What is the diagnosis and treatment for Mast Cell Activation Syndrome (MCAS)?

Mast Cell Activation Syndrome: Diagnosis and Treatment

Diagnostic Criteria

MCAS requires all three of the following criteria to be met simultaneously: recurrent episodic symptoms affecting at least 2 organ systems, documented elevation of mast cell mediators during symptomatic episodes, and clinical response to mast cell-targeted therapies. 1

Clinical Presentation

• Symptoms must be episodic and recurrent, not chronic or persistent—chronic symptoms should direct you toward alternative diagnoses 1
• At least 2 organ systems must be involved concurrently during episodes: 1
  • Cardiovascular: hypotension, syncope, presyncope, tachycardia
  • Dermatologic: flushing, pruritus, urticaria, angioedema
  • Gastrointestinal: diarrhea, abdominal cramping, nausea, vomiting
  • Respiratory: wheezing, bronchospasm, nasal congestion
  • Neurologic: headache, brain fog, cognitive dysfunction

Laboratory Confirmation

Serum tryptase is the cornerstone biomarker—obtain baseline when completely asymptomatic, then acute levels 1-4 hours after symptom onset. 1, 2

• Diagnostic threshold: ≥20% increase above personal baseline PLUS absolute increase ≥2 ng/mL 1, 2
• Baseline tryptase establishes the patient's personal reference value, which is critical since normal ranges vary 2

24-hour urine collection for mediator metabolites provides additional diagnostic support: 1, 2

• N-methylhistamine (histamine metabolite)—more reliable than direct histamine measurement, which is not recommended 1, 2
• Leukotriene E4 (LTE4)—peaks in 0-6 hour collections, guides leukotriene antagonist therapy 1, 2
• 11β-prostaglandin F2α—peaks in 0-3 hour collections, correlates with anaphylaxis severity 1, 2

Classification by Subtype

After confirming MCAS diagnosis, determine the subtype: 1, 3, 4

Primary MCAS (clonal):

• Peripheral blood KIT D816V mutation testing using highly sensitive allele-specific oligonucleotide quantitative PCR (ASO-qPCR) 1, 2
• If peripheral blood negative but clinical suspicion high, proceed to bone marrow biopsy 1, 2
• Buccal swab for TPSAB1 α-tryptase copy number variation (CNV) to identify hereditary α-tryptasemia 1, 2

Bone marrow evaluation indicated when: 1, 2

• Baseline serum tryptase persistently >20 ng/mL
• Adult-onset cutaneous mastocytosis
• Abnormal blood counts or organomegaly

Secondary MCAS:

• Underlying IgE-mediated allergy or other reactive condition triggers mast cell activation 3, 4
• Exclude allergies, drug reactions, infections 2

Idiopathic MCAS:

• No identifiable trigger and no KIT mutation detected 1, 3, 4

Treatment Algorithm

First-Line Preventive Therapy

Start with nonsedating H1 antihistamines at 2-4 times standard FDA-approved doses combined with H2 antihistamines. 1, 2

• H1 antihistamines: nonsedating preferred (cetirizine, loratadine, fexofenadine) to avoid cognitive decline, especially in elderly 1
• H2 antihistamines: particularly effective for gastrointestinal symptoms and may help attenuate cardiovascular symptoms 1
• Avoid sedating H1 antihistamines (diphenhydramine) chronically due to anticholinergic effects causing cognitive decline 1

Oral cromolyn sodium for gastrointestinal symptoms: 1, 5

• FDA-indicated for mastocytosis with proven efficacy for diarrhea, abdominal pain, flushing, urticaria, pruritus 5
• Divided dosing with weekly upward titration improves tolerance 1
• Clinical improvement occurs within 2-6 weeks of treatment initiation 5

Mediator-Specific Therapy

Tailor treatment based on elevated mediator levels: 1

• If urinary LTE4 elevated: add montelukast or zileuton (leukotriene inhibitors) for bronchospasm or gastrointestinal symptoms 1
• If urinary 11β-PGF2α elevated: consider aspirin 325-650 mg twice daily to reduce flushing and hypotension 1
  • Critical caveat: aspirin is contraindicated in patients with NSAID hypersensitivity and must be used with extreme caution as it can trigger mast cell activation 1
  • Start low and titrate slowly while monitoring for adverse reactions

Additional Preventive Agents

• Doxepin: potent H1 and H2 antihistamine with tricyclic antidepressant activity for neuropsychiatric manifestations, but avoid in elderly due to cognitive effects 1
• Omalizumab: prevents anaphylactic episodes in refractory cases 1
• Cyproheptadine: sedating H1 antihistamine with antiserotonergic activity for gastrointestinal symptoms 1

Acute Episode Management

For anaphylaxis or severe episodes: 1

• Epinephrine autoinjector intramuscularly—prescribe for all patients with history of systemic anaphylaxis or airway angioedema 1
• Supine positioning immediately for hypotensive episodes 1
• Albuterol via nebulizer or metered-dose inhaler for bronchospasm 1

Refractory Disease

Corticosteroid burst for refractory symptoms: 1

• Initial dose 0.5 mg/kg/day prednisone (approximately 50 mg), slow taper over 1-3 months 1
• For procedures: 50 mg prednisone at 13 hours, 7 hours, and 1 hour before when mast cell activation has been problematic 1
• Long-term use limited by side effects 1

Trigger Avoidance

Identify and eliminate specific triggers through detailed history: 1

• Temperature extremes (hot water, cold exposure)
• Mechanical irritation (friction, pressure)
• Alcohol
• Specific medications (opioids, NSAIDs, contrast agents)
• Stress and anxiety
• Exercise
• Insect venoms
• Infections

Critical Diagnostic Pitfalls

MCAS is substantially overdiagnosed—do not diagnose based on: 1, 2

• Nonspecific symptoms alone without documented mediator elevation
• Single organ system involvement
• Chronic persistent symptoms (these suggest alternative diagnoses)
• Symptoms without therapeutic response to mast cell-targeted therapy

Tests NOT recommended: 2

• Plasma or urine histamine levels (use N-methylhistamine instead)
• Heparin (not validated)
• Chromogranin A (resides in neuroendocrine cells, not mast cells)

Treatment Response as Diagnostic Criterion

Clinical improvement with mast cell-targeted therapy is mandatory for diagnosis—if symptoms do not respond to H1/H2 antihistamines, mast cell stabilizers, or leukotriene modifiers, reconsider the diagnosis. 1, 2