Mast cell activation syndrome (MCAS) is a collection of symptoms resulting from mast cells in the body releasing inflammatory mediators too frequently and too often. High levels of these mediators can cause symptoms of an allergic reaction, such as itching, mucus, and inflammation.

Mast cells are an important part of the immune system and are found throughout the body in connective tissue, including the skin, the lining of the stomach, intestine, and other areas. Because of the widespread physiological function of mast cells, MCAS has the potential to affect many different organ systems. When mast cells are dysregulated in MCAS, they release an overabundance of chemicals, including histamine.

MCAS may be involved in multiple conditions, and increased mast cell activation symptoms can vary from allergic reactions, such as anaphylaxis, to more chronic symptoms, including depression or osteoporosis. (1) A recent study indicates that MCAS affects as much as 17% of the general population.

MCAS can be challenging to diagnose because it has similar symptoms to other conditions, and the criteria for diagnosis are not currently standardized. (2),(3) As research on MCAS continues, we hope to learn more about the root cause, diagnosis, and best treatments over time.

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Mast Cell Activation Syndrome Signs & Symptoms

The release of mediators due to mast cell activation can impact almost every part of the body. Symptoms of MCAS can vary from mild to life-threatening and most often include the gastrointestinal tract, skin, nervous system, and heart. A full list of symptoms is extensive, covering all body systems, and has been published based on studies and survey data. Individuals may have one predominant symptom or may have many overlapping symptoms.

20 Common Symptoms of Mast Cell Activation Syndrome (MCAS)

Mast Cell Activation Syndrome Possible Causes

The functional medicine model seeks to address the root cause of disease and promote wellness, as opposed to only treating symptoms. MCAS has no definitive cause, but a combination of factors, including genetics, gut health, diet, and total toxin load, can have an additive effect and contribute to symptoms.

Genetics

Because the condition can occur in family groups, it is thought that there may be a genetic element to MCAS. Genetic single nucleotide polymorphisms, or SNPs, that play a role in histamine and mast cell function include:4

• HNMT (histamine N-methyltransferase) plays a key role in degrading histamine and in regulating the response to histamine.  
• ALDH (aldehyde dehydrogenase) helps reduce histamine metabolites after being converted by DAO and HNMT.
• MAO-A (monoamine oxidase A) helps break down dietary compounds, including histamine (found in aged cheese, cured or smoked meat and fish, pickled or fermented vegetables, alcoholic drinks, chocolate, soy products, and shellfish).
• DAO (D-amino acid oxidase) The accumulation of histamine directly impacts inflammatory responses, and DAO deficiency has been linked to histamine intolerance.
• Duplication of the α-tryptase–encoding sequence in TPSAB1 has been associated with increased serum tryptase levels. Researchers have found that this genetic mutation links three overlapping conditions: Ehlers-Danlos Syndrome (EDS), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS).

Toxins

We are exposed to more chemicals in our food, environment, and products than at any other time in history. Chemical, food and drug intolerances are all growing concerns in today's current environment. These intolerances have been shown to trigger mast cell activation in individuals. Mast cells are also activated by many substances, such as mycotoxins (toxins from mold), medications, infections, stress-related triggers, smells (ex., smoke or perfume), insect bites, and reptile venoms.

Notably, Chronic Inflammatory Response Syndrome (CIRS) has been studied in relation to MCAS. Many individuals with CIRS have genes that reduce the ability to clear toxins from the body, which can lead to chronic activation of mast cells. Recent data also shows the prevalence of mast cell activation symptoms in individuals with Long-COVID.

Gut Health

A growing body of research shows a correlation between gut health and MCAS. Leaky gut syndrome, SIBO, dysbiosis, and candida have all been shown to influence mast cell activation and increase histamine production.

Gastrointestinal symptoms are one of the most frequent symptoms of MCAS. This is not surprising due to the high presence of mast cells in the gut, which are a major component of the immune system. Mast cells drive inflammatory mediators, and a diet high in inflammatory foods can set the stage for inflammation to occur. This can contribute to leaky gut, dysbiosis, immune reactions, and food sensitivities. Removing inflammatory foods and assessing gut health is essential in addressing the root cause of MCAS.  

Vitamin D Deficiency

Vitamin D deficiency is involved in many immune conditions, including mast cell disorders. Vitamin D is required to maintain the stability of mast cells. In one study, mast cells automatically increased in a Vitamin D-deficient environment. The researchers concluded that a deficiency of Vitamin D could result in mast cell activation in susceptible individuals.

How is Mast Cell Activation Disorder Diagnosed?

Mast cell activation disorder (MCAD) is an umbrella term that encompasses both mastocytosis and mast cell activation disorder (MCAS). MCAS is different from mastocytosis. Mastocytosis is a rare disorder characterized by accumulating too many mast cells in organs.

An American Academy of Allergy, Asthma & Immunology work group report proposed the following criteria for diagnosing MCAS:

• Recurrent, severe symptoms (ex. anaphylaxis) that affect at least two organs
• Medications that block the effects or release of mast cell mediators reduce or resolve symptoms
• Blood or urine tests taken during an episode show elevations of markers for mediators than when not having an episode

Diagnosing MCAS is complex and does not rely on any one test but instead will take into account a complete medical history, symptom presentation, medical exam, and blood or urine tests for elevated levels of mediators. Bone marrow tests may also be used to differentiate between MCAS and mastocytosis.

Other tests can be used to rule out all possible causes of symptoms. For example, inflammatory bowel disease, autoimmune diseases, reactions to environmental toxins, allergic reactions, and food sensitivities can all have overlapping symptoms with MCAS and should be considered on an individual basis.

Functional Medicine Labs to Test for Root Cause

Metabolites Often Elevated in MCAS

There are over 200 mediators released when mast cells degranulate, but only a few are measurable. Testing is also complicated by temperature, as many of the mediators can disappear within a few minutes at room temperature.

Two reliable markers offered through Rupa Health that can be used to gain information about an individual's mast cell function are Tryptase and Histamine.

Tryptase is useful in determining mast cell activation in diseases such as anaphylaxis, mastocytosis, urticaria, and asthma. An increase from normal (<10–15 ng/ml) to greater than 20 ng/ml can indicate mast cell activation.

Histamine is a chemical released by white blood cells into the bloodstream when the immune system is defending against a potential allergen. Basal plasma histamine concentrations of 0.3 to 1.0 ng/mL are considered normal; elevations above this can indicate mast cell involvement.

11B -Prostaglandin F2α (11B-PGF2α), Prostaglandin D2, Leukotrienes C4, and E4 Leukotriene E4 (LTE4) are also valuable tests in the diagnosis of MCAS; however, the availability of these lab tests are more limited at this time.

Genetic Testing

Knowing if there is a genetic predisposition to histamine overload contributing to mast cell activation can be helpful. 3x4 Genetics Test + Blueprint Report provides information about an individual's overall histamine balance and tendency toward histamine overload using a pathway approach for the body's systems, as well as information on the following individual SNPs: HNMT, ALDH, MAO-A, and DAO. A trained 3x4 practitioner can help with the interpretation of this panel.

Heavy Metal Toxicity

Metals Hair Test can help screen for physiological excess, deficiency, or maldistribution of elements. Elevated heavy metals have been shown to destabilize mast cells.

Mold and Mycotoxins

MycoTOX Profile is a comprehensive mycotoxin test. It uses advanced mass spectrometry to screen for eleven different mycotoxins, from 40 species of mold, in one urine sample.

Vitamin D

Vitamin D deficiency is very common and has been shown to activate an increase in mast cells. Supplementation is warranted if levels are below the functional range.  

Comprehensive Stool Test

A Comprehensive Stool Test can help identify parasites, other infections, and dysbiosis that could be contributing to mast cell activation. In addition, the GI-MAP includes a few markers explicitly related to histamine.

Functional Medicine Treatment for Mast Cell Activation

Nutrition

Utilizing a low-histamine diet can be very beneficial in managing symptoms of MCAS. This diet limits foods high in the chemical histamine, which mast cells release when they are activated. It is important to note that histamine is also only one of the mediators produced in MCAS, and the root cause of mast cell activation should continue to be addressed for the best health outcome.

A low-histamine diet can serve as an essential diagnostic tool. The individual's tolerance can be observed by eliminating histamine-rich foods from the diet for several weeks and then gradually adding them back in. For optimal results, remove high histamine foods for 30 days and reintroduce foods one at a time.  

Foods high in histamine:

• Fermented dairy products, such as cheese, yogurt, sour cream, buttermilk, and kefir
• Vegetables naturally high in histamine include tomatoes (including ketchup), eggplant, spinach, and mushrooms, and vegetables that are fermented or pickled such as sauerkraut and kimchi or pickles.
• Fruit, including citrus fruit, banana, pineapple, avocado, and any overly-ripe fruits.
• Meat that is cured or fermented, including sausage, bacon, salami, and fermented ham.
• Fish that are naturally high in histamine include shellfish, tuna, mackerel, mahi-mahi, anchovy, sardines, herring, bluefish, amberjack, and marlin.
• Bone broth and collagen can trigger a histamine response.
• Alcohol such as wine, beer, cider, malt beverages, hard seltzer, and champagne
• Fermented soy products, including tempeh, miso, soy sauce, and natto
• Fermented grains, such as sourdough bread
• Kombucha is a fermented drink made with tea, sugar, bacteria, and yeast.
• Vinegar, especially red wine vinegar, which is very high in histamine
• Yeast and yeast extracts are found in many prepared products.
• Artificial preservatives and food dyes can trigger a histamine response in some.
• Leftovers will have higher histamine than freshly prepared foods. The bacteria that produce histamines will increase over time, especially with meat, but this also occurs with vegetables to a lesser degree.

In addition to removing foods high in histamine for symptom relief, a functional medicine approach to MCAS would allow the body to heal itself by reducing inflammation and stabilizing the mast cells. Consider choosing foods that are not only low-histamine but also nutrient-dense and anti-inflammatory while simultaneously addressing the individual root cause(s) of MCAS.

It should be noted that it is difficult to determine the histamine content of foods. The SIGHI food list is a comprehensive printable guide that is commonly used.

Some nutrient-dense foods low in histamine include:

• Fresh meat
• Freshly caught or frozen seafood that is low in histamines like cod and salmon (avoid canned seafood)
• Non-citrus fruits
• Eggs
• Grains, such as quinoa and rice
• Dairy substitutes, including coconut milk and almond milk
• Fresh vegetables except for tomatoes, avocados, mushrooms, spinach, and eggplant
• Healthy fats, such as olive oil and nuts

Supplements

Many individuals can reduce symptoms of MCAS through diet alone, while others may find additional relief through the use of supplements or medication.

Some supplements that may be of help include:  

• ‍Diamine oxidase (DAO) is the major enzyme that breaks down histamine. DAO enzyme supplements taken before meals have been shown to help improve histamine-related symptoms and reduce their intensity by increasing histamine breakdown. Foods that block DAO production include high histamine foods, alcohol, black tea, green tea, mate tea, and some energy drinks.‍
• Vitamin C may help to support histamine degradation. High levels of Vitamin C can also increase DAO levels. Note: Avoid Vitamin C produced via fermentation.‍
• Quercetin has been shown to stabilize the membranes of mast cells and reduce the release of histamine. ‍
• Magnesium deficiency has been shown to induce the emergence of mast cells. ‍
• Zinc, in adequate amounts, is important for its role in mast cell signaling and regulating mast cell function.‍
• Vitamin D is required to maintain the stability of mast cells, and a deficiency has been shown to activate them.‍
• Probiotics have been shown to help breakdown histamine through the use of specific species of bacteria, including Bifidobacterium adolescentis, Bacteroides thetaiotaomicron, Bacteroides fragilis, and Lactobacillus rhamnosus.

Herbs

• The Traditional Chinese Herbal Formula Shuang-Huang-Lian has been comprehensively studied and shown to be a potent inhibitor of mast cell activation. The herbal formula consists of the following three herbs Lonicerae Japonicae Flos, Scutellariae Radix, and Fructus Forsythia.
• Other herbs and spices have been studied to reduce histamine reactions, including chamomile, thai ginger, nettle, moringa, and turmeric.

OTC Medications

In addition, over-the-counter medications are sometimes necessary to reduce symptoms during the healing process. Always work with your healthcare provider when taking medications for MCAS. These treatments should be temporary due to possible side effects and may include:

• H1 or H2 antihistamines block the effects of histamines, which are one of the primary mediators that mast cells release.
• Cromolyn sodium can be used as a mast cell stabilizer.
• Aspirin may decrease flushing by blocking the production of prostaglandin D2.
• Corticosteroids (like hydrocortisone) are sometimes used to treat edema or hives.

Avoid Chemicals & Toxins

Various microbes and toxins can disrupt the immune system and cause mast cells to increase. Toxins include heavy metals like lead, mercury, and cadmium, industrial chemicals and pollutants, pesticides, and mycotoxins (volatile-organic compounds released by certain types of mold). These can be in our water, air, and food supply. They can also include chemicals in everyday household products, including cleaning products, body products, and makeup. Exposure to many toxins, even at low levels, can add up over time.

Summary

While more research is needed to understand the mechanisms of MCAS, working with a practitioner specializing in this area can be very beneficial. The root cause can vary depending on the individual, and it is often necessary to use a process of experimenting with various methods to find the best path to successful results.

For individuals with MCAS, it is essential to reduce the body's total microbial, chemical, and toxin burden, while at the same time alleviating symptoms through diet and lifestyle changes. This could mean eliminating sources of toxins, choosing low-histamine foods, limiting inflammatory foods, healing the gut, and supporting the body through targeted supplements.

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