What is the recommended approach for a mast cell activation workup and initial treatment?

Mast Cell Activation Syndrome (MCAS) Workup and Initial Treatment

The recommended approach for mast cell activation workup requires comprehensive diagnostic testing including serum tryptase during symptomatic episodes, 24-hour urine studies for mediator metabolites, and a stepwise treatment approach beginning with H1 and H2 antihistamines. 1, 2

Diagnostic Workup Algorithm

Step 1: Clinical Evaluation

• Document episodic symptoms affecting multiple organ systems:
  • Skin: Pruritus, flushing, urticaria, angioedema, dermatographism
  • Gastrointestinal: Diarrhea, abdominal cramping, nausea, vomiting
  • Neurologic: Headache, poor concentration, memory issues, brain fog
  • Naso-ocular: Nasal stuffiness, nasal pruritus, conjunctival injection
  • Cardiovascular: Hypotension, tachycardia, syncope

Step 2: Laboratory Testing

• Serum tryptase during symptomatic episodes (ideally within 30-120 minutes of onset) and at baseline
  • Diagnostic criteria: Increase of >20% + 2 ng/mL above baseline 3
• 24-hour urine studies 1, 4:
  • N-methylhistamine
  • Prostaglandin D2
  • 2,3-dinor-11 beta-prostaglandin F2 alpha
  • Leukotriene E4
• KIT D816V mutation testing to rule out systemic mastocytosis 5
• Bone marrow biopsy if systemic mastocytosis is suspected (elevated baseline tryptase >20 ng/mL)
• DEXA scan to evaluate for osteopenia/osteoporosis 1

Step 3: Classification

Categorize into one of three types based on findings 2, 5:

1. Primary MCAS: KIT-mutated, clonal mast cells detected
2. Secondary MCAS: Underlying inflammatory disease (often IgE-dependent allergy)
3. Idiopathic MCAS: No detectable allergy, underlying disease, or KIT-mutated mast cells

Initial Treatment Protocol

First-Line Therapy

• H1 antihistamines: Second-generation (non-sedating) for daytime, first-generation for nighttime
• H2 antihistamines: Famotidine or ranitidine
• Mast cell stabilizers: Oral cromolyn sodium 200mg QID (shown to improve GI symptoms, urticaria, pruritus, and flushing within 2-6 weeks) 6

Second-Line Therapy

• Leukotriene receptor antagonists (montelukast)
• Aspirin (if prostaglandin levels are elevated and no contraindications exist)
• Low-dose ketotifen for persistent symptoms

Acute Management

• Epinephrine auto-injectors: All patients should carry two for anaphylaxis management 1
• Premedication protocol for procedures/surgery:
  • Anxiolytic agents (benzodiazepines)
  • H1 and H2 blockers
  • Corticosteroids

Additional Measures

• Trigger avoidance: Document and avoid identified triggers (hot water, alcohol, medications, stress, exercise)
• Bone health management if osteopenia/osteoporosis is present:
  • Calcium and vitamin D supplementation
  • Bisphosphonates with continued antihistamine use 1

Important Caveats

• MCAS is frequently suspected but rarely confirmed (only 2% confirmation rate in one prospective study) 7
• Symptoms may overlap with other conditions including anxiety, depression, and autoimmune disorders
• Serum tryptase elevation during episodes is the most accepted biomarker, but can be difficult to obtain during acute episodes 4
• Urine mediator testing provides a non-invasive alternative that can be collected at home during symptomatic periods 4
• Response to mast cell-targeted therapy is a required diagnostic criterion 5
• Referral to specialized centers with expertise in mastocytosis/MCAS is strongly recommended 1

Treatment Response Monitoring

• Document symptom improvement with treatment
• Repeat mediator testing to assess biochemical response
• Consider alternative diagnoses if no response to appropriate therapy after 8-12 weeks

Bold text indicates the most important recommendations for diagnosis and initial management of suspected MCAS.