Diagnosing Mast Cell Activation Syndrome (MCAS)
The diagnosis of MCAS requires meeting three mandatory criteria simultaneously: recurrent episodic symptoms affecting at least two organ systems concurrently, documented elevation of mast cell mediators during symptomatic episodes, and clinical response to mast cell-targeted therapies. 1, 2, 3
Three Essential Diagnostic Criteria
1. Clinical Criteria: Multi-System Episodic Symptoms
Symptoms must affect at least 2 of these 4 organ systems concurrently during discrete episodes: 1
- Cardiovascular: Hypotension, tachycardia, syncope or near-syncope 1
- Dermatologic: Flushing, urticaria, pruritus, angioedema 1
- Respiratory: Wheezing, shortness of breath, inspiratory stridor 1
- Gastrointestinal: Diarrhea, nausea with vomiting, crampy abdominal pain 1
Critical distinction: Symptoms must be episodic (lasting minutes to hours) with symptom-free intervals between attacks, not chronic or continuous. 3, 4 This pattern resembles systemic anaphylaxis and distinguishes MCAS from chronic inflammatory conditions. 4
2. Laboratory Criteria: Documented Mediator Elevation
Primary biomarker - Serum Tryptase (most validated): 2, 5
- Obtain baseline serum tryptase when completely asymptomatic to establish personal reference value 2
- Collect acute serum tryptase 1-4 hours after symptom onset during an episode 2, 5
- Diagnostic threshold: Increase ≥20% above baseline PLUS absolute increase ≥2 ng/mL 2, 5, 6
- This acute-to-baseline comparison is optimal for tryptase as a preformed mediator 2
Secondary biomarkers - 24-hour urine collection (when tryptase difficult to obtain): 2, 7
- N-methylhistamine (histamine metabolite): More reliable than direct histamine measurement, which is NOT recommended 2, 7
- Acute/baseline ratio ≥1.3 supports MCAS diagnosis 6
- Leukotriene E4 (LTE4): Peaks in 0-6 hour collections after episodes 2
- 11β-prostaglandin F2α: Peaks in 0-3 hour collections, correlates with anaphylactic severity 2
- Acute/baseline ratio ≥1.3 supports diagnosis 6
Tests NOT recommended: 2
- Plasma or urine histamine levels (use N-methylhistamine instead) 2
- Heparin (not validated) 2
- Chromogranin A (resides in neuroendocrine cells, not mast cells) 2
3. Treatment Response Criterion
Patients must demonstrate clinical improvement with mast cell-targeted therapies: 1, 3
- H1 antihistamines at 2-4 times FDA-approved doses 3
- H2 antihistamines for gastrointestinal symptoms 3
- Leukotriene receptor antagonists (montelukast, zafirlukast, zileuton) 1, 3
- Mast cell stabilizers (oral cromolyn sodium) 3
- Aspirin (if prostaglandin metabolites elevated, use cautiously in controlled setting) 1, 3
Therapeutic response should be evaluated over 2-6 weeks before considering escalation. 3 This response serves as both a diagnostic criterion and confirmation that the patient meets MCAS criteria. 3
Classification: Determining MCAS Subtype
After confirming the three diagnostic criteria, classify as Primary (clonal), Secondary, or Idiopathic MCAS: 2, 3
Clonality Assessment
Peripheral blood testing: 1, 2
- KIT D816V mutation using highly sensitive allele-specific oligonucleotide quantitative PCR (ASO-qPCR) identifies clonal (primary) MCAS 1, 2
- Sensitivity is limited in peripheral blood; negative result does not exclude clonality 3
Genetic testing: 2
- Buccal swab for TPSAB1 α-tryptase copy number variation (CNV) diagnoses hereditary α-tryptasemia 2
- Note: Hereditary α-tryptasemia can coexist with Ehlers-Danlos syndrome and POTS, but these are NOT caused by MCAS 1
Bone Marrow Evaluation Indications
Bone marrow biopsy is indicated when: 2, 3
- Baseline serum tryptase persistently >20 ng/mL 2
- Clinical features suggesting systemic mastocytosis (adult-onset mastocytosis in skin, abnormal blood counts, organomegaly) 2
- Peripheral blood KIT D816V negative but high clinical suspicion for clonal disease 3
Bone marrow analysis should include: 2
- Aspirate and core biopsy
- Immunohistochemistry
- Flow cytometry (looking for CD25 expression on mast cells as surrogate marker for clonality) 1
- KIT D816V mutation testing on bone marrow if peripheral blood negative 2
Practical Diagnostic Algorithm
Step 1: Recognize the clinical pattern 1, 3
- Recurrent, episodic symptoms affecting ≥2 organ systems concurrently
- Symptom-free intervals between episodes
Step 2: Obtain biomarker evidence during symptomatic episodes 2, 3
- Ideal: Acute serum tryptase 1-4 hours after symptom onset + baseline tryptase when asymptomatic
- Alternative: 24-hour urine collection for N-methylhistamine, LTE4, and 11β-PGF2α during or immediately after episode
Step 3: Initiate mast cell-targeted therapy and document response 3
- Start H1 antihistamines (2-4x standard dose) + H2 antihistamines
- Add leukotriene antagonists if LTE4 elevated
- Evaluate response over 2-6 weeks
Step 4: Classify MCAS subtype 2, 3
- Peripheral blood KIT D816V mutation testing
- Buccal swab for TPSAB1 α-tryptase CNV
- Bone marrow evaluation only if baseline tryptase >20 ng/mL persistently or clinical features of systemic mastocytosis
Step 5: Exclude secondary causes 2, 8
- Rule out IgE-mediated allergies, drug reactions, infections before diagnosing primary or idiopathic MCAS
Critical Diagnostic Pitfalls
MCAS is substantially overdiagnosed. 3 Avoid these common errors:
- Do NOT diagnose based on nonspecific symptoms alone (fatigue, fibromyalgia-like pain, headache, mood disturbances, anxiety, weight change, thyroid dysfunction) 1, 3
- Do NOT diagnose with single organ system involvement - requires ≥2 systems concurrently 3
- Do NOT diagnose without documented mediator elevation during symptomatic episodes 3
- Do NOT diagnose based on chronic, continuous symptoms - must be episodic with symptom-free intervals 3, 4
- Increased mast cell numbers alone (e.g., in gastrointestinal biopsies) does NOT diagnose MCAS or indicate mast cell activation 1
Even with precise MCAS diagnosis, other conditions must be correctly diagnosed and treated independently. 1 MCAS does not explain all symptoms in a patient, and appropriate workup for other conditions remains essential. 1