How can I determine if I have mast‑cell activation syndrome (MCAS)?

How to Determine if You Have Mast Cell Activation Syndrome (MCAS)

You have MCAS only if you meet all three mandatory criteria simultaneously: (1) recurrent acute episodes involving at least two organ systems at the same time, (2) documented elevation of mast cell mediators during at least two separate episodes, and (3) clinical improvement with mast cell-targeted medications. 1

Step 1: Assess Your Symptom Pattern

MCAS requires episodic, not chronic symptoms. The hallmark is acute attacks with symptom-free intervals between episodes. 2

Required Clinical Features

You must experience simultaneous involvement of at least two organ systems during acute episodes: 1, 2

• Cardiovascular: Hypotension, tachycardia, syncope or near-syncope 2
• Dermatologic: Urticaria (hives), flushing, angioedema of eyelids/lips/tongue 2
• Respiratory: Wheezing, shortness of breath, inspiratory stridor 2
• Gastrointestinal: Crampy abdominal pain, diarrhea, nausea, vomiting 2

Critical Red Flags That Rule Out MCAS

• Persistent or chronic symptoms between episodes argue strongly against MCAS and suggest alternative diagnoses such as functional gastrointestinal disorders, chronic urticaria, or autonomic dysfunction. 2
• Single organ system involvement does not meet MCAS criteria, even if symptoms are severe. 1, 2

Step 2: Obtain Laboratory Evidence of Mast Cell Activation

You must document acute mediator elevation during symptoms on at least two separate occasions. 1

Tryptase Testing (Primary Diagnostic Test)

1. Baseline tryptase: Obtain when completely asymptomatic to establish your personal reference value 1

2. Acute tryptase: Draw blood 1-4 hours after symptom onset during an episode 1, 2

3. Diagnostic threshold: An increase of ≥20% above your baseline AND an absolute increase of ≥2 ng/mL 1, 2

4. Repeat documentation: This rise must be documented in at least two separate episodes 1

Common pitfall: A single elevated tryptase or chronically elevated baseline tryptase does not diagnose MCAS. You need the acute rise above your personal baseline documented twice. 2, 3

Alternative Mediator Testing (When Tryptase Is Unavailable or Negative)

If you cannot obtain acute tryptase or it remains negative despite typical symptoms: 1

• 24-hour urine N-methylhistamine (more reliable than direct histamine) 1
• Urinary leukotriene E4 (collect 0-6 hours after episode onset) 1
• Urinary 11β-prostaglandin F2α (collect 0-3 hours after episode) 1

Step 3: Demonstrate Treatment Response

You must show clinical improvement with mast cell-targeted therapy. 1, 2 This typically includes:

• H1 antihistamines at 2-4 times standard doses 1
• H2 antihistamines (e.g., famotidine) 1
• Mast cell stabilizers (cromolyn sodium 200 mg four times daily) 1
• Leukotriene antagonists (montelukast) if urinary LTE4 is elevated 1

The requirement for treatment response is a diagnostic criterion, not just a management strategy. 1, 2

Step 4: Exclude Alternative Diagnoses

Before confirming MCAS, rule out: 1

• IgE-mediated allergies (food, drug, venom)
• Drug-induced reactions (especially NSAIDs, opioids)
• Autonomic dysfunction (POTS, which can mimic MCAS symptoms)
• Functional gastrointestinal disorders (IBS, functional dyspepsia)

Histamine intolerance presents with chronic gastrointestinal symptoms in a single organ system without episodic mediator spikes—this is not MCAS. 1

Step 5: Classify MCAS Subtype (After Diagnosis Is Confirmed)

Once all three core criteria are met, determine the underlying cause: 1, 4

Clonality Testing

• Peripheral blood KIT D816V mutation (using high-sensitivity ASO-qPCR) identifies clonal/primary MCAS 1, 5
• TPSAB1 α-tryptase copy number variation (buccal swab) diagnoses hereditary α-tryptasemia 1

Bone Marrow Evaluation

Only indicated if: 1, 3

• Baseline tryptase persistently >20 ng/mL
• Clinical features suggesting systemic mastocytosis (urticaria pigmentosa skin lesions, hepatosplenomegaly, unexplained osteoporosis)

Key Diagnostic Pitfalls to Avoid

1. Over-diagnosis: MCAS is frequently misdiagnosed in patients with chronic, nonspecific symptoms. The episodic nature and documented mediator rises are non-negotiable. 2

2. Baseline tryptase misinterpretation: A baseline tryptase of 8-20 ng/mL suggests hereditary α-tryptasemia (present in 4-6% of the population), not MCAS. 3 A baseline >20 ng/mL suggests systemic mastocytosis and requires bone marrow evaluation. 3

3. Timing errors: Acute tryptase drawn outside the 1-4 hour window or during asymptomatic periods will not capture mast cell activation. 1, 2

4. Single-system symptoms: Isolated gastrointestinal complaints, chronic urticaria alone, or respiratory symptoms without other organ involvement do not meet MCAS criteria. 1, 2

Practical Diagnostic Algorithm Summary

Step	Action	Interpretation
1	Document symptom pattern	Episodic, multisystem (≥2 organs), with symptom-free intervals [2]
2	Baseline tryptase (asymptomatic)	Establishes personal reference [1]
3	Acute tryptase (1-4h after symptoms)	Must rise ≥20% + ≥2 ng/mL above baseline [1]
4	Repeat acute tryptase in second episode	Confirms reproducible mediator elevation [1]
5	Trial of mast cell-targeted therapy	Clinical improvement required for diagnosis [1,2]
6	KIT D816V & TPSAB1 testing	Classifies subtype (clonal vs hereditary vs idiopathic) [1]
7	Bone marrow (if baseline >20 ng/mL)	Rules out systemic mastocytosis [1,3]

If you do not meet all three core criteria—episodic multisystem symptoms, documented mediator rises in ≥2 episodes, and treatment response—you do not have MCAS. 1, 2 Referral to an allergy specialist or dedicated mast cell center is recommended for comprehensive evaluation once initial criteria are met. 1