What are the features, evaluation, and treatment options for Mast Cell Activation Syndrome (MCAS)?

Mast Cell Activation Syndrome (MCAS): Features, Evaluation, and Treatment

Mast Cell Activation Syndrome (MCAS) is characterized by recurrent episodes of symptoms affecting at least two organ systems, documented increase in mast cell mediators during symptomatic episodes, and response to medications targeting mast cell mediators or their effects. 1

Clinical Features

MCAS presents with episodic symptoms affecting multiple organ systems:

• Cardiovascular: Hypotension, tachycardia, syncope or near-syncope 2, 1
• Dermatologic: Urticaria, pruritus, flushing, angioedema (particularly of eyelids, lips, and tongue) 2, 1
• Respiratory: Wheezing, shortness of breath, inspiratory stridor 2, 1
• Gastrointestinal: Crampy abdominal pain, diarrhea, nausea, vomiting 2, 1

Common triggers include:

• Hot water
• Alcohol
• Medications
• Stress
• Exercise
• Hormonal fluctuations
• Infections
• Physical stimuli (pressure, friction) 2

Diagnostic Evaluation

For a diagnosis of MCAS, all three criteria must be met:

1. Recurrent episodes affecting ≥2 organ systems
2. Documented increase in mast cell mediators during episodes
3. Response to medications targeting mast cell mediators 2, 1

Laboratory Testing

• Serum tryptase: Collect during symptomatic episodes; diagnostic increase is >20% above baseline plus 2 ng/mL (>baseline × 1.2 + 2) 2
• 24-hour urine studies:
  • N-methylhistamine
  • Prostaglandin D2 or 11β-PGF2α
  • Leukotriene E4 2, 1

Differential Diagnosis

Important conditions to distinguish from MCAS:

• Systemic mastocytosis: Features clonal proliferation of mast cells with KIT D816V mutation and consistently elevated baseline tryptase
• Hereditary α-tryptasemia: Associated with increased copy numbers of TPSAB1 gene encoding α-tryptase
• Allergic reactions: Typically have identifiable triggers and IgE-mediated mechanisms 1

Treatment Approach

First-Line Therapy

• H1 antihistamines: Non-sedating options (cetirizine, fexofenadine, loratadine) starting at standard dose, potentially increasing to 2-4 times standard dose 1
• H2 antihistamines: Famotidine, cimetidine - particularly effective for gastrointestinal symptoms 1

Second-Line Therapy

• Cromolyn sodium: Particularly effective for gastrointestinal symptoms (bloating, diarrhea, cramps); start at lowest dose and gradually increase to 200 mg 4 times daily before meals and at bedtime 1, 3
• Leukotriene receptor antagonists (montelukast): Consider when urinary LTE4 levels are elevated; most effective for respiratory and dermatologic symptoms 1
• Aspirin: May reduce flushing and hypotension in patients with increased urinary prostaglandin metabolites; use with caution due to risk of triggering mast cell degranulation 1
• Doxepin: Potent H1 and H2 antihistamine with tricyclic antidepressant activity; may reduce CNS manifestations but can cause drowsiness 1

Refractory Symptoms

• Corticosteroids: For refractory symptoms; initial oral dosage of 0.5 mg/kg/day with slow taper over 1-3 months; not recommended for long-term use due to side effects 1

Emergency Management

• Epinephrine autoinjector: Essential for patients with history of systemic anaphylaxis or airway angioedema; patients should carry two autoinjectors 1
• Albuterol: For bronchospasm symptoms 1
• Supine positioning: Beneficial for recurrent hypotensive episodes 1

Treatment Monitoring and Follow-up

• 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 1
• Bone health management: DEXA scan recommended to evaluate for osteopenia/osteoporosis 1

Important Clinical Pitfalls

• Persistent rather than episodic symptoms should direct clinicians to different underlying diagnoses (e.g., chronic urticaria, poorly controlled asthma) 2
• Chronic increases in mediator levels might reflect systemic mastocytosis or hereditary α-tryptasemia rather than MCAS 2
• Non-specific symptoms like fatigue, fibromyalgia-like pain, dermographism, tinnitus, adenopathy, constipation, and mood disturbances lack precision for diagnosing MCAS 2
• Referral to specialized centers with expertise in mastocytosis/MCAS is strongly recommended for complex cases 1