What is the significance of an elevated tryptase (enzyme) level of 22.0 in an asymptomatic individual?

Elevated Tryptase of 22.0 ng/mL in an Asymptomatic Patient

A tryptase level of 22.0 ng/mL in an asymptomatic individual meets a minor diagnostic criterion for systemic mastocytosis and mandates bone marrow evaluation to assess for clonal mast cell disease. 1, 2

Immediate Clinical Significance

This level requires diagnostic workup, not emergency treatment. Asymptomatic elevated tryptase never requires epinephrine or anaphylaxis emergency protocols, as elevated tryptase itself does not cause symptoms—only active mast cell degranulation produces clinical manifestations. 1

The threshold of >20 ng/mL is specifically designated as a minor criterion for systemic mastocytosis by international diagnostic standards. 1, 2 This patient crosses that diagnostic threshold and requires systematic evaluation.

Mandatory Diagnostic Evaluation

Confirm True Baseline Status

• Verify this measurement was obtained when truly asymptomatic—not within 1-4 hours of any acute symptoms, flushing episodes, or allergic reactions. 1, 2
• If there is any uncertainty about timing relative to symptoms, repeat the tryptase measurement during a confirmed asymptomatic period separated by >24 hours from any potential acute event. 2, 3

Physical Examination Priorities

• Examine the entire skin surface for urticaria pigmentosa (small red-brown macules that urticate with stroking—Darier's sign). 2
• Palpate for hepatosplenomegaly, which may indicate organ involvement. 2
• Document any history of unexplained osteoporosis or pathologic fractures. 2

Required Laboratory and Bone Marrow Workup

Bone marrow aspiration and biopsy with specialized testing is mandatory for any patient with baseline tryptase >20 ng/mL. 1, 2 This must include:

• Bone marrow 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 cases) 2
• Flow cytometry for mast cell immunophenotyping 2
• Evaluation for associated hematologic neoplasms, which occur in up to 71% of advanced cases 2

The diagnosis of systemic mastocytosis requires either 1 major criterion plus 1 minor criterion, or 3 minor criteria. 1 The major criterion is multifocal dense infiltrates of ≥15 mast cells in aggregates in bone marrow. 2 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. 2

Differential Diagnosis Considerations

While systemic mastocytosis is the primary concern, other causes of persistently elevated baseline tryptase include:

• Hereditary alpha-tryptasemia (HαT): Found in 4-6% of the general population, caused by TPSAB1 gene duplications, typically produces tryptase levels of 8-20 ng/mL but can occasionally reach 22 ng/mL. 3, 4 Consider genetic testing for HαT, particularly if bone marrow is negative for mastocytosis. 3
• Other myeloid neoplasms: Acute myelocytic leukemia, myelodysplastic syndromes, and hypereosinophilic syndrome with FLP1L1-PDGFRA mutation can elevate tryptase. 5
• End-stage renal failure can cause elevated tryptase. 5

However, a level of 22 ng/mL exceeds the diagnostic threshold and cannot be dismissed as benign without bone marrow evaluation. 1, 2 Studies show that more than 50% of patients with persistently elevated tryptase >20 ng/mL who do not have mastocytosis still require bone marrow biopsy to definitively exclude it. 6

Essential Preventive Measures (Implement Immediately)

Even while awaiting bone marrow results, all patients with confirmed elevated baseline tryptase require:

• Prescription for epinephrine auto-injector (EpiPen or equivalent), as these patients have increased risk of severe anaphylaxis. 1, 2
• Medic Alert identification documenting elevated tryptase and anaphylaxis risk. 1, 2
• Education on avoiding mast cell degranulation triggers: extreme temperatures, physical trauma to skin, alcohol, NSAIDs (particularly avoid ketorolac), opioids (especially morphine and meperidine), certain antibiotics, contrast media, general anesthesia without premedication, stress, vigorous exercise, and hot water exposure. 7, 1

Surveillance and Ongoing Management

• Annual tryptase measurements to monitor disease burden once diagnosis is established. 1
• Multidisciplinary management involving allergy/immunology and hematology. 1
• If symptomatic manifestations develop (flushing, pruritus, abdominal pain, diarrhea), initiate antimediator therapy with H1 antihistamines, H2 antihistamines, leukotriene inhibitors, and cromolyn sodium. 1, 2 These medications treat symptoms, not the elevated tryptase itself. 1

Critical Pitfalls to Avoid

• Do not assume this is benign hereditary alpha-tryptasemia without bone marrow evaluation. While HαT is common, a level of 22 ng/mL crosses the diagnostic threshold for systemic mastocytosis workup. 1, 2, 3
• Do not wait for symptoms to develop before prescribing epinephrine. Patients with elevated baseline tryptase have increased risk of severe anaphylaxis, particularly to hymenoptera stings. 1, 2
• Do not perform skin testing to anesthetic drugs or other medications as a screening tool. Skin testing is unreliable in predicting adverse reactions in patients with mastocytosis, as some drugs directly degranulate mast cells in vivo. 7
• If this patient requires surgery, ensure anesthesia team is aware. Obtain baseline coagulation studies (PT/PTT may be mildly prolonged due to mast cell heparin), use fentanyl or sufentanil rather than morphine or meperidine, avoid ketorolac, and have emergency anaphylaxis protocols ready. 7