What labs should be checked to diagnose mast cell activation syndrome (MCAS)?

Laboratory Testing for Mast Cell Activation Syndrome (MCAS) Diagnosis

The diagnosis of MCAS requires documenting serum tryptase increase of >20% + 2 ng/mL from baseline during symptomatic episodes and 24-hour urine studies showing increased mast cell mediators such as N-methylhistamine, prostaglandin D2 (or 11β-PGF2α), and leukotriene E4. 1

Diagnostic Criteria for MCAS

MCAS diagnosis requires meeting all three of the following criteria:

1. Recurrent episodes affecting ≥2 organ systems (skin, gastrointestinal, cardiovascular, respiratory)
2. Laboratory evidence of mast cell activation during symptomatic episodes
3. Response to antimediator therapy

Essential Laboratory Tests

Serum Tryptase

• Timing is critical:
  • Collect during symptomatic episode: 30-120 minutes after symptom onset 1
  • Collect baseline sample when asymptomatic (at least 24 hours after episode) 2
  • Calculate using the consensus formula: increase of >20% + 2 ng/mL from baseline 3
• Interpretation notes:
  • Normal range: 1-15 ng/mL according to ECNM and AIM experts 2
  • Elevated baseline (>8 ng/mL) may indicate hereditary alpha tryptasemia 2
  • Persistently elevated tryptase (>20 ng/mL) is a minor criterion for systemic mastocytosis 4

24-Hour Urine Collection

• Essential mediators to measure:
  • N-methylhistamine
  • Prostaglandin D2 or its metabolite 11β-PGF2α (peaks 0-3 hours after episode)
  • Leukotriene E4 (LTE4) 1, 5
• Collection timing:
  • Ideally collected during or immediately after symptomatic episodes
  • Compare to baseline collections when asymptomatic

Additional Testing to Consider

Bone Marrow Evaluation

• Indicated when:
  • Persistently elevated baseline serum tryptase
  • Strong suspicion of systemic mastocytosis
  • Suspected clonal MCAS with potential KIT mutation 1
• Should include:
  • Bone marrow biopsy and aspirate
  • Mast cell immunophenotyping (CD117, CD25, CD2) 4
  • Molecular testing for KIT D816V mutation 4

Genetic Testing

• Consider testing for hereditary α-tryptasemia (TPSAB1 gene duplications) in patients with elevated baseline tryptase 1, 2

Important Caveats and Pitfalls

• Timing is crucial: Tryptase levels peak 30-120 minutes after symptom onset and decline rapidly
• False negatives: Some MCAS patients may not show elevated tryptase during reactions 6
• False positives: Elevated tryptase can occur in:
  • Chronic kidney disease
  • Obesity
  • Hematological neoplasms 2
• Avoid unreliable markers:
  • Heparin is not validated for mast cell activation in blood
  • Chromogranin A is not specific to mast cells
  • Plasma/urine histamine levels are less useful than histamine metabolites 1

When to Refer to Specialists

Refer to an allergist/immunologist with expertise in mast cell disorders when:

• Recurrent episodes affecting multiple organ systems
• Evidence of mast cell mediator release
• Response to antimediator therapy
• Severe or life-threatening anaphylactic episodes 1

Additional specialists (gastroenterologists, dermatologists, hematologists) may be necessary based on predominant symptoms.

Algorithm for Laboratory Testing in Suspected MCAS

1. During symptomatic episode:

   • Collect serum tryptase (30-120 minutes after onset)
   • Begin 24-hour urine collection for mast cell mediators

2. When asymptomatic (≥24 hours after episode):

   • Collect baseline serum tryptase

3. Calculate tryptase increase using 20% + 2 ng/mL formula

4. If criteria met or strong suspicion remains:

   • Consider bone marrow evaluation if persistently elevated tryptase
   • Consider genetic testing for hereditary α-tryptasemia

Remember that laboratory confirmation is just one component of diagnosis - clinical symptoms and response to therapy are equally important parts of the diagnostic triad for MCAS.