) and it’s slowly but surely gaining awareness, particularly in the realm of functional medicine doctors and naturopaths. These practitioners are wonderful resources for getting at the root issues that may be underlying or predisposing a patient to excess mast cell activation.

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