What are the normal and abnormal serum tryptase values and their clinical interpretation?

Serum Tryptase: Normal Values and Clinical Interpretation

Normal serum tryptase ranges from 1-15 ng/mL, with the manufacturer's upper limit at 11.4 ng/mL, though expert consensus from the European Competence Network on Mastocytosis recommends using 15 ng/mL as the clinical threshold. 1, 2

Normal and Abnormal Baseline Values

Baseline tryptase interpretation:

• <8 ng/mL: Normal range for most individuals 1, 2
• 8-15 ng/mL: May indicate hereditary alpha-tryptasemia (HαT), present in 4-6% of the general population due to increased TPSAB1 gene copy number 1, 3
• 15-20 ng/mL: Warrants bone marrow examination if KIT D816V mutation detected or high clinical suspicion for systemic mastocytosis 1
• >20 ng/mL: Meets minor diagnostic criterion for systemic mastocytosis and mandates bone marrow evaluation 4, 1
• >200 ng/mL: Indicates high mast cell burden requiring urgent hematology referral and possible hospitalization, suggesting advanced systemic mastocytosis or mast cell leukemia 1, 5

Types of Tryptase

Two main forms exist with distinct clinical significance:

• Alpha-tryptase: Constitutively secreted by mast cells; elevated in systemic mastocytosis and hereditary alpha-tryptasemia 4
• Beta-tryptase: Stored in mast cell granules and released during degranulation; elevated during anaphylaxis 4
• Current assays (ImmunoCAP FEIA) measure total tryptase (sum of alpha and beta forms) 4

Acute Tryptase Elevation in Anaphylaxis

For diagnosing mast cell activation during anaphylaxis, use the formula: acute tryptase (sAT) > (1.2 × baseline tryptase [sBT]) + 2 ng/mL 4

Critical timing considerations:

• Peak elevation: 60-90 minutes (30-120 minutes) after symptom onset 4
• Half-life: Approximately 2 hours 4
• Sample collection protocol: Obtain three timed samples:
  • Initial sample as soon as feasible after symptom onset 4, 5
  • Second at 1-2 hours after onset 4, 5
  • Third at 24+ hours after complete symptom resolution (true baseline) 4, 5

Important caveat: Anaphylaxis can occur via basophil or complement activation pathways without tryptase elevation, so normal tryptase does not exclude anaphylaxis 4

Clinical Conditions Affecting Tryptase

Elevated baseline tryptase occurs in:

• Systemic mastocytosis: 75% have levels >20 ng/mL 4, 6
• Hereditary alpha-tryptasemia: Typically 8-15 ng/mL, occasionally higher 1, 3
• Acute myelocytic leukemia and myelodysplastic syndromes 6
• End-stage renal disease 2, 6
• Hypereosinophilic syndrome with FIP1L1-PDGFRA mutation 6

Acute elevation during mast cell activation:

• Systemic anaphylaxis: Requires >20% increase plus 2 ng/mL above baseline on at least 2 occasions for mast cell activation syndrome diagnosis 4, 5, 7
• Sensitivity varies: Higher with hypotension (correlates with clinical severity), lower with isolated cutaneous reactions 4
• Specificity: >90% when properly timed 4

Diagnostic Algorithm for Elevated Tryptase

When tryptase >20 ng/mL:

1. Confirm true baseline by repeating when patient completely asymptomatic (>24 hours after any symptoms) 1, 5
2. Proceed directly to bone marrow evaluation including:
   • Bone marrow aspiration and core biopsy 1
   • Immunohistochemistry for CD117, CD25, CD2 on mast cells 1
   • KIT D816V mutation testing 1
   • Flow cytometry for mast cell immunophenotype 1

When tryptase 8-20 ng/mL:

• Consider hereditary alpha-tryptasemia testing (TPSAB1 gene copy number) 1, 3
• Evaluate for KIT D816V mutation in peripheral blood using allele-specific quantitative PCR 1
• Bone marrow examination if mutation positive or high clinical suspicion 1

When tryptase <8 ng/mL:

• Elevated tryptase unlikely to explain symptoms; pursue alternative diagnoses 1

Confounding Factors

Critical pitfalls to avoid:

• IV fluid resuscitation during anaphylaxis dilutes tryptase concentration; account for hemodilution when interpreting values 4
• Post-mortem samples have lower predictive value than antemortem samples; beta-tryptase may be elevated in trauma or myocardial infarction 4
• Associated hematologic neoplasms in systemic mastocytosis may independently elevate tryptase 1
• Timing errors: Samples collected too early (<30 minutes) or too late (>6 hours) after symptom onset reduce sensitivity 4, 5

Ratio Analysis for Differential Diagnosis

Total tryptase to beta-tryptase ratio distinguishes conditions:

• Ratio ≤10: Suggests anaphylaxis without mastocytosis 5
• Ratio ≥20: Suggests systemic mastocytosis 5

This ratio helps differentiate acute mast cell activation from chronic mast cell burden 5.

Genotyping Recommendations

Tryptase genotyping should be considered when:

• Baseline serum tryptase exceeds 6.5 ng/mL in symptomatic individuals 3
• This screens for hereditary alpha-tryptasemia, which affects interpretation of both baseline and acute values 3
• Presence of HαT redefines what constitutes "abnormal" elevation in mastocytosis diagnosis 3