What is the management approach for a patient with elevated tryptase levels?

Management of Elevated Tryptase

All patients with persistently elevated baseline tryptase >20 ng/mL require bone marrow aspiration and biopsy with immunohistochemistry and KIT D816V mutation testing to evaluate for systemic mastocytosis. 1, 2, 3

Initial Diagnostic Distinction

The first critical step is determining whether tryptase was measured during acute symptoms or at baseline when asymptomatic, as this fundamentally changes the management approach. 2, 3

Acute Elevation (Measured During Symptoms)

• If tryptase was measured within 1-4 hours of acute symptoms, this represents acute mast cell degranulation requiring immediate anaphylaxis treatment with intramuscular epinephrine 0.3-0.5 mg into the anterolateral thigh. 2, 3
• Establish large-bore IV access and administer rapid fluid boluses with normal saline or lactated Ringer's at 5-10 mL/kg in the first 5 minutes, then 20 mL/kg boluses as needed. 3
• Obtain serial tryptase measurements: initial sample as soon as feasible, second at 1-2 hours after symptom onset, and third at 24 hours or in convalescence to establish both acute and baseline values. 4

Persistent Baseline Elevation (Measured When Asymptomatic)

• If tryptase >20 ng/mL when asymptomatic, this meets a minor diagnostic criterion for systemic mastocytosis and mandates bone marrow evaluation. 1, 2, 3
• Baseline tryptase >200 ng/mL indicates high mast cell burden requiring urgent hematology referral and strongly suggests advanced systemic mastocytosis or mast cell leukemia. 3, 4

Comprehensive Diagnostic Workup

Clinical Evaluation

• Examine skin thoroughly for urticaria pigmentosa or mastocytosis lesions, checking for positive Darier's sign (wheal formation with stroking of skin lesions). 3, 4
• Document symptoms of mast cell mediator release including episodic flushing, urticaria, pruritus, gastrointestinal distress (diarrhea, abdominal cramping, nausea), cardiovascular instability (hypotension, tachycardia, syncope), or anaphylaxis affecting at least two organ systems concurrently. 4
• Review for risk factors including history of severe anaphylaxis to insect stings, unexplained osteoporosis, and hepatosplenomegaly. 3

Laboratory Testing

• Screen for hereditary alpha-tryptasemia via TPSAB1 gene copy number testing in any patient with baseline tryptase >6.5 ng/mL, as this affects 5-7% of the general population and explains many cases of "idiopathic" elevation. 2
• Calculate the beta-tryptase to total tryptase ratio: in systemic mastocytosis this ratio is usually >20, whereas in idiopathic anaphylaxis it is ≤10. 2
• Use the 20% + 2 formula to confirm mast cell activation syndrome: acute elevation >20% + 2 μg/L above baseline on at least 2 separate occasions is diagnostic. 4, 5

Bone Marrow Evaluation (When Indicated)

Bone marrow evaluation is mandatory for baseline tryptase >20 ng/mL and should include: 1, 3

• Bone marrow aspiration and core biopsy
• Immunohistochemistry for CD117 (tryptase), CD25, and CD2 expression on mast cells
• KIT D816V mutation testing
• Evaluation for associated hematologic neoplasms (present in up to 71% of advanced cases)

Diagnostic criteria for systemic mastocytosis require one major criterion (multifocal dense infiltrates of ≥15 mast cells in aggregates) plus one minor criterion, or three minor criteria. 3 Minor criteria include: >25% spindle-shaped or atypical mast cells, KIT D816V mutation, CD25 and/or CD2 expression on mast cells, and baseline tryptase >20 ng/mL. 3

Treatment Approach

Acute Episode Management

• All patients must carry two epinephrine auto-injectors at all times. 2
• Epinephrine 0.3-0.5 mg IM is first-line treatment for anaphylaxis without absolute contraindications. 2
• Treatment of acute episodes is identical to any form of anaphylaxis regardless of underlying cause. 2

Preventive Therapy

• H1 antihistamines combined with H2 antihistamines are first-line preventive agents. 2, 4
• Leukotriene inhibitors and cromolyn sodium may be added for gastrointestinal symptoms and additional symptom control. 3, 4
• Corticosteroids may be used based on frequency and severity of episodes. 2

Lifestyle Modifications and Safety

• Patients should wear Medic Alert identification because syncope can occur during episodes. 2
• Avoid known triggers including extreme heat, alcohol, certain medications (NSAIDs, opioids), temperature changes, hot water, stress, exercise, and physical stimuli such as pressure or friction. 2, 4
• Avoid exercise postprandially if food-associated exercise-induced anaphylaxis is suspected. 2
• Patients on beta-blockers or ACE inhibitors are at higher risk for severe anaphylaxis and may require medication adjustment. 2

Monitoring and Follow-Up

• Serial tryptase levels every 3-6 months once diagnosis is established. 2
• If anaphylaxis occurs, measure serum tryptase 1-2 hours after symptom onset to document acute elevation. 2
• Complete allergologic workup including skin tests or specific IgE antibodies to identify IgE-mediated hypersensitivity. 2
• Referral to specialized Allergy/Immunology center for comprehensive evaluation and long-term management. 2

Critical Pitfalls to Avoid

• Do not assume normal tryptase excludes anaphylaxis, as anaphylaxis can occur through basophil or complement activation pathways without tryptase elevation. 3, 6
• Do not rely on a single elevated tryptase measurement; obtain both acute and baseline values separated by >24 hours to calculate the diagnostic ratio. 3
• More than 50% of patients with non-mastocytosis conditions such as urticaria, angioedema, drug reactions, or anaphylaxis can have persistently elevated baseline tryptase >20 ng/mL, so bone marrow evaluation remains necessary to exclude systemic mastocytosis. 7
• Serum tryptase may be transiently elevated during anaphylaxis or severe allergic reactions, so timing of measurement is critical: peak levels occur 60-90 minutes after onset and persist up to 6 hours. 1