What is the recommended workup for mast cell activation syndrome (MCAS)?

Workup for Mast Cell Activation Syndrome

The diagnosis of MCAS requires three essential criteria: (1) episodic symptoms affecting at least two organ systems consistent with mast cell mediator release, (2) documented elevation of mast cell mediators during symptomatic episodes on at least two occasions, and (3) clinical response to mast cell-targeted therapies. 1

Clinical Criteria: Identifying the Symptom Pattern

The diagnosis begins with recognizing recurrent, episodic symptoms affecting at least two organ systems concurrently (consistent with systemic anaphylaxis criteria): 1

Required Organ System Involvement (≥2 systems):

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

Important Clinical Distinctions:

Symptoms that lack precision for MCAS diagnosis and should not be used as primary diagnostic criteria include: fatigue, fibromyalgia-like pain, dermographism, chronic constipation, headache, mood disturbances, anxiety, weight changes, and various psychiatric/neurologic disorders. 1 These symptoms are common in many conditions and do not specifically indicate mast cell activation.

Laboratory Testing: Documenting Mast Cell Activation

Essential Biomarker Testing:

Serum tryptase measurement is the cornerstone of laboratory diagnosis: 1

• Baseline serum tryptase: Obtain when patient is asymptomatic to establish individual baseline 1
• Acute serum tryptase: Measure within 30-120 minutes of symptom onset during an episode 1
• Diagnostic threshold: Acute tryptase must exceed baseline by >20% + 2 ng/mL on at least two separate occasions 1

Additional Mediator Testing:

24-hour urine collection for histamine metabolites (N-methylhistamine) is recommended over plasma or serum histamine levels due to superior sensitivity and specificity. 1

Urinary prostaglandin D2 metabolite (11-β-prostaglandin F2α) provides additional diagnostic support. 1, 2

Urinary leukotriene E4 (LTE4) can guide therapeutic decisions, particularly if elevated. 1, 3

Tests NOT Recommended:

• Plasma or urine histamine levels (inferior to metabolites) 1
• Heparin levels (not validated as MC activation marker) 1
• Chromogranin A (resides in neuroendocrine cells, not mast cells) 1

Determining MCAS Subtype: Critical for Management

Genetic and Clonality Testing:

Peripheral blood testing for KIT D816V mutation should be performed to identify clonal MCAS. 1 However, sensitivity is limited in peripheral blood. 1

Buccal swab for hereditary alpha-tryptasemia (TPSAB1 α-tryptase copy number variation) identifies this genetic condition associated with MCAS. 1

When to Pursue Bone Marrow Evaluation:

Bone marrow biopsy and aspirate are indicated when: 1

• Baseline serum tryptase persistently >20 ng/mL (suggests possible systemic mastocytosis) 1
• Positive REMA score (sex, baseline tryptase, pruritus/hives/angioedema, presyncope/syncope) or NIH score suggests clonal disease 1
• Peripheral blood KIT mutation is negative but clinical suspicion for clonal disease remains high 1
• Patient fails to respond adequately to standard antimediator therapy (may identify KIT mutation amenable to tyrosine kinase inhibitor therapy) 1

The bone marrow evaluation can: 1

• Diagnose or stage systemic mastocytosis
• Identify clonal mast cells with KIT mutations missed in peripheral blood
• Detect CD25 expression on mast cells (surrogate marker for clonality)
• Identify dense aggregates of spindle-shaped mast cells

Critical caveat: Bone marrow biopsy cannot identify mast cell activation itself—it only identifies clonal expansion or mastocytosis. 1

Therapeutic Trial as Diagnostic Criterion

Response to mast cell-targeted therapy is a required diagnostic criterion: 1

The patient must demonstrate clinical improvement with:

• H1 antihistamines (nonsedating preferred, can increase to 2-4× standard dose) 1, 3
• H2 antihistamines 1, 3
• Mast cell stabilizers (cromolyn sodium) 3
• Leukotriene modifiers (if urinary LTE4 elevated) 1, 3

Classification After Workup

Based on testing results, classify as: 1, 4

1. Primary MCAS: KIT mutation or other clonal marker identified 1, 4
2. Secondary MCAS: Underlying IgE-mediated allergy or inflammatory condition identified, no clonal markers 4
3. Idiopathic MCAS: No underlying allergy, inflammatory condition, or clonal markers identified 1, 4

Critical Pitfalls to Avoid

MCAS is substantially overdiagnosed. A prospective study found only 2% of patients with suspected MCAS actually met diagnostic criteria. 5 The majority had other conditions, frequently including depression and anxiety disorders. 5

Do not diagnose MCAS based solely on: 1

• Nonspecific symptoms like fatigue, chronic pain, or mood disturbances
• Single organ system involvement
• Symptoms without documented mediator elevation
• Increased mast cell numbers on gastrointestinal biopsies (does not indicate activation) 1

Rule out other conditions that can mimic MCAS before making the diagnosis, as patients require evidence-based treatment for their actual underlying condition. 1, 6 Many patients require multidisciplinary evaluation. 6, 7