I have an elevated serum tryptase level and chronic urticaria; what diagnosis should I consider and how should I be evaluated and managed?

Elevated Tryptase and Chronic Urticaria: Diagnostic and Management Approach

If you have chronic urticaria with elevated baseline tryptase, you should first distinguish whether this represents persistent mast cell burden (systemic mastocytosis, hereditary alpha-tryptasemia) versus episodic mast cell activation syndrome, as chronic persistent urticaria itself argues against MCAS and suggests an alternative diagnosis. 1

Critical Distinction: Chronic vs. Episodic Symptoms

The nature of your urticaria is diagnostically crucial:

• Persistent, chronic urticaria should direct you away from mast cell activation syndrome (MCAS) as the primary diagnosis, as MCAS characteristically presents with episodic, recurrent symptoms affecting at least 2 organ systems concurrently, not chronic continuous symptoms. 1
• Chronic urticaria with elevated tryptase more likely represents either underlying systemic mastocytosis with cutaneous manifestations, hereditary alpha-tryptasemia, or chronic urticaria from another cause coincidentally occurring with elevated tryptase. 1

Immediate Diagnostic Workup

Confirm True Baseline Elevation

• Repeat tryptase measurement when completely asymptomatic (>24 hours after any symptoms) to establish a true baseline, as acute measurements may reflect recent mast cell degranulation even without recognized symptoms. 2, 3
• If baseline tryptase remains >20 ng/mL on repeat testing, this meets a minor WHO diagnostic criterion for systemic mastocytosis and mandates bone marrow evaluation. 1, 2

Triage by Tryptase Level

• Tryptase 20-200 ng/mL: Proceed with outpatient bone marrow evaluation and comprehensive workup. 2
• Tryptase >200 ng/mL: Requires urgent hematology referral and possible hospitalization, as this strongly suggests advanced systemic mastocytosis or mast cell leukemia. 2, 3
• Tryptase 8-20 ng/mL: Consider hereditary alpha-tryptasemia (present in 4-6% of general population), which causes elevated baseline tryptase with symptoms including cutaneous flushing, pruritus, dysautonomia, gastrointestinal symptoms, chronic pain, and joint hypermobility. 1

Comprehensive Clinical Assessment

Examine for Systemic Mastocytosis Features

• Thoroughly examine skin for urticaria pigmentosa lesions (small red-brown macules or papules that urticate with stroking—positive Darier's sign occurs in 89-94% of cutaneous mastocytosis). 2, 3
• Assess for B-findings and C-findings indicating organ involvement: hepatosplenomegaly, lymphadenopathy, unexplained osteoporosis, cytopenias, or malabsorption. 1, 2
• Review history for severe anaphylaxis to Hymenoptera (wasp/bee) stings, which is strongly associated with underlying mastocytosis. 2

Distinguish MCAS from Other Diagnoses

MCAS requires all three criteria to be met: 1, 4

1. Episodic symptoms affecting ≥2 organ systems concurrently (cardiovascular, dermatologic, respiratory, gastrointestinal)—not chronic continuous symptoms
2. Acute tryptase elevation >20% + 2 ng/mL above baseline on ≥2 separate occasions during symptomatic episodes
3. Response to antimediator therapy (H1/H2 antihistamines, mast cell stabilizers)

Your chronic urticaria does not fit the episodic pattern required for MCAS diagnosis. 1

Mandatory Bone Marrow Evaluation (if tryptase >20 ng/mL)

The bone marrow workup must include: 1, 2

• Bone marrow aspiration and core biopsy
• Immunohistochemistry for CD117, CD25, and CD2 expression on mast cells
• KIT D816V mutation testing (present in >90% of systemic mastocytosis)
• Flow cytometry to assess mast cell immunophenotype
• Evaluation for associated hematologic neoplasms (present in up to 71% of advanced cases)

WHO diagnostic criteria require either the major criterion (≥15 mast cells in aggregates in bone marrow) plus one minor criterion, or three minor criteria. 1

Consider Hereditary Alpha-Tryptasemia

• If bone marrow is negative for systemic mastocytosis but baseline tryptase remains elevated (typically 8-15 ng/mL), consider genetic testing for TPSAB1 gene duplications/triplications. 1
• This condition affects 4-6% of the general population and causes elevated baseline tryptase with multisystem symptoms including cutaneous flushing, pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and joint hypermobility. 1

Immediate Safety Measures (Regardless of Final Diagnosis)

All patients with confirmed elevated baseline tryptase require: 2, 5, 3

• Two epinephrine auto-injectors to carry at all times (even if currently asymptomatic)—dose: >12 years 500 μg IM, 6-12 years 300 μg IM, <6 years 150 μg IM
• Medic Alert identification documenting elevated tryptase and anaphylaxis risk
• Trigger avoidance education: extreme temperatures, physical trauma to skin, alcohol, NSAIDs (especially aspirin, ketorolac), opioids (especially morphine, codeine, meperidine), certain antibiotics (vancomycin, fluoroquinolones), contrast media, vigorous exercise, hot water exposure, emotional stress

Symptomatic Management

For Chronic Urticaria

• H1 antihistamines (cetirizine, loratadine, fexofenadine) for urticaria and pruritus—may use up to 4× standard dose for chronic urticaria. 1, 5, 3
• H2 antihistamines (ranitidine, famotidine) provide additional benefit, particularly for gastrointestinal symptoms. 1, 5
• Cromolyn sodium 200 mg orally four times daily for gastrointestinal and neurologic symptoms; topical cromolyn cream 2-4 times daily for localized cutaneous symptoms. 5, 3
• Leukotriene receptor antagonists (montelukast) as adjunctive therapy. 2, 5

For Acute Systemic Reactions (if they occur)

• Intramuscular epinephrine 0.3-0.5 mg immediately into anterolateral thigh—no absolute contraindications; multiple doses may be required. 5, 3
• Aggressive fluid resuscitation with normal saline 5-10 mL/kg boluses for hypotension. 5
• Chlorphenamine 10 mg IV and hydrocortisone 200 mg IV (adult doses). 3

Critical Pitfalls to Avoid

• Do not assume normal tryptase excludes anaphylaxis risk, as anaphylaxis can occur through basophil or complement activation pathways without tryptase elevation. 2
• Do not rely on a single elevated tryptase measurement—obtain both acute (during symptoms) and baseline (>24 hours after symptoms) values to calculate diagnostic ratios. 2, 3
• Do not withhold necessary analgesics, but exercise caution with direct mast cell degranulators like morphine and codeine; fentanyl and sufentanil are safer alternatives. 2, 3
• If surgery is required, notify anesthesia team about elevated tryptase; avoid morphine, meperidine, ketorolac; have emergency anaphylaxis protocols ready; obtain baseline coagulation studies. 2

Ongoing Monitoring

• Annual tryptase monitoring to assess disease burden in confirmed systemic mastocytosis. 2
• Multidisciplinary care involving allergy/immunology and hematology for ongoing symptom management and disease monitoring. 2
• Maintain detailed symptom diary documenting timing, potential exposures, and activities to identify previously unrecognized triggers. 2