What is Mast Cell Activation Syndrome (MCAS)?

Mast Cell Activation Syndrome (MCAS): Overview

Definition and Core Concept

Mast Cell Activation Syndrome is a disorder characterized by recurrent, episodic symptoms affecting at least two organ systems simultaneously due to inappropriate mast cell mediator release, confirmed by documented elevation of mast cell mediators during symptomatic episodes on at least two occasions, and demonstrating clinical response to mast cell-targeted therapies. 1, 2

MCAS represents systemic, severe, and recurrent mast cell activation—typically manifesting as anaphylaxis-like episodes—with a substantial event-related increase in serum tryptase above the individual's baseline. 3

Clinical Presentation

Multi-System Involvement Required

The diagnosis mandates concurrent involvement of at least two organ systems during acute episodes, consistent with systemic anaphylaxis criteria: 1, 2

Cardiovascular manifestations:

• Hypotension, tachycardia, syncope or near-syncope 1

Dermatologic manifestations:

• Flushing, urticaria, pruritus, angioedema (particularly eyelids, lips, tongue) 1

Respiratory manifestations:

• Wheezing, shortness of breath, inspiratory stridor 1

Gastrointestinal manifestations:

• Crampy abdominal pain, diarrhea, nausea with vomiting 1

Episodic vs. Chronic Symptoms

A critical diagnostic feature is that symptoms must be episodic and recurrent, not chronic and persistent. 2 Chronic, isolated symptoms affecting a single organ system do not meet MCAS criteria and should prompt evaluation for alternative diagnoses. 1, 2

Common Triggers

Reported triggers include hot water, alcohol, drugs, stress, exercise, hormonal fluctuations, infection, and physical stimuli such as pressure or friction. 1, 4 However, the connection between triggers and mast cell activation remains generally inconclusive except in rare monogenic disorders. 1

Diagnostic Criteria: The Three Essential Requirements

1. Clinical Criteria: Multi-System Episodic Symptoms

Recurrent episodes affecting at least two organ systems concurrently, with symptoms consistent with mast cell mediator release. 1, 2

2. Laboratory Confirmation: Documented Mediator Elevation

Serum tryptase measurement:

• Obtain baseline serum tryptase when asymptomatic to establish individual baseline 2
• Measure acute serum tryptase within 30-120 minutes of symptom onset during an episode 2
• A significant increase requires the acute level to exceed baseline by the formula: sBT × 1.2 + 2 ng/mL 1

24-hour urine collection for histamine metabolites (N-methylhistamine):

• Superior sensitivity and specificity compared to plasma or serum histamine 2

Additional supportive biomarkers:

• Urinary prostaglandin D2 metabolite (11-β-prostaglandin F2α) 2
• Urinary leukotriene E4 (LTE4)—particularly useful for guiding therapeutic decisions 1, 2

Mediator elevation must be documented on at least two separate occasions during symptomatic episodes. 1, 2

3. Therapeutic Response: Clinical Improvement with Mast Cell-Targeted Therapy

The patient must demonstrate measurable clinical improvement with H1 antihistamines, H2 antihistamines, mast cell stabilizers, or leukotriene modifiers. 2 Therapeutic response should be evaluated over a 2-6 week period before considering escalation. 2

Classification of MCAS Subtypes

Based on testing results, MCAS is classified into three categories: 2

Primary MCAS:

• Associated with clonal mast cell disorders
• Peripheral blood testing for KIT D816V mutation should be performed 2
• Bone marrow biopsy indicated when baseline serum tryptase persistently >20 ng/mL or when clinical suspicion for clonal disease remains high 2
• Surface expression of CD25 on mast cells serves as a surrogate marker for clonality 1

Secondary MCAS:

• Triggered by identifiable external factors (IgE-mediated allergies, medications, infections) 3

Idiopathic MCAS:

• No identifiable clonal disorder or external trigger 3

Management Approach

First-Line Pharmacologic Therapy

H1 antihistamines at 2-4 times FDA-approved doses:

• First-line therapy for most symptoms 2, 4

H2 antihistamines:

• Particularly for gastrointestinal symptoms 2

Leukotriene receptor antagonists (montelukast or zafirlukast):

• Work synergistically with H1 antihistamines 2
• Particularly efficacious for dermatologic symptoms 2
• Specifically indicated if urinary LTE4 levels are elevated 1

Mast cell stabilizers (oral cromolyn sodium):

• Requires at least 1 month at 200 mg four times daily for onset of action 2

Targeted Therapy Based on Mediator Profiles

Treatment should be adjusted based on which mediators are elevated: 1

• Elevated urinary LTE4 → leukotriene antagonists
• Elevated urinary prostaglandin metabolites → aspirin (introduced cautiously in controlled setting due to risk of mast cell degranulation) 1, 2

Prophylactic Strategies

If specific triggers (such as hormonal fluctuations) are consistently identified in confirmed MCAS, consider prophylactic escalation of mast cell-targeted therapy during predictable trigger periods. 4

Critical Diagnostic Pitfalls and Overdiagnosis

MCAS is substantially overdiagnosed in clinical practice. 2 The diagnosis should NOT be made based on: 1, 2

• Nonspecific symptoms alone (fatigue, fibromyalgia-like pain, chronic pain, mood disturbances, anxiety, weight changes, thyroid abnormalities, immunoglobulin abnormalities) 1
• Single organ system involvement 2
• Chronic rather than episodic symptoms 1
• Symptoms without documented mediator elevation on at least two occasions 1, 2
• Dermographism, tired appearance, chronically ill appearance, edema, various rashes, tinnitus, adenopathy, constipation, headache, or multiple psychiatric/neurologic disorders in isolation 1

Many patients referred for suspected MCAS are ultimately diagnosed with autoimmune, neoplastic, infectious diseases, or functional disorders unrelated to mast cell activation. 5 A thorough medical evaluation must exclude alternative diagnoses before applying the MCAS label. 5

Special Considerations

Hereditary Alpha-Tryptasemia

Patients with hereditary alpha-tryptasemia can have concomitant Ehlers-Danlos syndrome and postural orthostatic tachycardia syndrome (POTS), but neither of these manifestations are caused by MCAS. 1 However, MCAS can occur in those with hereditary alpha-tryptasemia, though many affected individuals do not have MCAS. 1

Relationship to Mastocytosis

Detection of an activating KIT mutation (such as D816V) in peripheral blood or tissue demonstrates clonality; dense aggregates of spindle-shaped mast cells suggest underlying mastocytosis. 1 Patients with indolent systemic mastocytosis demonstrate normal life expectancy. 1

Local vs. Systemic Mast Cell Activation

An increase in mast cell numbers in the gastrointestinal tract or elsewhere by itself does not provide a diagnosis of mast cell activation or indicate that mast cell activatability is affected. 1 The diagnostic criteria specifically address systemic, not local, mast cell activation. 1

Prognosis and Multidisciplinary Care

Most MCAS patients require multidisciplinary investigations, and only a personalized treatment approach based on documented mediator profiles and therapeutic response can provide optimal quality of life and low risk of anaphylaxis. 3 When multiple conditions coexist (hereditary alpha-tryptasemia, mastocytosis, atopic diathesis, IgE-dependent or IgE-independent allergies), all must be taken into account when establishing the management plan. 3