What are the diagnostic criteria and treatment options for a patient with a history of recurrent allergic reactions, autoimmune disorders, or other chronic conditions, presenting with symptoms such as hives, itching, flushing, or gastrointestinal issues, suspected of having Mast Cell Activation Syndrome (MCAS)?

Diagnostic Testing for Mast Cell Activation Syndrome (MCAS)

MCAS diagnosis requires meeting all three criteria simultaneously: episodic symptoms affecting at least 2 organ systems, documented acute elevation of mast cell mediators during symptomatic episodes, and clinical response to mast cell-targeted therapies. 1, 2

Essential Clinical Features Required Before Testing

Only pursue MCAS testing when patients present with acute, recurrent, episodic symptoms—not chronic continuous symptoms. 1 The key distinguishing feature is that symptoms must be intermittent with symptom-free intervals between episodes. 1

Symptoms Must Involve ≥2 Organ Systems Simultaneously

The following combinations qualify 3, 1:

• Cardiovascular: Hypotension, tachycardia, syncope or near-syncope 1
• Dermatologic: Urticaria, pruritus, flushing, angioedema (particularly eyelids, lips, tongue) 1
• Respiratory: Wheezing, shortness of breath, inspiratory stridor 1
• Gastrointestinal: Crampy abdominal pain, diarrhea, nausea, vomiting occurring during acute episodes 1

Critical Pitfall: Chronic Symptoms Exclude MCAS

Persistent daily symptoms or chronically elevated mediator levels are inconsistent with MCAS and indicate alternative diagnoses. 1 Chronic gastrointestinal symptoms between flares suggest disorders of gut-brain interaction (IBS, functional dyspepsia), POTS, gastroparesis, or motility disorders rather than MCAS. 1

Laboratory Testing Algorithm

Step 1: Establish Baseline Serum Tryptase

Obtain baseline serum tryptase when the patient is completely asymptomatic to establish their personal reference value. 1, 2 This baseline is essential because the diagnostic threshold is relative to each individual's baseline, not an absolute number. 2

Step 2: Capture Acute Mediator Elevation During Episodes

Collect acute serum tryptase 1-4 hours after symptom onset during a suspected mast cell activation episode. 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 (24-Hour Urine Collection)

When serum tryptase is difficult to obtain during episodes or remains negative, collect 24-hour urine for 3, 2:

• N-methylhistamine (NOT direct histamine, which is unreliable) 2
• Leukotriene E4 (peaks in 0-6 hour collections; guides leukotriene antagonist therapy) 3, 2
• 11β-prostaglandin F2α (peaks in 0-3 hour collections; correlates with anaphylactic severity) 3, 2

Tests NOT to Order

The following are not validated markers and should not be used 2:

• Plasma or urine histamine levels 2
• Heparin 2
• Chromogranin A (resides in neuroendocrine cells, not mast cells) 2

Genetic and Clonality Testing to Classify MCAS Subtype

Peripheral Blood Testing

Perform KIT D816V mutation testing using highly sensitive allele-specific oligonucleotide quantitative PCR (ASO-qPCR) on peripheral blood to identify clonal (primary) MCAS. 2 If positive, this confirms primary MCAS with somatic mutation. 3

Obtain buccal swab for TPSAB1 α-tryptase copy number variation (CNV) testing to diagnose hereditary α-tryptasemia. 3, 2 This identifies patients with germline mutations predisposing to mast cell hyperactivation. 3

When to Pursue Bone Marrow Evaluation

Bone marrow biopsy is indicated only if baseline serum tryptase is persistently >20 ng/mL or if clinical features suggest systemic mastocytosis (adult-onset mastocytosis in skin, abnormal blood counts, organomegaly). 2 The evaluation must include aspirate, core biopsy, immunohistochemistry, flow cytometry, cytogenetics, and FISH. 2

If peripheral blood KIT D816V is negative but clinical suspicion remains high (positive REMA score: sex, elevated baseline tryptase, pruritus/hives/angioedema, presyncope/syncope), bone marrow testing for KIT mutations should be considered. 3

Confirming the Third Diagnostic Criterion: Treatment Response

Document clinical improvement with mast cell-targeted therapies to complete the diagnostic triad. 3, 1 This includes response to 3:

• H1 antihistamines (at 2-4 times standard doses) combined with H2 antihistamines 3
• Oral cromolyn sodium for gastrointestinal symptoms 3
• Leukotriene antagonists (montelukast, zileuton) if urinary LTE4 is elevated 3
• Aspirin if prostaglandin metabolites are elevated (use cautiously due to potential triggering) 3

Classification After Diagnosis

Once all three criteria are met, classify the patient as 3, 4, 5:

• Primary MCAS: KIT-mutated clonal mast cells detected 3, 5
• Secondary MCAS: Underlying IgE-dependent allergy or other reactive condition identified, no KIT mutation 5
• Idiopathic MCAS: Neither triggering reactive state nor KIT-mutated mast cells identified 5

Differential Diagnosis Considerations

Exclude secondary causes before confirming MCAS, including 2, 6:

• IgE-mediated allergies (food, drug, venom) 2, 6
• Autoimmune disorders 6
• Infectious processes 2
• Neoplastic conditions 6
• Functional gastrointestinal disorders 1
• POTS and autonomic dysfunction 1

Many patients referred for suspected MCAS have other unrelated diseases or less severe forms of mast cell activation that do not meet MCAS criteria. 7, 6 The most severe MCAS events typically occur in combined forms where KIT-mutated mast cells, IgE-dependent allergies, and sometimes hereditary α-tryptasemia coexist. 4