What is Mast Cell Activation Syndrome (MCAS) and its symptoms?

Mast Cell Activation Syndrome (MCAS): Definition and Symptoms

Mast Cell Activation Syndrome (MCAS) is a primary clinical condition characterized by recurrent episodes of systemic anaphylaxis-like reactions affecting at least two organ systems simultaneously, caused by inappropriate release of inflammatory mediators from mast cells, with symptoms improving with medications that block mast cell mediators. 1

Definition and Pathophysiology

MCAS belongs to a group of disorders where mast cell activation plays a pivotal pathophysiologic role. These disorders are classified into:

• Primary MCAS: Involves more activatable mast cells, either spontaneously or in response to triggers

  • Systemic mastocytosis (SM): Associated with KIT D816V mutation
  • Clonal MCAS: Similar KIT mutations but lacking other criteria for SM
  • Hereditary α-tryptasemia: Increased copy numbers of TPSAB1 gene
  • Idiopathic MCAS: No identifiable trigger, mutation, or genetic trait 1

• Secondary MCAS: Normal mast cells activated by external triggers such as:

  • Allergens (via IgE/FcεRI)
  • Antigens (via IgG/FcγRI/IIa)
  • Physical stimuli (pressure, temperature, vibration) 1, 2

Key Diagnostic Features

For diagnosis, patients must demonstrate:

1. Recurrent episodes of systemic symptoms affecting ≥2 organ systems
2. Laboratory evidence of mast cell activation during symptomatic episodes
3. Response to medications targeting mast cell mediators or their effects 3

Laboratory confirmation requires:

• Serum tryptase elevation >20% above baseline plus 2 ng/mL (collected within 1-4 hours after symptom onset)
• Urinary mediators (if tryptase is normal): N-methylhistamine, 11β-prostaglandin F2α, and Leukotriene E4 3

Symptom Presentation by Organ System

MCAS symptoms are episodic, affecting multiple organ systems simultaneously:

1. Cardiovascular System

• Hypotension
• Tachycardia
• Syncope or near-syncope
• Chest pain
• Arrhythmias 1, 3

2. Dermatologic System

• Flushing
• Urticaria (hives)
• Angioedema
• Pruritus (itching)
• Dermatographism 1, 3

3. Respiratory System

• Wheezing
• Shortness of breath
• Throat tightness
• Nasal congestion
• Cough 1, 3

4. Gastrointestinal System

• Abdominal pain
• Diarrhea
• Nausea/vomiting
• Heartburn
• Dyspepsia
• Cyclical nausea 1, 4

5. Neurologic System (less commonly recognized)

• Headache
• Brain fog
• Memory issues
• Difficulty concentrating 5

Important Clinical Considerations

1. Symptom Triggers: Symptoms may be triggered by:

   • Foods
   • Medications
   • Environmental factors
   • Physical stimuli
   • Emotional stress 2, 5

2. Severity Spectrum: Symptoms range from mild to severe to life-threatening anaphylaxis 6, 5

3. Differential Diagnosis: Must rule out:

   • Systemic mastocytosis (persistent tryptase >20 ng/mL in 75% of cases)
   • Hereditary α-tryptasemia
   • Other causes of anaphylaxis
   • Macrophage activation syndrome 3

4. Specialized Testing:

   • Peripheral blood testing for KIT D816V mutation if tryptase >15 ng/mL
   • Bone marrow evaluation if tryptase persistently >20 ng/mL 3

Clinical Pitfalls and Caveats

1. Misdiagnosis: MCAS is frequently misdiagnosed as functional disorders, particularly irritable bowel syndrome or functional dyspepsia 4

2. Diagnostic Delay: Patients often experience significant delays in diagnosis due to the multisystem nature of symptoms 4

3. Combined Forms: Most severe MCA events occur in combined forms of MCAS, where KIT-mutated mast cells, IgE-dependent allergies, and sometimes hereditary α-tryptasemia coexist 5

4. Persistent vs. Episodic: Persistent symptoms (as seen in chronic urticaria or poorly controlled asthma) should direct clinicians to different underlying diagnoses rather than MCAS 1

5. Anesthetic Risk: Patients with MCAS are at increased risk during surgical procedures due to potential anaphylactic reactions to medications and other triggers 6

MCAS requires a multidisciplinary approach for proper diagnosis and management, with referral to allergy specialists or mast cell disease research centers recommended for comprehensive evaluation 3.