The Connection Between EDS and Mast Cell Activation Syndrome (MCAS)

Estimated reading time: 8 minutes I received my diagnosis of hypermobile EDS because of MCAS, which is probably not the usual route. Back in 2016, I started having a number of symptoms that no doctor could explain. One of the main symptoms was repeated bladder infections and bladder irritability. This went on for 18 months, along with other symptoms like headaches, flushing, rashes, and increased sensitivity to foods and smells I had previously tolerated.  I was becoming sicker and sicker with repeated infections and inflammation.

I am forever grateful to the urogynecologist who recognized MCAS immediately. I literally cried in his office after so many doctors had dismissed me. He provided a clinical diagnosis of EDS based on observation of my hypermobile joints. I went home that evening with a stack of information about MCAS and a diagnosis of hEDS. I realise now that I probably had symptoms of MCAS all my life, but they had become something I learnt to live with.

But what exactly is MCAS?

To find out more, I asked Linda Bluestein, MD to share her expertise on MCAS. She will be joining The Zebra Club members for our September monthly meet-up to explain more about how to manage this condition.

Reminder, this blog post is for educational purposes and does not replace or provide specific medical advice.

What is Mast Cell Activation Syndrome (MCAS)?

Mast cell activation syndromes (MCAS) are a group of disorders related to the inappropriate activation of mast cells (1). This results in abnormal mediator (chemical messenger) release which causes inflammatory, allergic, and dystrophic (abnormal tissue growth) changes in the body (2).

Mast cells (MCs) are a type of immune cell exclusively found in the tissues of the body where they collect around nerves, blood vessels, and lymphatic vessels (3). These cells normally play a role in maintaining tissue repair and coordinating defensive immune responses to a wide range of pathogens like bacteria, viruses, and environmental toxins (3). Mast cells are essential for life and are located where we interface with the outside world (e.g.: skin and mucus membranes). Here they are ideally positioned to respond when our tissues are being attacked by pathogens.

Mast cells have receptors on their surface that respond to a wide variety of molecules. These include pathogens, immune mediators (like antibodies and complement), hormones, toxins, and physical stimuli (e.g.: air pressure, vibration, low oxygen, or temperature) (3).

Once activated, they degranulate and release messenger substances called mediators. There are hundreds of different mediators including histamine, heparin (involved in clot prevention), proteases (enzymes that break down proteins), prostaglandins, leukotrienes, and a range of cytokines and chemokines (immune signaling molecules), and more (3). The type of mediators released depends on which receptors are activated and where the MCs are located. This leads to the recruitment of other immune cells to trigger responses like tissue remodeling and wound healing (4).

These normally tightly regulated immune cells can be involved in mast cell activation diseases (MCAD). MCAD involves repeated episodes of MC mediator release in various organ systems (5). MCAD includes conditions like allergic illnesses (IgE-specific signaling that activates MCs)(3), mastocytosis (excess number of MCs), and mast cell activation syndrome (MCAS). MCAS refers to abnormal activation of the mast cells, but the number of mast cells is normal (6).

The mechanisms that allow MCs to protect us can also wreak havoc when poorly controlled (7). Because mast cells contain hundreds of different mediators and are found in nearly every tissue of the body – including connective tissue – this can lead to a wide range of symptoms. Symptoms range from trivial to life-threatening (8).

Photo: Microscopic image of a mast cell full of granules (stained purple) surrounded by muscle fibers (stained purple).

What causes MCAS?

There are three types of MCAS (3).

• Primary MCAS: This results from a genetic alteration in the mast cells resulting in a clonal population of mast cells (genetically identical cells).
• Secondary MCAS occurs due to another disease or condition (e.g.: immune deficiency, IgE-dependent allergy, and environmental exposures). Treating the underlying cause is an important part of a successful treatment plan.
• The third type is idiopathic MCAS. This involves nonclonal mast cells, yet other diseases or causes have been excluded.

What are the symptoms?

Symptoms caused by mast cell activation can occur in any part of the body, including the skin, the gastrointestinal tract, the cardiovascular system, the respiratory system, the musculoskeletal system, and the neurological system (1). The symptoms can range from mild to life-threatening in the case of systemic anaphylaxis (8)

Patients with MCAS can present with a wide variety of symptoms, many of which are not exclusive or even highly specific to MCAS. These symptoms can also be waxing, waning, and migratory making diagnosis challenging. Symptoms that may be associated with MCAS include (6):

• Flushing
• Fatigue
• Dermatographism – when light scratching of the skin leads to inflamed lines or welts
• Cognitive dysfunction
• Irritation of the eyes, nose, mouth, and/or throat
• Allergic type issues
• Shortness of breath
• Palpitations
• Nausea
• Gastroesophageal reflux
• Abdominal pain
• Diarrhea – sometimes alternating with constipation
• Gynecological symptoms (interstitial cystitis, vulvovaginitis, heavy menstruation, menstrual pain)
• Fibromyalgia-type pain
• Headaches
• Dysautonomia
• Anxiety and mood disorders
• Metabolic and endocrine issues
• Persistent pain (especially nociplastic pain)

Common triggers of mast cell activation include (3,9):

• Temperature: Heat, cold, or sudden temperature changes
• Emotional stress
• Physical exertion
• Fatigue
• Food or beverages, including alcohol
• Drugs (opioids, NSAIDs, antibiotics, and some local anesthetics) and contrast dyes
• Natural odors, chemical odors, perfumes and scents
• Insect venoms
• Infections (viral, bacterial or fungal)
• Mechanical irritation, friction, vibration
• Invasive procedures (general anesthesia, biopsy, endoscopy)
• Sun/sunlight

What is anaphylaxis?

Anaphylaxis is a serious and acute systemic (whole-body) reaction that can occur in response to systemic mast cell degranulation. This is a life-threatening condition that can lead to airway obstruction and cardiac arrest if not treated promptly (9). Anaphylaxis is likely when there is an acute onset of illness (minutes to several hours) and two or more systems are involved. Low blood pressure or airway involvement may occur but are not required for the diagnosis or treatment.

Symptoms may include:

• Integumentary symptoms: skin or mucosal tissue (e.g.: hives, itching, flushing, swollen lips or tongue)
• Respiratory symptoms: shortness of breath, wheezing, bronchospasm, low oxygen, stridor
• Cardiovascular symptoms: low blood pressure
• Gastrointestinal symptoms: vomiting or persistent painful cramps

How is MCAS diagnosed?

Unfortunately, considerable disagreement remains in the scientific community about how MCAS is diagnosed.  One set of diagnostic criteria states (6):

1. “Must have symptoms consistent with chronic MC activation that is aberrant (abnormal).”
   1. This can be constitutive (ongoing) or reactive to some identifiable trigger. Some have both. Sometimes these occur in periodic flares.
2. “Must have signs/symptoms of aberrant (abnormal) MC activation in multiple (at least 2) organ systems”
3. Must (with reasonable confidence) not have some other disease accounting for the range and duration of MC activation symptoms.

Other criteria add that symptoms must respond to treatment that prevents either MC degranulation or MC mediators like histamine receptor blockade, mast cell stabilizers, leukotriene antagonists, and 5-lipoxygenase inhibitors (4, 5).  Most specialists agree that MCAS can be diagnosed when there are (a) typical symptoms, (b) abnormal lab findings, and (c) treatment response (4).

Urine can be used for diagnosis by measuring mediators that include:

• N-Methylhistamine
• 2,3-Dinor 11 Beta-Prostaglandin F2 Alpha
• Leukotriene E4
• Prostaglandin D2

A note on tryptase

Tryptase is an enzyme that is found in basophils and mast cells. It can be used as a marker of MC degranulation. An elevated serum tryptase (compared to a baseline level) helps establish an MCAS diagnosis, but this cannot always be demonstrated. Mast cell degranulation does not always result in tryptase release, and tryptase is extremely thermolabile (temperature sensitive). Tryptase should be measured as soon as possible following a “flare” (increased symptoms) and may need to be drawn on multiple occasions (ideally each time within 30-120 minutes of flare onset). Due to the temperature sensitivity, the specimen should also be processed in a refrigerated centrifuge and transported on ice (3).

Other laboratory evidence can include serum prostaglandin D2, heparin, histamine, and chromogranin A. Urine mediator testing is normally collected for 24 hours and must also be transported on ice. The diagnostic process for MCAS continues to evolve.

Photo: Illustration of a degranulating mast cell.

Is MCAS Connected with EDS?

Researchers have demonstrated an extraordinarily high MCAS diagnosis rate in patients with hEDS (3,10,11, 12) and unusually high rates of hEDS in patients with MCAS (11, 13,). Other MC diseases also appear more common (e.g.: eosinophilic gastrointestinal disorders, asthma, food allergy, and venom allergy) (3). Mutations in the gene that encodes alpha-tryptase (TPSAB1) have been found in some studies of people with MCAS. One study demonstrated that 28% of people with this mutation had hypermobility (14).

There are multiple theories as to why MCAS and EDS are connected and more research is needed.

How to Best Manage These Conditions

Treatment starts with the identification of triggers and exposure modification. Some MCAS patients experience symptom reduction following the removal of potential triggers such as:

• Fragrances and unnecessary chemicals.
• Opioids, antibiotics, NSAIDs, and alcohol-containing medicines
• Excipients, the “inactive” ingredients in medications or supplements, include fillers and capsules.
  • Many of these substances are known triggers of mast cell activation so “reactions to medications” can be the medication (e.: active ingredient) or can be due to an excipient.Working with a pharmacist can help determine the most likely culprit(s).

Many patients respond well to reducing foods that are known to have higher histamine levels. Working with a dietician well-versed in MCAS can be very helpful. This video with Lorna Ryan may be helpful. Histamine-rich foods you may want to experiment with reducing include:

• Avocado
• Citrus
• Chocolate
• Dried Fruit
• Tomatoes
• Spinach
• Canned or smoked fish
• Aged cheese
• Alcohol
• Eggs
• Nuts
• Cured meats
• Leftovers (especially ones with meat)

Psychologic stress can exacerbate MCAS symptoms (15). Addressing stressors and modulating the nervous system are important components of any comprehensive treatment plan. Breathing exercises and activities that incorporate the breath are helpful – including videos found in The Zebra Club. Neural retraining programs like the Gupta Program, Primal Trust, DNRS (Dynamic Neural Retraining System), and SmartBody SmartMind can be helpful. These companies often have books, instructional videos, and free information on their websites. Many patients improve dramatically with programs like these.

Medications and supplements that you can speak with your medical providers about include:

• Antihistamines – H1 and H2
• Cromolyn sodium (nasal, inhaled, or oral)
• Low dose naltrexone (an opioid antagonist)
• Leukotriene antagonists (e.g.: montelukast and zafirlukast)
• Aspirin
• Flavonoids (e.g.: quercetin or luteolin)
• Vitamin C
• Glucocorticoids
• Monoclonal antibodies like omalizumab (XOLAIR®)

When Should I Seek Professional Advice?

Anyone who suspects they may have symptoms related to MCAS should seek a medical evaluation.  Medical gaslighting unfortunately is still common amongst patients with hEDS, HSD, and MCAS so finding a professional with the appropriate knowledge and background can be challenging. Treatment can alleviate symptoms and improve quality of life though so should be sought whenever possible.

Dr. Linda Bluestein, MD, is a multifaceted professional renowned for her expertise in hypermobility disorders. As the founder of Hypermobility MD, she offers specialized medical care to individuals grappling with these conditions. Dr. Bluestein is the driving force behind Bendy Bodies, a coaching practice aimed at empowering and supporting individuals with hypermobility and related conditions. She is also the host of the esteemed podcast, “Bendy Bodies with the Hypermobility MD.” Dr. Bluestein actively engages in advocacy and research serving on the Allergy and Immunology Working Group for the International Consortium on EDS and HSD, the Medical Advisory Board for Standing up to POTS, and the Board of Directors for the Bridge Dance Project. Furthermore, she chairs the Pain Management Committee for the EDS Research Foundation and contributes to the Resources Committee for the Dance Healthy Alliance of Canada. As an assistant professor at the Medical College of Wisconsin, Central Wisconsin, Dr. Bluestein has played a pivotal role in directing the RISHI Healer’s Art Program, nurturing compassionate healthcare providers.

For more information about Dr. Bluestein and her comprehensive approach to hypermobility care, please visit her website and listen to her podcast.

Literature Review by Catherine Nation, MSc, PhD

Works Cited

1. Bonamichi-Santos & Castells (2016) Mast Cell Activation Syndromes. Current Treat Options Allergy.
2. Afrin (2021) Some cases of hypermobile Ehlers–Danlos syndrome may be rooted in mast cell activation syndrome. American Journal of Medical Genetics Part C: Seminars in medical genetics
3. Seneviratne, et al. (2017) Mast cell disorders in Ehlers-Danlos syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics.
4. Brock, et al. (2021) Mast cell activation disease and immunoglobulin deficiency in patients with hypermobile Ehlers‐Danlos syndrome/hypermobility spectrum disorder. American Journal of Medical Genetics Part C: Seminars in Medical Genetics.
5. Monaco, et al. (2022) Association of mast-cell-related conditions with hypermobile syndromes: a review of the literature. Immunologic Research.
6. Afrin et al (2021) Diagnosis of mast cell activation syndrome: a global “consensus-2”. Diagnosis.
7. Molderings & Afrin (2023) A survey of the currently known mast cell mediators with potential relevance for therapy of mast cell‑induced symptoms. Naunyn-Schmiedeberg’s Archives of Pharmacology
8. Afrin, et al. (2016) Often seen, rarely recognized: mast cell activation disease–a guide to diagnosis and therapeutic options. Annals of Medicine.
9. Gulen, Theo (2023) A Puzzling Mast Cell Trilogy: Anaphylaxis, MCAS, and Mastocytosis. Diagnostics.
10. Chang, A. R., & Vadas, P. (2019). Prevalence of Symptoms of Mast Cell Activation in Patients with Postural Orthostatic Tachycardia Syndrome and Hypermobile Ehlers-Danlos Syndrome.Journal of Allergy and Clinical Immunology
11. Mathias, et al. (2021) Pos 1366 The relationship of Mast Cell Activation Syndrome and Hypermobile Ehlers-Danlos Syndrome in Hospitalized Patients in the United States. Annals of the Rheumatic Diseases.
12. Wang, et al. (2021) The relationship between mast cell activation syndrome, postural tachycardia syndrome, and Ehlers-Danlos syndrome. Allergy and Asthma Proceedings.
13. Afrin, et al. (2017) Characterization of Mast Cell Activation Syndrome. American Journal of Medical Science.
14. Lyons, et al. (2016). Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nature Genetics.
15. Theoharides, Theoharis (2020) The impact of psychological stress on mast cells. Annals of Allergy, Asthma, and Immunology.

Jeannie Di Bon

Jeannie Di Bon is a movement therapist, educator and author specializing in hypermobility, Ehlers-Danlos Syndrome and chronic pain. She is the founder of The Zebra Club app and the creator of the Integral Movement Method.