What is the approach to evaluate a patient for mast cell activation syndrome (MCAS)?

Evaluation of Mast Cell Activation Syndrome

To evaluate for MCAS, confirm episodic symptoms affecting ≥2 organ systems simultaneously, document acute mast cell mediator elevation during symptomatic episodes (serum tryptase increase ≥20% above baseline plus ≥2 ng/mL), and demonstrate clinical response to mast cell-targeted therapies—all three criteria must be met. 1, 2

Essential Clinical Criteria

Verify episodic, not chronic symptoms. MCAS requires recurrent acute episodes with symptom-free intervals between attacks. 2 Persistent or continuous symptoms are inconsistent with MCAS and should redirect you toward alternative diagnoses such as systemic mastocytosis, functional gastrointestinal disorders, or other unrelated pathology. 2

Multi-System Involvement Required

Document concurrent involvement of at least 2 organ systems during acute episodes: 1, 2

• Cardiovascular: Hypotension, tachycardia, syncope or near-syncope 2
• Dermatologic: Urticaria, pruritus, flushing, angioedema (particularly eyelids, lips, tongue) 2
• Respiratory: Wheezing, dyspnea, inspiratory stridor 2
• Gastrointestinal: Crampy abdominal pain, diarrhea, nausea, vomiting 2
• Neurologic: Neuropsychiatric manifestations 1

Laboratory Evaluation Algorithm

Step 1: Establish Baseline Tryptase

Obtain baseline serum tryptase when the patient is completely asymptomatic to establish their personal reference value. 1 This baseline is critical for interpreting acute values.

Step 2: Capture Acute Episode Mediators

During a suspected mast cell activation episode, collect acute serum tryptase 1-4 hours after symptom onset. 1, 2 The diagnostic threshold requires an increase ≥20% above the patient's baseline PLUS an absolute increase ≥2 ng/mL. 1, 2

Step 3: Additional Mediator Testing

When serum tryptase is difficult to obtain or negative, perform 24-hour urine collection for: 1

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

Tests to Avoid

Do not order plasma or urine histamine levels—use N-methylhistamine instead. 1 Heparin is not validated as a marker of mast cell activation. 1 Chromogranin A is not reliable as it resides in neuroendocrine cells, not mast cells. 1

Clonality and Genetic Assessment

Peripheral Blood Testing

Perform highly sensitive allele-specific oligonucleotide quantitative PCR (ASO-qPCR) for KIT D816V mutation to identify clonal (primary) MCAS. 1 Use buccal swab for TPSAB1 α-tryptase copy number variation (CNV) to diagnose hereditary α-tryptasemia. 1

Bone Marrow Evaluation Indications

Bone marrow biopsy is indicated if: 1

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

Bone marrow analysis should include aspirate, core biopsy, immunohistochemistry, flow cytometry, cytogenetics, and FISH for associated hematologic neoplasm-related abnormalities. 1 If peripheral blood KIT D816V is negative, repeat testing on bone marrow using highly sensitive assays. 1

Differential Diagnosis Considerations

Exclude secondary causes before confirming MCAS diagnosis: 1

• IgE-mediated allergies
• Drug reactions
• Infections
• Disorders of gut-brain interaction (functional dyspepsia, IBS) if mild persistent GI symptoms exist between flares 2
• POTS (can cause chronic nausea, abdominal pain, early satiety independent of MCAS) 2
• Gastroparesis or other motility disorders, particularly with hypermobility spectrum disorder 2

Treatment Response Confirmation

The third mandatory criterion is documented improvement with mast cell-targeted therapies: 1, 2

• H1 antihistamines at 2-4 times standard doses 1
• H2 antihistamines 1
• Oral cromolyn sodium for gastrointestinal symptoms 1
• Leukotriene antagonists (montelukast or zileuton) if urinary LTE4 is elevated 1
• Aspirin therapy if prostaglandin metabolites are elevated (use with caution due to risk of triggering mast cell activation) 1

Critical Pitfalls to Avoid

Do not diagnose MCAS based on symptoms alone. All three criteria (episodic multi-system symptoms, documented mediator elevation during episodes, and treatment response) must be met simultaneously. 1, 2

Do not pursue MCAS testing in patients with chronic, persistent symptoms. This presentation is inconsistent with MCAS and warrants investigation for alternative diagnoses. 2

Do not rely on a single elevated baseline tryptase. You must demonstrate acute elevation above the patient's personal baseline during symptomatic episodes. 1, 2

Refer patients to an allergy specialist or mast cell disease research center for additional testing and management when the diagnosis remains uncertain or symptoms are refractory. 1