What are the diagnostic tests and treatment options for mast cell activation syndrome (MCAS)?

Diagnostic Testing for Mast Cell Activation Syndrome

For suspected MCAS, obtain serum tryptase at baseline and 1-4 hours after symptom onset, looking for an increase of ≥20% above baseline plus 2 ng/mL, combined with clinical criteria of episodic multi-system symptoms and response to antimediator therapy. 1

Diagnostic Criteria Framework

The diagnosis of MCAS requires meeting three specific criteria simultaneously 1, 2:

• Clinical symptoms: Episodic signs of systemic mast cell activation affecting at least 2 organ systems (skin, gastrointestinal, cardiovascular, respiratory, neurologic) 1
• Laboratory evidence: Documented increase in mast cell mediators during symptomatic episodes 1
• Treatment response: Improvement with medications blocking mast cell mediators or their production 1

Laboratory Testing Protocol

Serum Tryptase (Primary Biomarker)

Obtain tryptase levels at three time points 1, 2:

• Baseline tryptase when asymptomatic (establish personal baseline) 1
• During acute symptoms (as soon as feasible, ideally within 1-4 hours of symptom onset) 1
• At 24 hours or during convalescence 3

Diagnostic threshold: Increase of ≥20% above baseline PLUS 2 ng/mL during symptomatic episodes 1, 2

Important caveat: Serum tryptase may be <20 ng/mL or only transiently elevated in MCAS, unlike systemic mastocytosis where baseline is typically >20 ng/mL 1

Urine Mast Cell Mediators (Complementary Testing)

When serum tryptase is difficult to obtain or negative, consider 24-hour urine collection for 1, 4:

• N-methylhistamine (histamine metabolite) - more reliable than plasma/urine histamine 1, 4
• Leukotriene E4 (LTE4) - indicates leukotriene pathway activation 1, 4
• 11β-prostaglandin F2α (PGD2 metabolite) - indicates prostaglandin pathway activation 1, 4

Advantage: Non-invasive, can be collected at home during symptomatic episodes 4

Distinguishing MCAS from Systemic Mastocytosis

When to Pursue Bone Marrow Evaluation

Proceed with bone marrow biopsy if 1:

• Baseline serum tryptase persistently >20 ng/mL 1
• Adult-onset mastocytosis in the skin (MIS) present 1
• Abnormal blood counts or organomegaly (B or C findings) 1

Bone Marrow Testing Components

If bone marrow biopsy indicated 1:

• Molecular testing for KIT D816V mutation (confirms clonality) 1
• Additional KIT gene sequencing if D816V negative 1
• Mast cell immunophenotyping by flow cytometry: CD117, CD25, CD2 1
• Immunohistochemistry: CD117, CD25, tryptase (CD30 optional) 1
• Screen for FIP1L1-PDGFRA if eosinophilia present 1

Diagnostic distinction: Detection of KIT D816V mutation or CD25 expression on mast cells indicates primary (clonal) MCAS, which may progress to systemic mastocytosis 1

Classification After Testing

Primary MCAS

• KIT-mutated clonal mast cells detected OR aberrant CD25 expression 1, 5
• Does not meet full WHO criteria for systemic mastocytosis 1

Secondary MCAS

• Underlying IgE-dependent allergy or inflammatory condition identified 1, 5
• No KIT mutations or clonal markers 1, 5

Idiopathic MCAS

• No identifiable trigger, allergy, or clonal markers 1, 5
• Diagnosis of exclusion after comprehensive evaluation 1

Hereditary Alpha-Tryptasemia

• Elevated baseline tryptase with TPSAB1 gene duplications/triplications 1
• Associated symptoms: flushing, pruritus, dysautonomia, GI symptoms, joint hypermobility 1

Additional Considerations

Problematic biomarkers to avoid 1:

• Plasma or urine histamine (not validated; use N-methylhistamine instead) 1
• Heparin (not validated for MC activation) 1
• Chromogranin A (resides in neuroendocrine cells, not mast cells) 1

Gastrointestinal biopsies: CD-117 immunohistochemical staining in duodenum or ileum is more sensitive than counting mast cells per high-power field, though thresholds remain controversial 1

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Treatment of Mast Cell Activation Syndrome

Initiate treatment with nonsedating H1 antihistamines at 2-4 times standard doses combined with H2 antihistamines, then add oral cromolyn sodium for gastrointestinal symptoms, tailoring therapy based on specific mediator elevations. 1

Acute Episode Management

Anaphylaxis Protocol

For hypotension, laryngeal angioedema, or severe bronchospasm 1:

• Assume supine position immediately 1
• Administer intramuscular epinephrine (patients should carry autoinjector) 1
• Call emergency services; transport supine by ambulance 1
• Supplemental oxygen 100%, IV fluids 3
• Secondary management: chlorphenamine, hydrocortisone 3

Critical point: 20-50% of systemic mastocytosis patients experience anaphylaxis, typically with hypotension rather than laryngeal angioedema 1

Preventive Pharmacotherapy

First-Line: H1 Antihistamines

Nonsedating H1 antihistamines are preferred 1, 6, 3:

• Fexofenadine, cetirizine, or loratadine 1, 6
• Dose: 2-4 times FDA-approved standard dose for symptom control 1, 6
• Superior to first-generation agents due to lack of sedation and cognitive impairment 1, 6

First-generation H1 antihistamines (diphenhydramine, hydroxyzine, doxepin) 1, 6:

• May cause acute drowsiness, impaired driving ability 1
• Chronic use associated with cognitive decline, especially in elderly 1, 6
• Doxepin has dual H1/H2 activity and may help neuropsychiatric symptoms but increases suicidal tendencies in young adults with depression 1

Add H2 Antihistamines

Famotidine or ranitidine 1, 6, 3:

• First-line for gastrointestinal symptoms 1, 6
• Enhances cardiovascular symptom control when combined with H1 blockers 1, 3
• Can be used as initial therapy alongside H1 antihistamines 1

Mast Cell Stabilizers

Oral cromolyn sodium 1, 6, 3:

• Reduces abdominal bloating, diarrhea, cramps 1
• May benefit neuropsychiatric manifestations 1
• Dosing strategy: Start at lowest dose, gradually titrate weekly to target of 200 mg four times daily 1, 3
• Divided dosing and slow upward titration improves tolerance and adherence 1

Mediator-Specific Therapy

Tailor treatment based on elevated mediators 1, 6:

If Urinary LTE4 Elevated

• Leukotriene antagonists: Montelukast or zileuton 1, 6
• Add if inadequate response to antihistamines 6

If Prostaglandin Metabolites Elevated

• Aspirin therapy may be beneficial 1, 6
• Major caveat: Can trigger mast cell activation in some patients; use with extreme caution 1, 6
• Monitor closely for paradoxical worsening 6

Trigger Avoidance

Identify and eliminate specific triggers 1, 6, 3:

• Insect venoms (consider lifelong venom immunotherapy if history of anaphylaxis) 1
• Temperature extremes 1, 3
• Mechanical irritation 1, 3
• Alcohol 1, 3
• Medications: aspirin, radiocontrast agents, certain anesthetics 1, 3
• NSAIDs (may trigger reactions in some patients) 6

For venom-allergic patients: Omalizumab during immunotherapy reduces anaphylaxis risk 1

Special Considerations

Opioid Use

• Codeine and morphine may trigger mast cell activation 6
• However: Should not be withheld if needed, as pain itself can trigger mast cell activation 6
• Use with caution but do not categorically avoid 6

Perioperative Management

• Multidisciplinary coordination with anesthesia and surgical teams 1, 3
• Pre-anesthetic treatment: anxiolytics, antihistamines, possibly corticosteroids 3
• Avoid known mast cell-triggering anesthetic agents 3

Bone Pain Management (if present)

• Supplemental calcium and vitamin D 6
• Bisphosphonates improve vertebral bone mineral density and resolve bone pain (continue antihistamines concurrently) 6

Treatment Monitoring

If symptoms persist despite first-line therapy 6:

• Measure mediator levels at baseline and during acute episodes 6
• Adjust therapy based on specific mediator elevations 6
• If only histamine products elevated: focus on antihistamines 6
• If prostaglandins elevated: consider aspirin (with caution) 6

Prognosis and Duration

• Some clonal MCAS patients progress to indolent systemic mastocytosis 1
• Patients with indolent SM demonstrate normal life expectancy 1
• Treatment is typically long-term and symptom-based 1

Referral Indications

Refer to allergy specialist or mast cell disease research center when 1:

• Diagnosis confirmed through clinical and laboratory features 1
• Complex cases requiring advanced testing or management 1
• Consideration of additional therapies beyond first-line agents 1