Diagnostic Criteria for Mast Cell Activation Syndrome (MCAS)
MCAS diagnosis requires meeting all three criteria simultaneously: episodic multi-system symptoms affecting at least 2 organ systems, documented acute elevation in mast cell mediators during symptomatic episodes (serum tryptase increase ≥20% above baseline PLUS ≥2 ng/mL absolute increase), and clinical response to mast cell-targeted therapies. 1, 2
Clinical Criteria: Episodic Multi-System Symptoms
The clinical presentation must demonstrate episodic (not chronic) symptoms involving at least 2 organ systems: 1, 3
- Cutaneous: Flushing (face, neck, chest), urticaria, angioedema, pruritus with or without rash 4, 3
- Gastrointestinal: Diarrhea, abdominal cramping, nausea, vomiting 4, 3
- Cardiovascular: Hypotensive syncope or near-syncope, tachycardia, anaphylaxis 4, 3
- Respiratory: Wheezing, nasal congestion 3
- Neurologic: Neuropsychiatric symptoms, headache 4
Critical pitfall: Chronic, persistent symptoms without episodic flares should redirect you toward alternative diagnoses rather than MCAS. 5
Laboratory Criteria: Documented Mast Cell Mediator Elevation
Primary Test: Serum Tryptase
Obtain baseline serum tryptase when the patient is completely asymptomatic to establish their personal reference value. 1, 6
During a suspected mast cell activation episode, collect acute serum tryptase 1-4 hours after symptom onset. 6, 1, 2
The diagnostic threshold is an increase ≥20% above the patient's baseline PLUS an absolute increase ≥2 ng/mL. 6, 1, 2
Secondary Mediator Tests (When Tryptase is Difficult to Obtain or Negative)
Collect 24-hour urine during symptomatic periods for: 1
- N-methylhistamine (histamine metabolite): More reliable than direct histamine measurement, which is NOT recommended 1
- Leukotriene E4 (LTE4): Peaks in 0-6 hour collections after episodes; guides leukotriene antagonist therapy 1
- 11β-prostaglandin F2α (11β-PGF2α): Peaks in 0-3 hour collections; correlates with anaphylactic severity 1
Tests NOT Recommended
- Plasma or urine histamine levels: Not validated; use N-methylhistamine instead 1
- Heparin: Not validated as a marker of mast cell activation 1
- Chromogranin A: Resides in neuroendocrine cells, not mast cells; not reliable 1
Treatment Response Criteria
Improvement with medications blocking mast cell mediators or their production confirms the diagnosis. 1, 3
First-line therapy includes: 1, 4
- H1 antihistamines at 2-4 times standard doses
- H2 antihistamines
- Oral cromolyn sodium for gastrointestinal symptoms
Additional Diagnostic Testing to Classify MCAS Subtype
Clonality Assessment (Primary vs. Secondary vs. Idiopathic MCAS)
Peripheral blood KIT D816V mutation testing using highly sensitive allele-specific oligonucleotide quantitative PCR (ASO-qPCR) to identify clonal (primary) MCAS. 6, 1
Buccal swab for TPSAB1 α-tryptase copy number variation (CNV) to diagnose hereditary α-tryptasemia. 1
Bone Marrow Evaluation (When Indicated)
Bone marrow biopsy is indicated if: 6, 1
- Baseline serum tryptase persistently >20 ng/mL
- Adult-onset mastocytosis in the skin (MIS)
- Abnormal blood counts or organomegaly
Bone marrow analysis includes: 6
- Aspirate and core biopsy
- Flow cytometry: CD34, CD117, CD25, CD2 (CD30 optional) 6
- Immunohistochemistry: CD117, CD25, tryptase (CD30 optional) 6
- Cytogenetics and FISH for associated hematologic neoplasm-related abnormalities 6
- KIT D816V mutation testing on bone marrow if peripheral blood is negative 1
For intestinal symptoms, CD-117 immunohistochemical staining on duodenal or ileal biopsies is more sensitive than mast cell counts per high-power field. 6
Practical Diagnostic Algorithm
Initial evaluation during symptomatic episodes: Serum tryptase (baseline and 1-4 hours post-symptom onset) and 24-hour urine collection for N-methylhistamine, LTE4, and 11β-PGF2α 1
Clonality assessment: Peripheral blood KIT D816V mutation testing and buccal swab for TPSAB1 α-tryptase CNV 1
Bone marrow evaluation: Only if baseline tryptase persistently >20 ng/mL or clinical features suggesting systemic mastocytosis 1
Exclude secondary causes: Rule out IgE-mediated allergies, drug reactions, infections 6
Confirm treatment response: Document improvement with mast cell-targeted therapies 1, 3
Once MCAS is supported through clinical and laboratory findings, refer to an allergy specialist or mast cell disease research center for additional testing and management. 6