What is mast cell activation syndrome?

What is Mast Cell Activation Syndrome?

Mast cell activation syndrome (MCAS) is a primary clinical condition characterized by spontaneous episodic signs and symptoms of systemic anaphylaxis that concurrently affect at least 2 organ systems, result from secreted mast cell mediators, and improve with medications that block these mediators or their production. 1

Core Pathophysiology

MCAS represents a disorder where mast cells become abnormally activatable—either spontaneously or with minimal provocation—rather than responding only to appropriate external triggers like allergens. 1, 2 This distinguishes MCAS from typical allergic reactions, where structurally and functionally normal mast cells respond appropriately to identifiable allergens through IgE-mediated pathways. 2

Key Mechanistic Features

• Mast cells in MCAS have a lower threshold for activation and release inflammatory mediators including histamine, tryptase, prostaglandin D2, and leukotriene C4 during episodes. 1, 2
• Activation can occur through multiple pathways beyond IgE/FcεRI receptors, including G protein-coupled receptors, complement anaphylatoxin receptors, Mas-related G protein receptors, and Toll-like receptors. 1
• The mediators released extend far beyond histamine and tryptase, encompassing numerous biologically active substances that can be prestored in granules or newly synthesized without degranulation. 3

Classification of MCAS Subtypes

MCAS is divided into primary disorders based on underlying pathophysiology: 1

Primary MCAS Categories

• Clonal MCAS: Associated with KIT mutations (particularly D816V) and/or aberrant CD25 expression, but lacking full criteria for systemic mastocytosis. 1, 4
• Hereditary α-tryptasemia: Caused by increased copy numbers of the TPSAB1 gene encoding α-tryptase. 1, 4
• Idiopathic MCAS: No identifiable trigger, mutation, or genetic trait has been found. 1

This contrasts with secondary mast cell activation disorders where normal mast cells respond to external triggers like allergens, and with systemic mastocytosis where clonal mast cell proliferation meets WHO diagnostic criteria. 1, 2

Clinical Presentation

Multi-System Involvement Required

Diagnosis requires episodic symptoms affecting at least 2 organ systems simultaneously, which may include: 1, 4

• Skin: Flushing, urticaria, angioedema, pruritus
• Gastrointestinal: Nausea, vomiting, diarrhea, abdominal cramping (often mistaken for irritable bowel syndrome or functional dyspepsia) 5
• Cardiovascular: Hypotension, tachycardia, syncope, chest pain
• Respiratory: Wheezing, dyspnea, throat swelling
• Neurologic: Headache, brain fog, dizziness

Episodic vs. Chronic Pattern

A critical diagnostic feature is the episodic rather than chronic nature of symptoms. 6 Persistent, unremitting symptoms should prompt consideration of alternative diagnoses rather than MCAS. 6, 7

Common Triggers

Reported triggers include hot water, alcohol, certain drugs, stress, exercise, infection, physical stimuli (pressure, temperature, vibration), and hormonal fluctuations. 1, 6 However, in idiopathic MCAS, episodes may occur without identifiable triggers. 1

Diagnostic Criteria: The Three-Part Requirement

All three of the following criteria must be met simultaneously for MCAS diagnosis: 2, 4

1. Clinical Symptoms

Recurrent episodic symptoms affecting ≥2 organ systems concurrently, consistent with systemic mast cell mediator release. 2, 4

2. Laboratory Evidence

Documented elevation of mast cell mediators during symptomatic episodes: 1, 4

• Serum tryptase: Increase of ≥20% above personal baseline PLUS absolute increase ≥2 ng/mL, measured 1-4 hours after symptom onset. 4
• 24-hour urine N-methylhistamine: More reliable than direct histamine measurement (which is not recommended). 4
• Urinary leukotriene E4: Peaks in 0-6 hour collections after episodes. 4
• Urinary 11β-prostaglandin F2α: Peaks in 0-3 hour collections and correlates with anaphylactic severity. 4

Critical pitfall: Baseline tryptase must be established when completely asymptomatic to serve as the patient's personal reference value. 4 Comparing acute to baseline levels is essential because tryptase is a preformed mediator. 4

3. Treatment Response

Clinical improvement with medications that block mast cell mediator binding to receptors or their production, including: 1, 4

• H1 and H2 histamine receptor antagonists
• Leukotriene receptor antagonists
• COX inhibitors for prostaglandin D2
• 5-lipoxygenase inhibitors for leukotriene C4
• Mast cell stabilizers (cromolyn sodium, omalizumab)

Diagnostic Testing Algorithm

Initial Workup During Symptomatic Episodes

Obtain serum tryptase at baseline (when asymptomatic) and 1-4 hours after symptom onset. 4 Simultaneously collect 24-hour urine for N-methylhistamine, leukotriene E4, and 11β-prostaglandin F2α. 4

Clonality Assessment

• Peripheral blood KIT D816V mutation testing using highly sensitive allele-specific oligonucleotide quantitative PCR (ASO-qPCR). 4
• Buccal swab for TPSAB1 α-tryptase copy number variation to diagnose hereditary α-tryptasemia. 4

When to Pursue Bone Marrow Evaluation

Bone marrow biopsy is indicated if: 4

• Baseline serum tryptase persistently >20 ng/mL
• Clinical features suggesting systemic mastocytosis (adult-onset mastocytosis in skin, abnormal blood counts, organomegaly)

The evaluation should include aspirate, core biopsy, immunohistochemistry, flow cytometry, and KIT D816V mutation testing if peripheral blood is negative. 4

Tests NOT Recommended

Do not order: 4

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

Management Approach

First-Line Chronic Prophylactic Therapy

Initiate nonsedating H1 antihistamines at 2-4 times standard doses, combined with H2 antihistamines. 4 Add oral cromolyn sodium specifically for gastrointestinal symptoms. 4

Targeted Mediator Therapy

• Leukotriene antagonists (montelukast or zileuton) if urinary leukotriene E4 is elevated. 4
• Aspirin therapy if prostaglandin metabolites are elevated, but use with extreme caution as it may paradoxically trigger mast cell activation. 4

Acute Episode Management

For anaphylaxis: Assume supine position, administer intramuscular epinephrine immediately, and activate emergency services. 4 Follow with supplemental oxygen, IV fluids, and secondary management with chlorphenamine and hydrocortisone. 4

Trigger Avoidance

Identify and eliminate specific triggers including insect venoms, temperature extremes, mechanical irritation, alcohol, and certain medications. 4 Use caution with opioids as they may trigger mast cell activation, but do not categorically avoid their use when medically necessary. 4

Refractory Cases

Consider omalizumab (anti-IgE) plus chronic antimediator therapy for combined cases or severe disease. 2 In severe clonal disease, cytoreductive therapy may be required. 2

Critical Diagnostic Pitfalls

Overdiagnosis Risk

Many patients referred for suspected MCAS are ultimately diagnosed with other conditions including autoimmune diseases, neoplastic disorders, infections, or allergic disorders that do not meet MCAS criteria. 7 The increasing number of patients self-diagnosing or being told they have MCAS without thorough medical evaluation represents a significant clinical problem. 7

Distinguishing from Functional Disorders

Gastrointestinal symptoms from MCAS are frequently mistaken for functional gastrointestinal disorders like irritable bowel syndrome or dyspepsia. 5 However, MCAS symptoms should be episodic and affect multiple organ systems simultaneously, not just chronic GI complaints. 6, 5

Secondary Causes Must Be Excluded

Before diagnosing MCAS, exclude secondary causes including IgE-mediated allergies, drug reactions, and infections. 4 Confirm that symptoms are not simply normal mast cell responses to identifiable allergens. 2

Laboratory Timing Is Critical

Mediator testing must be performed during acute symptomatic episodes to have diagnostic value, as these mediators degrade rapidly. 8 Baseline testing alone is insufficient except for establishing the personal reference tryptase level. 4

Perioperative Considerations

Coordinate perioperative management with anesthesia and surgical teams. 4 Consider pre-anesthetic treatment with anxiolytics, antihistamines, and corticosteroids. 4 This proactive approach reduces the risk of intraoperative mast cell activation. 4