Mast Cell Activation Syndrome (MCAS)

Mast Cell Activation Syndrome (MCAS) is a little-known but significant condition affecting the immune system. The syndrome belongs to the group of mast cell disorders and is characterized by an overreaction of the body’s mast cells – cells that are normally activated to protect us against potentially harmful stimuli. In MCAS, mast cells respond inappropriately, often without any known trigger, and symptoms may vary greatly both between and within individuals. The condition is frequently mistaken for other diseases, which means it may remain undiagnosed for many years¹.

Immune Response Out of Control

Normally, mast cells are activated in response to allergens, heat, pressure, or infection. This can occur through either an IgE-mediated or non-IgE-mediated mechanism¹. The mast cells then release various pro-inflammatory substances such as histamine and prostaglandins to initiate a local immune reaction². In people with MCAS, this activation occurs excessively or inappropriately – without any other explanation for the reaction².

Three Types of Mast Cell Activation

There are three main forms of MCAS³:

Monoclonal (primary):– Caused by a genetic abnormality, often mutations in the KIT gene or aberrant expression of CD25/CD2– Associated with increased mast cell production, and also seen in systemic mastocytosis

Secondary (non-clonal):– Normal number of mast cells, but overactivation due to allergic reactions– May be IgE- or non-IgE-mediated

Idiopathic:– No known cause can be identified– Likely the most common form– Patients may show features of more than one type simultaneously¹

In severe cases, the condition can lead to systemic reactions and anaphylaxis.

Clinically Relevant Anatomy

Mast cells are granulated immune cells formed in the bone marrow and found in most tissues, particularly in the skin, connective tissue, intestines, and airways⁴. They are often located near blood vessels and the lymphatic system. Inside mast cells are mediators – such as histamine, leukotrienes, prostaglandins, tryptase, and cytokines – which are released upon activation⁵⁶.

For survival, mast cells must bind to stem cell factor (KIT), a transmembrane tyrosine kinase receptor⁷. Once they migrate to a tissue, they mature based on local signals such as interleukins (IL-3, 4, 9) and TGF-β1⁸⁹.

Two main mast cell types are distinguished:– MCT (tryptase): Found in connective tissue, skin, and peritoneum– MCTC (tryptase and chymase): Found in the intestines and airways⁸

Physiology and Pathology

Mast cell immune responses are triggered through different receptors: for IgE, estrogen, ATP, mechanical pressure, and toxins. Upon stimulation, mediators are synthesized and released, leading to increased inflammation, vasodilation, itching, pain, and in severe cases, circulatory collapse⁵⁶¹⁰.

In addition to their role in immune defense, mast cells are also involved in:– Tissue homeostasis– Phagocytosis– Cytokine production– Regulation of blood vessels and lymphatics¹¹

They reside within tissues, surrounded by blood vessels, nerves, and lymphatics – explaining why MCAS can cause such widespread and systemic symptoms.

Clinical Presentation

The symptom profile in MCAS is highly variable and depends on which mediators are released as well as which organ systems are affected. Reactions may change over time and vary with repeated exposure to the same stimulus. Many patients experience symptoms from the gastrointestinal tract.

Common Symptoms

Common symptoms include⁵¹²:

• Skin: Flushing, itching, rashes, lesions

• General: Fatigue, headaches, body pain

• Skeletal: Osteoporosis, bone pain

• Gastrointestinal: Bloating, abdominal pain, nausea, diarrhea, GERD

• Respiratory: Throat swelling, shortness of breath

• Circulatory: Cramps, hypotension, bleeding problems

• Lymphatic: Enlarged lymph nodes, weight loss

Common Correlates and Overlapping Conditions

Frequently associated conditions include¹¹¹²¹³:

• Ehlers–Danlos syndrome

• Postural Orthostatic Tachycardia Syndrome (POTS)

• Autoimmune diseases

• Celiac disease and gluten intolerance

• Fibromyalgia-like pain

• Neurological and psychiatric symptoms

• Chronic sinusitis and skin conditions

These correlations may raise suspicion but are not diagnostic criteria in themselves.

Diagnostic Criteria

Diagnosis of MCAS requires the following three criteria¹¹¹³:

1. Systemic symptoms involving at least two organ systems

2. Detectable mast cell activation (e.g., elevated tryptase)

3. Response to mast cell–targeted treatment

Tests Used

• Serum tryptase: Sample taken within 4 hours after reaction and compared to baseline. Interpretation requires that levels exceed baseline by 20% + 2 ng/ml.

• Urine tests: For mediators such as N-methylhistamine, prostaglandin D2, leukotriene E4.

• Treatment response: Symptom relief from antihistamines or mast cell stabilizers supports the diagnosis.

• Endoscopy: May show mast cells in the intestine but rarely used routinely.

Treatment and the Role of Physiotherapy

Treatment is aimed at reducing symptoms and limiting mediator release:

• Antihistamines (H1- and H2-blockers)

• Mast cell stabilizers (cromolyn)

• Leukotriene antagonists

• Corticosteroids for severe episodes

• Elimination diet when food reactions are suspected

• Reduction of psychosocial stress

Physiotherapy’s Role

Physiotherapists play an important role, especially in the following areas:

• Stress management and breathing: MCAS patients may develop dysfunctional breathing patterns (e.g., hyperventilation) that worsen symptoms. Breathing techniques and relaxation can reduce reactions.

• Adapted physical activity: Regular exercise may help stabilize immune responses and support overall health.

• Awareness of hypersensitivity: When treating patients with EDS, POTS, or autoimmune conditions, physiotherapists should keep MCAS in mind as a differential diagnosis.

It is also important to understand the link between trauma and mast cell disorders – particularly in women’s health. Physiotherapists can act as bridges to other services and provide reassurance throughout the patient journey.

Challenges in Diagnosis

Diagnosing Mast Cell Activation Syndrome (MCAS) is difficult due to the highly variable symptom profile. To establish the diagnosis, three criteria must be met¹¹¹³:

1. Systemic symptoms involving at least two organ systems

2. Objective evidence of mast cell activation (biochemical markers or cell increase)

3. Clinical response to mast cell–targeted treatment

Organs Commonly Involved in MCAS

• Ear, nose, and throat

• Gastrointestinal tract

• Cardiovascular system: dizziness, inflammation, unstable heart rate

• Skeletal system: bone pain, osteoporosis

• Skin: rashes, flushing

• Urinary tract: bladder irritation

Tests and Measurements

Serum tryptase: Gold standard. The blood sample must be taken within 4 hours of symptom onset, and levels must be >20% above baseline + 2 ng/ml. If no baseline is available, a new sample must be taken 24–48 hours after the episode¹¹.

Urine tests: Should be analyzed within 24 hours for mediators such as N-methylhistamine, prostaglandin D2, F2α, and leukotriene E4⁵.

Treatment response: If symptoms are reduced after treatment with mast cell stabilizers, this supports the diagnosis – even when objective findings are lacking.

Endoscopy: May detect mast cells in the GI tract but is rarely used diagnostically due to its invasiveness.

Treatment and Management

Treatment consists of both medication and lifestyle measures. Identifying and avoiding triggers is essential – but often difficult, as reactions can be unpredictable. Stress is a well-known aggravating factor and should be addressed systematically¹³.

In IgE-related MCAS, immunotherapy may be considered¹⁴–¹⁶.

Pharmacological Treatment

• H1-antihistamines: Relieve acute symptoms such as itching, rashes, and headaches

  • 1st generation: hydroxyzine, diphenhydramine, doxepin, ketotifen

  • 2nd generation: cetirizine, fexofenadine, loratadine

• H2-antihistamines: Stabilize mast cells and relieve GI symptoms

  • famotidine, cimetidine

• Mast cell stabilizers and glucocorticoids: Reduce symptoms such as brain fog and GI issues

• Tyrosine kinase inhibitors: Broad effect on mast cells and IgE response

• High-dose aspirin: For elevated prostaglandins (brain fog, flushing, bone pain)¹⁷–¹⁹

Treatment must be individually tailored and often combined to achieve effect¹⁸.

Differential Diagnoses

Because MCAS resembles many other conditions, thorough differential diagnostics are required¹³. Relevant conditions include:

• Infections

• IBS and celiac disease

• Adrenal insufficiency

• Cardiovascular disorders

• Psychiatric and neurological conditions

• Endocrine diseases

• Toxic reactions

Other mast cell diseases that must be excluded:

• Systemic mastocytosis (SM)

• Cutaneous mastocytosis (CM)

• Smoldering systemic mastocytosis (SSM)

• Hereditary alpha-tryptasemia (HaT)

Relevance for Physiotherapy

MCAS patients often have many everyday triggers – several of which may occur in clinical practice. Physiotherapists should therefore be aware of factors such as:

• Physical activity (exertion)

• Temperature changes

• Friction, vibration, and pressure

• Medications (opioids, NSAIDs, local anesthetics)²⁰–²²

Patients should also be protected from known allergens, food intolerances, emotional stress, and infections.

MCAS, Connective Tissue and Autoimmunity

Mast cells are present in connective tissue and are believed to play a role in conditions such as Ehlers–Danlos syndrome (EDS) and Hypermobility Spectrum Disorders (HSD). It has been hypothesized that mast cell mediators – such as tryptase and histamine – affect fibroblast proliferation and collagen synthesis²³²⁴.

Several clinical similarities exist between MCAS and hEDS/HSD, and recognizing this relationship may help physiotherapists identify undiagnosed patients²³.

Urticaria and Autoimmune Conditions

Chronic urticaria is frequently observed in both EDS and MCAS and is likely caused by mast cell activity²³²⁵²⁶. Overlap between MCAS and lupus (SLE) has also been reported in patients with persistent urticaria²⁶.

Rheumatoid Arthritis and Mast Cells

Mast cells are found in increased numbers in the joints of people with rheumatoid arthritis (RA) and contribute to the disease process²⁷²⁸. Different synovitis phenotypes have been identified based on mast cell density, and IgE-mediated activity may contribute to joint destruction²⁹. This provides an important pathophysiological link between MCAS and rheumatic diseases.ykdommer.

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