What is the diagnosis and treatment for a patient with suspected mast cell activation syndrome?

Mast Cell Activation Syndrome: Diagnosis and Treatment

Diagnostic Approach

MCAS diagnosis requires three mandatory criteria: episodic symptoms affecting at least two organ systems concurrently, documented elevation of mast cell mediators during symptomatic episodes on at least two separate occasions, and clinical response to mast cell-targeted therapies. 1, 2

Clinical Criteria

• Symptoms must be episodic and recurrent, not chronic or persistent. Chronic symptoms suggest alternative diagnoses such as chronic urticaria or poorly controlled asthma. 1

• At least two organ systems must be involved concurrently during acute episodes, consistent with systemic anaphylaxis criteria: 1, 2

  • Cardiovascular: hypotension, tachycardia, syncope or near-syncope 1
  • Dermatologic: urticaria, pruritus, flushing, angioedema (particularly eyelids, lips, tongue) 1
  • Respiratory: wheezing, shortness of breath, inspiratory stridor 1
  • Gastrointestinal: crampy abdominal pain, diarrhea, nausea, vomiting 1

Laboratory Testing Protocol

Serum tryptase is the cornerstone biomarker. 2

1. Obtain baseline serum tryptase when asymptomatic to establish individual baseline. 2

2. Measure acute serum tryptase within 30-120 minutes of symptom onset during an episode. 2

3. MCAS diagnosis requires acute tryptase >baseline × 1.2 + 2 ng/mL on at least two occasions. 1

Additional biomarkers to obtain: 2

• 24-hour urine N-methylhistamine (superior to plasma/serum histamine due to better sensitivity and specificity) 2
• Urinary 11-β-prostaglandin F2α (prostaglandin D2 metabolite) for additional diagnostic support 2
• Urinary leukotriene E4 to guide therapeutic decisions, particularly if elevated 2

Determining MCAS Subtype

If baseline serum tryptase persistently >20 ng/mL or high clinical suspicion for clonal disease exists, proceed to bone marrow biopsy and aspirate. 1, 2

• Test peripheral blood for KIT D816V mutation to identify clonal MCAS (note: limited sensitivity in peripheral blood). 2

• Bone marrow evaluation assesses for systemic mastocytosis (multifocal dense infiltrates of ≥15 mast cells in aggregates, atypical mast cell morphology, aberrant CD25/CD2 expression). 1

Classify as: 2, 3

• Primary MCAS: KIT-mutated clonal mast cells detected
• Secondary MCAS: underlying IgE-dependent allergy or inflammatory disease without KIT mutation
• Idiopathic MCAS: no identifiable allergy, underlying disease, or KIT mutation

Critical Diagnostic Pitfalls

MCAS is substantially overdiagnosed. Do not diagnose based on: 1, 2

• Nonspecific symptoms alone (fatigue, fibromyalgia-like pain, dermographism, headache, mood disturbances, anxiety, weight change, thyroid dysfunction) 1
• Single organ system involvement 2
• Chronic persistent symptoms without episodic pattern 1
• Symptoms without documented mediator elevation on at least two occasions 1, 2

Consider hereditary alpha-tryptasemia in patients with elevated baseline tryptase (>8 ng/mL), joint hypermobility, dysautonomia, and chronic pain—this is a distinct genetic condition (TPSAB1 gene duplications/triplications), not MCAS. 1

Treatment Algorithm

First-Line Therapy

Start with dual H1 and H2 antihistamine therapy at high doses. 2, 4

• H1 antihistamines (cetirizine or fexofenadine preferred over first-generation agents due to lower sedation and cognitive impairment risk) at 2-4 times FDA-approved doses for dermatologic manifestations, tachycardia, abdominal discomfort. 2, 4

• Add H2 antihistamines for persistent gastrointestinal symptoms, gastric hypersecretion, peptic ulcer disease. 4

• Combined H1/H2 therapy controls severe pruritus and wheal formation when monotherapy fails. 4

Second-Line: Mast Cell Stabilizers

Add oral cromolyn sodium 200 mg four times daily for gastrointestinal symptoms (diarrhea, abdominal pain, nausea, vomiting) and may also help cutaneous symptoms. 4, 5

• Introduce progressively to reduce side effects (headache, sleepiness, irritability, abdominal pain). 4

• Clinical improvement occurs within 2-6 weeks of treatment initiation. 5

Additional Mediator-Blocking Agents

For specific refractory symptoms: 4

• Cyproheptadine for refractory diarrhea and nausea (functions as H1 antihistamine and serotonin receptor antagonist) 4

• Montelukast or zileuton for persistent symptoms, particularly if urinary leukotriene E4 elevated 2, 4

• Aspirin may reduce flushing and hypotensive episodes from prostaglandin D2 secretion, but must be introduced in controlled clinical setting due to potential paradoxical mast cell activation 4

• Proton pump inhibitors when H2 antihistamines fail to control gastrointestinal symptoms 4

Emergency Management

All patients must be prescribed epinephrine autoinjectors and carry them at all times. 4

• Administer epinephrine intramuscularly in recumbent position for hypotension, wheezing, laryngeal edema, cyanotic episodes, or recurrent anaphylactic attacks. 4

• Assume supine position immediately at symptom onset to prevent hypotensive episodes. 4

• Systemic corticosteroids may help acute episodes but taper quickly to limit adverse effects. 4

Refractory Cases

Consider omalizumab when MCAS is resistant to maximal antimediator therapy—prevents anaphylactic episodes and reduces emergency department visits. 4

PUVA therapy for bullous diffuse cutaneous mastocytosis with life-threatening mediator release episodes. 4

Treatment Implementation Caveats

Introduce medications cautiously in controlled settings with emergency equipment available—some patients experience paradoxical reactions. 4

Response to mast cell-targeted therapy is a required diagnostic criterion—patient must demonstrate clinical improvement with treatment. 2

Trigger identification and avoidance is crucial alongside pharmacologic interventions (hot water, alcohol, drugs, stress, exercise, hormonal fluctuations, infection, physical stimuli such as pressure or friction). 1, 4

Temperature control and stress/anxiety avoidance decrease symptoms and antihistamine requirements. 4