What is the diagnostic approach and referral process for Mast Cell Activation Syndrome (MCAS)?

Diagnostic Approach and Referral Process for Mast Cell Activation Syndrome (MCAS)

The diagnosis of MCAS requires documenting recurrent episodes affecting at least 2 organ systems, laboratory evidence of mast cell activation during symptomatic episodes, and response to antimediator therapy, with referral to an allergist/immunologist essential for proper evaluation and management. 1

Diagnostic Criteria for MCAS

MCAS diagnosis is based on three essential criteria:

1. Recurrent systemic symptoms affecting multiple organ systems:

   • Symptoms must affect at least 2 of 4 organ systems concurrently 2:
     • Skin (flushing, urticaria, pruritus, angioedema)
     • Gastrointestinal (diarrhea, nausea, vomiting, abdominal pain)
     • Cardiovascular (hypotension, tachycardia, near syncope)
     • Respiratory (wheezing, inspiratory stridor)

2. Laboratory evidence of mast cell activation during symptomatic episodes:

   • Serum tryptase increase of >20% + 2 ng/mL from baseline 1
     • Collect samples 1-4 hours after symptom onset
     • Compare to baseline levels
   • 24-hour urine studies during symptomatic periods showing increased:
     • N-methylhistamine
     • Prostaglandin D2 or 11β-PGF2α
     • Leukotriene E4

3. Documented response to antimediator therapy 1

Diagnostic Algorithm

1. Initial Assessment:

   • Document detailed symptom pattern focusing on:
     • Frequency and triggers of episodes
     • Specific symptoms by organ system
     • Severity and duration of attacks

2. Laboratory Testing During Symptomatic Episodes:

   • Serum tryptase (optimal collection: 30-120 minutes after symptom onset) 2
   • 24-hour urine collection for:
     • N-methylhistamine (limited utility alone but supportive with other markers) 2
     • 11β-PGF2α (peaks in 0-3 hours after episode) 2
     • LTE4 (comparable levels in 0-3 and 3-6 hour collections) 2

3. Baseline Testing:

   • Baseline serum tryptase (for comparison with acute levels)
   • Consider genetic testing for hereditary α-tryptasemia 2

4. Rule Out Mimicking Conditions:

   • Other allergic disorders
   • Autoimmune conditions
   • Endocrine disorders
   • Carcinoid syndrome

5. Classification of MCAS:

   • Primary MCAS: KIT-mutated clonal mast cells detected 3
   • Secondary MCAS: Underlying inflammatory disease (often IgE-dependent allergy) 3
   • Idiopathic MCAS: No identifiable trigger or KIT-mutated mast cells 3

When to Consider Bone Marrow Biopsy

A bone marrow biopsy and aspirate should be considered in patients with:

• Persistently elevated baseline serum tryptase
• Strong suspicion of systemic mastocytosis
• Suspected clonal MCAS with potential KIT mutation 2
• High Spanish Network on Mastocytosis score 4

Tests NOT Recommended for MCAS Diagnosis

• Heparin (not validated as marker of mast cell activation in blood) 2
• Chromogranin A (resides in neuroendocrine cells, not mast cells) 2
• Plasma or urine histamine levels (histamine metabolites preferred) 2

Referral Process

When to Refer:

• Patients with recurrent episodes of symptoms affecting multiple organ systems
• Evidence of mast cell mediator release during episodes
• Response to antimediator therapy
• Severe or life-threatening anaphylactic episodes

Who to Refer to:

• Primary referral: Allergist/Immunologist with expertise in mast cell disorders 1
• Additional specialists based on predominant symptoms:
  • Gastroenterologist (for predominant GI symptoms)
  • Dermatologist (for predominant skin manifestations)
  • Hematologist (if bone marrow evaluation needed)

Management Approach After Diagnosis

1. Trigger identification and avoidance 1

2. Pharmacological management:

   • H1 antihistamines (can be increased to 2-4 times standard dose) 1
   • H2 antihistamines (added concurrently) 1
   • Cromolyn sodium (particularly for GI symptoms) 1
   • Epinephrine auto-injectors for emergency use 1

3. Emergency preparedness:

   • All patients should carry two epinephrine auto-injectors 1
   • Learn supine positioning for hypotensive episodes 1

Clinical Pitfalls to Avoid

• Diagnosing MCAS without laboratory evidence of mast cell activation
• Failing to collect mediator levels during symptomatic episodes
• Overlooking other conditions that may mimic MCAS
• Delaying referral to specialists with expertise in mast cell disorders
• Misinterpreting symptoms as MCAS without thorough evaluation 5

The complexity of MCAS requires a systematic diagnostic approach and appropriate specialist referral to ensure accurate diagnosis and optimal management for affected patients.