What are the diagnostic criteria and treatment options for a patient with suspected Mast Cell Activation Syndrome (MCAS) presenting with chronic symptoms such as hives, itching, flushing, and gastrointestinal issues?

MCAS Diagnosis and Treatment

Diagnostic Criteria

MCAS diagnosis requires meeting all three criteria simultaneously: episodic symptoms affecting at least 2 organ systems, documented elevation of mast cell mediators during symptomatic episodes (≥20% increase above baseline plus 2 ng/mL for tryptase), and clinical improvement with mast cell-targeted therapies. 1

Clinical Criteria

The symptoms must be episodic, not chronic, and involve at least 2 of these 4 organ systems concurrently: 1

• Cardiovascular: Hypotension, tachycardia, syncope or near-syncope 1
• Respiratory: Wheezing, shortness of breath, inspiratory stridor 1
• Dermatologic: Flushing, urticaria, pruritus, angioedema 1
• Gastrointestinal: Diarrhea, nausea with vomiting, crampy abdominal pain 1

Critical pitfall: Chronic, persistent symptoms like fatigue, fibromyalgia-like pain, dermographism, headache, mood disturbances, or weight changes lack diagnostic precision for MCAS and should not be used as primary diagnostic criteria. 1 These symptoms often represent other conditions that require independent evaluation and treatment. 1

Laboratory Testing Algorithm

Step 1: Establish baseline 1, 2

• Obtain serum tryptase when completely asymptomatic to establish personal reference value 1, 2
• Consider baseline 24-hour urine collection for N-methylhistamine, leukotriene E4, and 11β-prostaglandin F2α 2

Step 2: Document acute elevation during symptoms 1, 2

• Collect acute serum tryptase 1-4 hours after symptom onset 1, 2
• Diagnostic threshold: ≥20% increase above baseline PLUS absolute increase ≥2 ng/mL 1, 2
• If acute tryptase collection is difficult, use 24-hour urine for N-methylhistamine (more reliable than direct histamine), leukotriene E4 (peaks 0-6 hours), and 11β-prostaglandin F2α (peaks 0-3 hours) 2

Important: Do NOT use plasma or urine histamine levels, heparin, or chromogranin A—these are not validated markers. 2

Clonality and Subtype Classification

After confirming MCAS diagnosis, determine the subtype: 2, 3

Primary (clonal) MCAS: 2, 3

• Peripheral blood KIT D816V mutation testing using highly sensitive allele-specific oligonucleotide quantitative PCR (ASO-qPCR) 2, 3
• Buccal swab for TPSAB1 α-tryptase copy number variation to diagnose hereditary α-tryptasemia 2

Bone marrow biopsy indications: 2, 3

• Baseline serum tryptase persistently >20 ng/mL 2, 3
• Positive peripheral blood KIT D816V mutation 3
• Clinical features suggesting systemic mastocytosis (adult-onset mastocytosis in skin, abnormal blood counts, organomegaly) 2

Bone marrow analysis must include aspirate, core biopsy, immunohistochemistry, flow cytometry, KIT D816V mutation analysis, and cytogenetics. 3

Secondary MCAS: Identify underlying IgE-mediated allergies, drug reactions, or infections as triggers. 2

Idiopathic MCAS: Neither clonal MCs nor reactive triggers identified. 2

Treatment Approach

First-Line Therapy

Initiate treatment with high-dose H1 antihistamines (2-4 times standard doses) combined with H2 antihistamines as the foundation of therapy. 2

• H1 antihistamines: Nonsedating agents at 2-4 times standard doses 2
• H2 antihistamines: Add for synergistic effect 2
• Oral cromolyn sodium: 200 mg four times daily for gastrointestinal symptoms 2

Mediator-Specific Therapy

Tailor additional medications based on elevated urinary mediators: 2

• Leukotriene antagonists (montelukast or zileuton): If urinary leukotriene E4 elevated 2
• Aspirin therapy: If prostaglandin metabolites elevated, but use cautiously as it may trigger mast cell activation in some patients 2

Acute Episode Management

For anaphylaxis: 2

• Assume supine position immediately 2
• Administer intramuscular epinephrine 0.3-0.5 mg (1:1000) into anterolateral thigh 2
• Call emergency services 2
• Provide supplemental oxygen and IV fluids 2
• Secondary management: chlorphenamine and hydrocortisone 2

All patients with history of anaphylaxis require epinephrine auto-injector prescription and training. 2

Trigger Avoidance

Identify and eliminate specific triggers: 2, 4

• Insect venoms, temperature extremes, mechanical irritation, alcohol 2
• Certain medications (NSAIDs, opioids, radiocontrast) 2
• Hormonal fluctuations (document temporal relationships with symptom episodes) 4

Opioid consideration: Use caution as they may trigger mast cell activation, but do not categorically avoid when medically necessary. 2

Perioperative Management

For patients requiring surgery: 2

• Coordinate with anesthesia and surgical teams 2
• Consider pre-anesthetic treatment with anxiolytics, antihistamines, and corticosteroids 2
• Avoid known mast cell-triggering anesthetic agents 2

Refractory Cases

If symptoms persist despite maximal medical therapy, refer to allergy specialist or mast cell disease research center for additional testing and consideration of advanced therapies. 1, 2

Common Diagnostic Pitfalls

1. Do not diagnose MCAS based solely on chronic symptoms without documented episodic multi-system involvement and laboratory confirmation. 1, 4

2. Exclude other conditions first: Many patients referred for suspected MCAS have autoimmune, neoplastic, infectious diseases, or disorders of gut-brain interaction that require independent treatment. 1

3. In patients with hypermobile Ehlers-Danlos syndrome or POTS: Test for MCAS only if episodic symptoms suggest generalized mast cell disorder involving multiple organ systems, not for routine GI symptoms alone. 1

4. Document treatment response: Improvement with mast cell-targeted therapies is required to confirm diagnosis. 1, 2