What is the diagnostic approach for mast cell activation?

Diagnosis of Mast Cell Activation Syndrome (MCAS)

The diagnosis of mast cell activation syndrome requires documenting recurrent episodes of systemic symptoms affecting at least two organ systems, laboratory evidence of mast cell mediator release during acute episodes, and response to medications targeting mast cell mediators. 1

Diagnostic Criteria

Clinical Presentation

• Recurrent episodes of systemic anaphylaxis-like reactions affecting ≥2 of these organ systems:
  • Cardiovascular: Hypotension, tachycardia, syncope or near-syncope
  • Dermatologic: Urticaria, pruritus, flushing, angioedema (especially eyelids, lips, tongue)
  • Respiratory: Wheezing, shortness of breath, inspiratory stridor
  • Gastrointestinal: Crampy abdominal pain, diarrhea, nausea, vomiting 1

Laboratory Evidence

• Serum tryptase during acute episodes:

  • Must exceed baseline level by at least 20% plus 2 ng/mL
  • Formula: Acute tryptase > (1.2 × baseline tryptase + 2 ng/mL) 1
  • Optimal collection time: 30-120 minutes after symptom onset 1
  • Baseline sample: Before event or ≥24 hours after symptom resolution 1

• Other mediator testing during acute episodes:

  • Urinary N-methylhistamine (NMH)
  • Urinary 11β-PGF2α (prostaglandin metabolite)
  • Urinary LTE4 (leukotriene metabolite) 1

Response to Therapy

• Symptoms must improve with:
  • Mast cell mediator-blocking agents (antihistamines, leukotriene antagonists)
  • Mast cell stabilizers
  • Medications that reduce mediator production 1

Diagnostic Algorithm

1. Initial evaluation for patients with suspected MCAS:

   • Document episodic symptoms affecting ≥2 organ systems
   • Rule out other conditions with similar presentations
   • Identify potential triggers (hot water, alcohol, drugs, stress, exercise, etc.) 1

2. Laboratory testing:

   • Baseline serum tryptase (normal range: 1-15 ng/mL) 2
   • Collect blood during acute episode for serum tryptase
   • Collect urine during/shortly after acute episode for:
     • N-methylhistamine
     • 11β-PGF2α
     • LTE4 1

3. Differential diagnosis - rule out:

   • Systemic mastocytosis (SM)
   • Hereditary α-tryptasemia
   • Other causes of anaphylaxis 1

4. Additional testing when indicated:

   • Peripheral blood testing for KIT D816V mutation (if tryptase >15 ng/mL) 2
   • Bone marrow evaluation if:
     • Serum tryptase persistently >20 ng/mL
     • KIT D816V mutation positive in peripheral blood
     • Strong clinical suspicion despite normal tryptase 2

Classification of MCAS

Once diagnosed, MCAS can be classified into:

1. Primary MCAS:

   • KIT-mutated, clonal mast cells detected
   • May include systemic mastocytosis or monoclonal mast cell activation disorder 3

2. Secondary MCAS:

   • Underlying inflammatory disease (often IgE-dependent allergy)
   • No KIT-mutated mast cells found 3

3. Idiopathic MCAS:

   • Neither allergy/underlying disease nor KIT-mutated mast cells detectable 3

Common Pitfalls and Caveats

• Timing matters: Tryptase levels peak 30-120 minutes after symptom onset; collection outside this window reduces sensitivity 1

• Normal tryptase doesn't rule out MCAS: Some patients may have normal tryptase levels during reactions; other mediator testing is crucial 2

• Avoid misdiagnosis: Many symptoms attributed to MCAS (fatigue, fibromyalgia-like pain, chronic low back pain, headache, etc.) lack specificity and should not be used as primary diagnostic criteria 1

• Persistent vs. episodic symptoms: Persistent symptoms (chronic urticaria, poorly controlled asthma) should direct clinicians to different diagnoses 1

• Transient tryptase elevation: Can occur during anaphylaxis or severe allergic reactions without indicating MCAS 2

• Hereditary α-tryptasemia: Can present with similar symptoms but is a distinct genetic condition with increased copy numbers of the TPSAB1 gene 1

By following this structured approach to diagnosis, clinicians can appropriately identify patients with true mast cell activation syndrome and distinguish it from other conditions with overlapping symptoms.