What laboratory tests are drawn to diagnose Mast Cell Activation Syndrome (MCAS)?

Laboratory Testing for Mast Cell Activation Syndrome

The essential laboratory tests for diagnosing MCAS are serum tryptase levels (baseline and during symptomatic episodes 1-4 hours after symptom onset) and 24-hour urine collection for mast cell mediators including N-methylhistamine, leukotriene E4, and 11β-prostaglandin F2α. 1

Primary Diagnostic Laboratory Tests

Serum Tryptase

• Obtain baseline serum tryptase and repeat 1-4 hours after symptom onset 1
• A positive result requires an increase of ≥20% above baseline PLUS 2 ng/mL 1
• Comparing acute levels to baseline is optimal for tryptase as a preformed mediator 1
• Baseline tryptase persistently >20 ng/mL warrants bone marrow evaluation to exclude systemic mastocytosis 1, 2

24-Hour Urine Mast Cell Mediators

• Collect 24-hour urine for N-methylhistamine (NMH), leukotriene E4 (LTE4), and 11β-prostaglandin F2α (11β-PGF2α) 1, 2
• These tests are particularly valuable when serum tryptase collection during acute episodes is impractical 2, 3
• Urine collection can be performed at home, making it more accessible than acute serum sampling 3
• 11β-PGF2α is the most frequently elevated mediator in MCAS and correlates strongly with flushing and pruritus 4
• LTE4 levels peak in both 0-3 hour and 3-6 hour collections after symptom onset 1
• 11β-PGF2α levels peak in the 0-3 hour collection 1

Important Caveats About Timing

• For lipid mediators (prostaglandins, leukotrienes), measuring levels shortly after symptom onset is optimal 1
• Having a baseline level may not be as critical for newly generated lipid mediators compared to preformed mediators like tryptase 1
• Serum or plasma collection for lipid mediators depends on whether secretion occurs in vivo versus ex vivo, though this requires further clarification 1

Secondary/Specialized Testing

Bone Marrow Evaluation

• Indicated when baseline serum tryptase is persistently >20 ng/mL 2
• Also indicated for adult-onset mastocytosis in the skin, abnormal blood counts, or organomegaly 2
• Bone marrow biopsy/aspirate is needed to diagnose systemic mastocytosis and identify clonal mast cells with KIT D816V mutations 1
• Cannot identify mast cell activation per se, but excludes clonal mast cell disorders 1
• If performed, should include immunohistochemistry for tryptase, CD117, CD25, and flow cytometry 1

KIT D816V Mutation Testing

• Use highly sensitive allele-specific oligonucleotide quantitative PCR (ASO-qPCR) on peripheral blood first 1
• If peripheral blood is negative but suspicion remains high, test bone marrow 1
• Detects mutation in >80% of systemic mastocytosis patients 1

Tests NOT Recommended

• Plasma or urine histamine levels are NOT recommended over histamine metabolites (N-methylhistamine) due to poor sensitivity and specificity 1
• Heparin is NOT validated as a marker of mast cell activation in blood 1
• Chromogranin A is NOT appropriate as it resides in neuroendocrine cells, not mast cells 1
• Next-generation sequencing myeloid panels have low sensitivity (~5%) for KIT D816V detection 1

Clinical Context for Testing

• Testing should be performed in patients with episodic symptoms affecting ≥2 organ systems (cutaneous, gastrointestinal, cardiovascular, respiratory, neuropsychiatric) 1
• Symptoms must be recurrent and systemic, not chronic or isolated to single organ systems 1
• Common symptoms include flushing, pruritus, urticaria, angioedema, wheezing, diarrhea, abdominal cramping, hypotension, tachycardia, and syncope 1

Practical Testing Algorithm

1. Obtain baseline serum tryptase in all patients with suspected MCAS 1
2. During symptomatic episodes, collect serum tryptase 1-4 hours after symptom onset 1
3. Collect 24-hour urine for NMH, LTE4, and 11β-PGF2α either at baseline or during/after symptomatic periods 1, 2, 4
4. If baseline tryptase >20 ng/mL or clinical features suggest systemic mastocytosis, proceed to bone marrow evaluation 1, 2
5. Refer to allergy specialist or mast cell disease center for additional testing and confirmation once initial laboratory evidence supports MCAS 1