What is the diagnostic approach for Mast Cell Activation Syndrome (MCAS)?

Diagnosing Mast Cell Activation Syndrome (MCAS)

The diagnosis of MCAS requires three essential criteria: recurrent episodes affecting at least two organ systems, documented increase in mast cell mediators during symptomatic episodes, and response to medications targeting mast cell mediators. 1

Diagnostic Criteria

1. Clinical Symptoms

• Must involve at least two organ systems concurrently during acute episodes 2:
  • Cardiovascular: Hypotension, tachycardia, syncope or near-syncope
  • Respiratory: Wheezing, shortness of breath, inspiratory stridor
  • Dermatologic: Flushing, urticaria, pruritus, angioedema
  • Gastrointestinal: Diarrhea, nausea with vomiting, crampy abdominal pain

2. Laboratory Evidence

• Serum tryptase: Must show increase of >20% + 2 ng/mL from baseline (formula: >baseline × 1.2 + 2) 2, 1, 3

  • Collect during symptomatic episodes (1-4 hours after onset) and compare to baseline
  • Baseline samples should be collected when patient is asymptomatic

• 24-hour urine studies (collect during symptomatic periods) 2, 1:

  • N-methylhistamine (histamine metabolite)
  • Prostaglandin D2 or 11β-PGF2α
  • Leukotriene E4

3. Response to Treatment

• Documented improvement with antimediator therapy 2, 1, 3:
  • H1 and H2 antihistamines
  • Leukotriene antagonists
  • Mast cell stabilizers (cromolyn sodium)

Diagnostic Algorithm

1. Initial Assessment:

   • Document recurrent episodes affecting ≥2 organ systems
   • Identify potential triggers (hot water, alcohol, drugs, stress, exercise, physical stimuli)
   • Rule out other conditions with overlapping symptoms 4, 5

2. Laboratory Testing:

   • Measure serum tryptase during symptomatic episode AND when asymptomatic (baseline)
   • Collect 24-hour urine during symptomatic period for:
     • N-methylhistamine
     • Prostaglandin D2 or 11β-PGF2α
     • Leukotriene E4

3. Classification Assessment:

   • Test for KIT D816V mutation in peripheral blood or bone marrow
   • Check TPSAB1 α-tryptase gene copy number variation
   • If positive for either: Primary MCAS with somatic or germline mutation
   • If negative: MCAS without known mutation 2

4. Therapeutic Trial:

   • Initiate targeted antimediator therapy based on symptoms and mediator profile
   • Document response to treatment
   • If no response after 8-12 weeks of appropriate therapy, reconsider diagnosis 1

Common Pitfalls in MCAS Diagnosis

1. Overdiagnosis: Many patients referred for suspected MCAS actually have less severe forms of mast cell activation or unrelated conditions 4, 5

2. Non-specific symptoms: The following symptoms alone lack precision for diagnosing MCAS 2:

   • Fatigue, fibromyalgia-like pain, dermographism
   • Chronically ill appearance, edema, tinnitus
   • Constipation, chronic low back pain, headache
   • Mood disturbances, anxiety, weight changes
   • Abnormal electrolytes or immunoglobulin levels

3. Inadequate laboratory testing: Failure to document increase in mast cell mediators during symptomatic episodes compared to baseline 3, 6, 7

4. Overlooking alternative diagnoses: Other conditions with overlapping symptoms must be ruled out before diagnosing MCAS 4, 5

5. Misinterpreting local mast cell activation: An increase in mast cell numbers in tissues (e.g., gastrointestinal tract) alone does not establish MCAS diagnosis 2

By following this structured diagnostic approach and avoiding common pitfalls, clinicians can accurately diagnose MCAS and provide appropriate treatment to improve patient outcomes.