What does an elevation in tryptase and Interleukin-6 (IL-6) indicate?

Elevated Tryptase and IL-6: Diagnostic Significance and Clinical Implications

Elevated tryptase and IL-6 levels most strongly indicate mast cell activation, which can occur in anaphylaxis, systemic mastocytosis, or mast cell activation syndrome (MCAS). These biomarkers reflect different but complementary aspects of mast cell-mediated inflammatory processes.

Tryptase Elevation: Primary Diagnostic Implications

Tryptase is a protease enzyme stored in mast cell granules and serves as a specific marker for mast cell activation and degranulation 1. When interpreting elevated tryptase levels, consider:

• Anaphylaxis: During anaphylaxis, tryptase peaks approximately 1 hour after onset and has a half-life of about 2 hours 1. An increase of >20% + 2 ng/mL from baseline is diagnostic for mast cell activation 2.

• Systemic Mastocytosis: Persistently elevated tryptase >20 ng/mL is a minor diagnostic criterion for systemic mastocytosis according to WHO criteria 1. This typically reflects increased numbers of mast cells rather than acute degranulation.

• Mast Cell Activation Syndrome (MCAS): Requires evidence of mast cell mediator release during symptomatic episodes affecting at least 2 organ systems, with response to antimediator therapy 2.

• Hereditary Alpha-Tryptasemia: Characterized by duplications in the TPSAB1 gene encoding α-tryptase, associated with baseline tryptase elevation (typically >8 ng/mL) 3.

IL-6 Elevation in Context of Mast Cell Disorders

While not specifically mentioned in the diagnostic criteria for mast cell disorders, IL-6 elevation provides complementary information:

• Tryptase stimulates the release of pro-inflammatory interleukins (including IL-6) during inflammation 1.
• IL-6 is a pro-inflammatory cytokine that can be released during mast cell activation.
• The combination of elevated tryptase and IL-6 suggests active inflammatory processes mediated by mast cells.

Diagnostic Algorithm

1. Determine if tryptase elevation is acute or persistent:

   • Acute elevation (returning to baseline within 24-48 hours): Suggests anaphylaxis or acute mast cell activation
   • Persistent elevation (>20 ng/mL): Consider systemic mastocytosis

2. Evaluate for systemic symptoms affecting multiple organ systems:

   • Skin: Flushing, urticaria, pruritus, angioedema
   • Gastrointestinal: Diarrhea, nausea, vomiting, abdominal pain
   • Cardiovascular: Hypotension, tachycardia, near syncope
   • Respiratory: Wheezing, stridor

3. Additional testing to consider:

   • Bone marrow biopsy (if systemic mastocytosis suspected)
   • 24-hour urine collection for N-methylhistamine, prostaglandin D2 metabolites, and leukotriene E4 2
   • KIT D816V mutation testing 1
   • TPSAB1 α-tryptase copy number testing for hereditary alpha tryptasemia 2

Clinical Pitfalls and Caveats

• False negatives: The tryptase assay has high specificity but relatively low sensitivity; some cases of anaphylaxis may be missed 1.

• Timing matters: Tryptase should be measured 1-4 hours after symptom onset for acute reactions, with a baseline sample collected at least 24 hours later 1, 2.

• Non-mast cell causes of tryptase elevation: Chronic renal failure, obesity, and certain hematological neoplasms can cause elevated baseline tryptase 3.

• Dilution effect: Intravenous fluid replacement during treatment of anaphylaxis can dilute tryptase levels, potentially leading to falsely lower values 1.

• Post-mortem considerations: Tryptase may be elevated in trauma or myocardial infarction after death, reducing its predictive value in post-mortem samples 1.

The combined elevation of tryptase and IL-6 provides strong evidence for mast cell activation with an inflammatory component, warranting further investigation for mast cell disorders, particularly if associated with characteristic clinical symptoms.