What is Mast Cell Activation Syndrome (MCAS)?

Mast Cell Activation Syndrome (MCAS)

Mast Cell Activation Syndrome (MCAS) is a clinical condition characterized by episodic, recurrent symptoms affecting multiple organ systems due to abnormal mast cell activation and mediator release, without the mast cell proliferation seen in mastocytosis. 1

Definition and Classification

MCAS is defined as a primary clinical condition where patients experience spontaneous episodic signs and symptoms of systemic anaphylaxis that:

• Concurrently affect at least 2 organ systems
• Result from secreted mast cell mediators
• Improve with medications that block these mediators or their production 2

MCAS can be categorized into three main types:

• Primary MCAS: Associated with intrinsic mast cell abnormalities (e.g., KIT mutations, CD25 expression)
• Secondary MCAS: Normal mast cells activated by external triggers (allergens, physical stimuli)
• Idiopathic MCAS: No identifiable trigger, mutation, or genetic trait 1

Clinical Manifestations

MCAS primarily affects multiple organ systems:

• Cardiovascular: Hypotension, tachycardia, syncope
• Dermatologic: Urticaria, pruritus, flushing, angioedema
• Respiratory: Wheezing, shortness of breath, stridor
• Gastrointestinal: Abdominal pain, diarrhea, nausea, vomiting 1

Gastrointestinal symptoms are frequently reported and often mistaken for functional gastrointestinal disorders such as irritable bowel syndrome, dyspepsia, chronic nausea, and heartburn 3.

Diagnostic Criteria

For a diagnosis of MCAS, patients must meet all three of the following criteria:

1. Recurrent episodes of systemic symptoms involving at least two organ systems
2. Documented increase in mast cell mediators during symptomatic episodes:
   • Serum tryptase >20% + 2 ng/mL above baseline within 1-4 hours of symptom onset
   • Increased urinary metabolites: N-methylhistamine, Prostaglandin D2, 11β-PGF2α, Leukotriene E4
3. Response to medications targeting mast cell mediators or their effects 1, 4

Common Triggers

Mast cell activation may be precipitated by:

• Hot water
• Alcohol
• Medications
• Psychological stress
• Exercise
• Hormonal fluctuations
• Infections
• Physical stimuli 1

Diagnostic Approach

A systematic approach is recommended:

1. Document symptoms affecting multiple organ systems
2. Measure mediator levels during symptomatic episodes:
   • Serum tryptase (most reliable)
   • 24-hour urine studies for mediator metabolites
3. Assess response to antimediator therapy
4. Rule out other conditions with similar presentations 5

Management

Treatment follows a stepwise approach:

1. First-line: H1 and H2 antihistamines
2. Additional options:
   • Mast cell stabilizers (cromolyn sodium)
   • Leukotriene antagonists
   • Low-dose aspirin (in selected cases)
   • Corticosteroids (for severe symptoms)
3. Emergency management: Patients should carry two epinephrine auto-injectors for anaphylaxis 1

Important Clinical Considerations

• MCAS is often underdiagnosed, leading to significant delays in proper treatment 3
• Patients with suspected MCAS should be referred to specialized centers with expertise in mast cell disorders 1
• Premedication protocols are recommended before procedures/surgery, including anxiolytics, H1/H2 blockers, and corticosteroids 1
• Bone health assessment with DEXA scan is recommended due to potential osteopenia/osteoporosis 1
• If no response to appropriate therapy after 8-12 weeks, alternative diagnoses should be considered 1

Differential Diagnosis

It's essential to distinguish MCAS from:

• Systemic mastocytosis: Features clonal proliferation of mast cells with KIT D816V mutation and consistently elevated baseline tryptase
• Allergic reactions: Typically have identifiable triggers and IgE-mediated mechanisms
• Hereditary α-tryptasemia: Associated with increased copy numbers of the TPSAB1 gene encoding α-tryptase 2, 1