What does an elevated serum tryptase indicate and how should it be evaluated?

Elevated Serum Tryptase: Diagnostic Significance and Evaluation

An elevated serum tryptase requires immediate distinction between acute mast cell activation (measured during symptoms) versus persistently elevated baseline (measured when asymptomatic), because a baseline tryptase >20 ng/mL mandates bone marrow evaluation for systemic mastocytosis. 1

Initial Triage: Timing of Measurement

The first critical step is determining when the tryptase was drawn:

• If measured during or within 1–4 hours of acute symptoms (urticaria, hypotension, bronchospasm, gastrointestinal distress), this represents acute mast cell degranulation and requires emergency anaphylaxis management with intramuscular epinephrine 0.01 mg/kg into the anterolateral thigh. 2

• If measured when completely asymptomatic, this represents a baseline elevation requiring systematic evaluation for underlying mast cell disorders. 2

• Critical timing window: Acute tryptase peaks at 60–90 minutes after symptom onset (range 30–120 minutes) and declines with a half-life of approximately 2 hours; sampling outside this window produces false-negative results. 1

Confirming True Baseline Elevation

• Repeat tryptase measurement ≥24 hours after complete symptom resolution to establish a true baseline, because even subclinical mast cell activation can transiently elevate levels. 1, 2

• The upper limit of normal is 11.4 ng/mL per manufacturer specifications, though expert consensus defines the normal range as 1–15 ng/mL. 3

Risk Stratification by Baseline Tryptase Level

Baseline Tryptase (ng/mL)	Clinical Significance	Immediate Action
<8	Normal	No further workup unless recurrent anaphylaxis
8–20	Possible hereditary alpha-tryptasemia (HαT)	Consider TPSAB1 genetic testing [1,4]
20–200	Meets WHO minor criterion for systemic mastocytosis	Mandatory outpatient bone marrow evaluation [1,2]
>200	High mast cell burden; advanced disease likely	Urgent hematology referral; possible hospitalization [1,2]

Diagnostic Workup for Baseline Tryptase >20 ng/mL

Bone marrow evaluation is non-negotiable when baseline tryptase exceeds 20 ng/mL, because approximately 75% of systemic mastocytosis patients have levels in this range. 1

Required Bone Marrow Studies

• Aspiration and core biopsy 2
• Immunohistochemistry for CD117, CD25, and CD2 expression on mast cells 2
• KIT D816V mutation testing (present in >90% of systemic mastocytosis) 1
• Flow cytometry for mast cell immunophenotype 2
• Evaluation for associated hematologic neoplasms (present in up to 71% of advanced cases) 1

WHO Diagnostic Criteria for Systemic Mastocytosis

Diagnosis requires either:

• Major criterion (≥15 mast cells in aggregates in bone marrow) plus one minor criterion, OR
• Three minor criteria 1, 2

Minor criteria:

1. 25% spindle-shaped or atypical mast cells

2. KIT D816V mutation detected
3. CD25 and/or CD2 expression on mast cells
4. Baseline tryptase >20 ng/mL 1

Physical Examination Red Flags

• Urticaria pigmentosa lesions (small red-brown macules/papules with positive Darier's sign in 89–94% of cutaneous mastocytosis) 1, 5
• Hepatosplenomegaly or lymphadenopathy (B-findings) 1, 2
• Unexplained cytopenias or malabsorption (C-findings indicating aggressive disease) 1, 2
• Unexplained osteoporosis 2

Hereditary Alpha-Tryptasemia (HαT)

When baseline tryptase is 8–20 ng/mL and bone marrow studies are negative:

• HαT affects 4–6% of the general population and results from TPSAB1 gene copy-number duplications/triplications. 1, 4

• Order TPSAB1 genetic testing (buccal swab DNA analysis) as first-line investigation. 1

• Clinical phenotype: Cutaneous flushing, pruritus, dysautonomia, functional gastrointestinal complaints, chronic pain, joint hypermobility. 1

• HαT is a lifelong genetic trait; tryptase levels remain chronically elevated but stable. 1

Acute Tryptase Elevation in Anaphylaxis

Diagnostic Formula for Mast Cell Activation

Acute tryptase is diagnostic when it exceeds: (1.2 × baseline tryptase) + 2 ng/mL 1

Recommended Sampling Schedule

1. First sample: As soon as possible after symptom onset
2. Second sample: 1–2 hours after onset (captures peak)
3. Third sample: ≥24 hours after complete resolution (establishes true baseline) 1

Critical Caveats

• Anaphylaxis can occur without tryptase elevation via basophil or complement pathways; normal tryptase does not exclude anaphylaxis. 1, 2

• Sensitivity varies by presentation: Highest with hypotension (cardiovascular compromise), lowest with isolated cutaneous reactions. 1

• Intravenous fluid resuscitation dilutes circulating tryptase, potentially lowering observed concentrations. 1

• Specificity exceeds 90% when samples are correctly timed, making positive results highly reliable. 1

Mast Cell Activation Syndrome (MCAS)

MCAS is diagnosed when:

• Episodic symptoms affecting ≥2 organ systems concurrently 5
• Acute tryptase elevation >20% + 2 ng/mL above baseline on ≥2 separate occasions 1, 5
• Baseline tryptase may be normal or mildly elevated 1

Key distinction: MCAS presents with episodic multisystem symptoms, not chronic continuous urticaria. 2

Immediate Safety Measures for All Patients with Elevated Baseline Tryptase

Regardless of final diagnosis:

• Prescribe two epinephrine auto-injectors to carry at all times 2, 5
• Provide Medic Alert identification documenting elevated tryptase and anaphylaxis risk 2
• Trigger avoidance education: Extreme temperatures, physical trauma, alcohol, NSAIDs (especially ketorolac), opioids (morphine, codeine), certain antibiotics, radiocontrast media, unpremedicated general anesthesia, stress, vigorous exercise, hot water exposure 1, 2

Symptomatic Management

First-Line Therapies

• H1 antihistamines (cetirizine, loratadine, fexofenadine) for urticaria, pruritus, flushing; may increase up to 4-fold for refractory symptoms 2, 5
• H2 antihistamines (famotidine, ranitidine) for gastrointestinal symptoms 2, 5
• Cromolyn sodium (oral or topical) for cutaneous, gastrointestinal, and neurologic symptoms refractory to antihistamines 2

Second-Line Therapies

• Leukotriene receptor antagonists (montelukast) for skin and gastrointestinal symptoms 2
• Systemic corticosteroids (prednisone 0.5 mg/kg/day for 1–2 weeks with taper) for acute flares 2
• Omalizumab (anti-IgE monoclonal antibody) for recurrent anaphylaxis insufficiently controlled by conventional therapy 2, 5

Cytoreductive Therapy

• Tyrosine kinase inhibitors (midostaurin, avapritinib) are the only agents that reduce mast cell burden and lower baseline tryptase in advanced systemic mastocytosis; these require hematology/oncology management. 2

Perioperative Management

For patients requiring surgery or procedures:

• Notify anesthesia team of elevated tryptase 2
• Premedicate with H1 + H2 antihistamines plus corticosteroids 2
• Preferred opioids: Fentanyl or sufentanil (avoid morphine, meperidine) 2
• Avoid: Ketorolac, unpremedicated general anesthesia 2
• Obtain baseline coagulation studies 2

Confounding Conditions That Elevate Tryptase

Beyond mastocytosis and HαT, consider:

• Acute myelocytic leukemia 6
• Myelodysplastic syndromes 6
• Hypereosinophilic syndrome with FIP1L1-PDGFRA mutation 6
• End-stage renal failure 6, 3
• Post-mortem samples (less reliable; beta-tryptase modestly elevated after trauma or myocardial infarction) 1

Follow-Up and Monitoring

• Annual tryptase monitoring for confirmed systemic mastocytosis to assess disease burden 2, 5
• Multidisciplinary care involving allergy/immunology and hematology 2, 5
• Symptom diary documenting episodic symptoms, timing, exposures, and activities to identify unrecognized triggers 2