What are the symptoms and treatment options for Mast Cell Activation Syndrome (MCAS)?

Symptoms of Mast Cell Activation Syndrome

MCAS presents with recurrent, episodic symptoms of systemic anaphylaxis that concurrently affect at least 2 organ systems—not chronic persistent symptoms—and must be documented with acute increases in mast cell mediators during symptomatic episodes. 1

Key Clinical Features

Multi-System Episodic Presentation

The hallmark of MCAS is acute, recurrent episodes involving at least 2 of the following 4 organ systems simultaneously: 1, 2

Cardiovascular symptoms: 2

• Hypotension
• Tachycardia
• Syncope or near-syncope

Dermatologic symptoms: 2

• Urticaria (hives)
• Pruritus (itching)
• Flushing
• Angioedema, particularly affecting eyelids, lips, and tongue

Respiratory symptoms: 2

• Wheezing
• Shortness of breath
• Inspiratory stridor

Gastrointestinal symptoms: 2, 3

• Crampy abdominal pain
• Diarrhea
• Nausea and vomiting

Additional Reported Symptoms

Beyond the core organ systems, patients may experience: 3

• Headaches
• Cognitive dysfunction 3

Critical Diagnostic Distinction

Persistent, chronic symptoms should direct you away from MCAS toward alternative diagnoses such as chronic urticaria, poorly controlled asthma, functional gastrointestinal disorders, or POTS. 1, 2 The episodic nature is non-negotiable for diagnosis.

Diagnostic Requirements

All three criteria must be met simultaneously: 2, 4

1. Clinical: Episodic symptoms affecting ≥2 organ systems concurrently
2. Laboratory: Documented acute increases in mast cell mediators during symptomatic episodes (serum tryptase increase of 20% above baseline plus 2 ng/mL, measured 1-4 hours after symptom onset, or elevated urinary metabolites including N-methylhistamine, 11β-PGF2α, or LTE4) 1, 2
3. Therapeutic: Clinical response to mast cell-targeted therapies 1, 2

Laboratory Timing

Measure mediators at baseline AND during acute episodes—chronic elevations in mediators suggest systemic mastocytosis or other conditions, not MCAS. 1, 2

Common Triggers

Reported triggers that may precipitate episodes include: 5

• Hormonal fluctuations
• Hot water exposure
• Alcohol
• Certain medications
• Physical or emotional stress
• Exercise
• Infections
• Physical stimuli (pressure, temperature, vibration)

When hormonal triggers are suspected, document temporal relationships between hormonal changes and multi-system symptom episodes, and measure mediators during these episodes. 5

Treatment Approach

First-Line Mediator-Blocking Agents

Symptoms should improve with medications targeting mast cell mediators: 1

H1 and H2 antihistamines block histamine receptor binding 1, 4

Leukotriene receptor antagonists (type 1 cysteinyl leukotriene receptor antagonists) block leukotriene effects 1, 4

COX inhibitors (aspirin with appropriate precautions) reduce prostaglandin D2 production 1

5-lipoxygenase inhibitors reduce leukotriene C4 production 1

Mast Cell Stabilizers

Cromolyn sodium oral solution is FDA-approved for mastocytosis and has demonstrated clinical benefit in MCAS-related conditions, with improvement in diarrhea, flushing, headaches, vomiting, urticaria, abdominal pain, nausea, and itching. 3 Clinical improvement typically occurs within 2-6 weeks of treatment initiation. 3

Omalizumab diminishes mast cell activatability 1

Prophylactic Strategy

If specific triggers (such as hormonal fluctuations) are consistently identified in confirmed MCAS, consider prophylactic escalation of mast cell-targeted therapy during predictable trigger periods. 5

Critical Pitfalls to Avoid

Do not diagnose MCAS based solely on chronic symptoms without documented episodic multi-system involvement and laboratory confirmation during acute episodes. 2, 4 Many patients referred for suspected MCAS actually have other conditions including autoimmune diseases, functional disorders, POTS, gastroparesis, or hypermobility spectrum disorders. 2, 6

Fibromyalgia-like pain may occur in MCAS patients but is not a diagnostic criterion and should not be used to diagnose MCAS without the full triad of episodic multi-system symptoms, laboratory confirmation, and treatment response. 4

Mild persistent GI symptoms between flares suggest disorders of gut-brain interaction (functional dyspepsia, IBS) or comorbid conditions like POTS rather than MCAS. 2