What is the recommended work‑up and management for a patient with persistent hypertryptasemia (>11 ng/mL) in the absence of an acute allergic reaction?

Work-Up and Management of Persistent Hypertryptasemia

For a patient with persistent baseline tryptase >11 ng/mL measured when completely asymptomatic, first confirm the elevation with a repeat measurement at least 24 hours after any symptoms, then stratify by level: 11–20 ng/mL warrants genetic testing for hereditary alpha-tryptasemia; ≥20 ng/mL mandates bone marrow evaluation if red-flag features are present; and >200 ng/mL requires urgent hematology referral. 1

Confirm True Baseline Elevation

• Repeat the tryptase measurement when the patient is completely asymptomatic and at least 24 hours after any symptoms to distinguish persistent baseline elevation from recent mast cell degranulation. 1, 2
• Acute tryptase peaks 60–90 minutes after mast cell activation and can persist up to 6 hours, so timing is critical to avoid misclassifying a transient rise as chronic disease. 2

Risk Stratification by Tryptase Level

Tryptase 11–20 ng/mL

• Order TPSAB1 genetic testing for hereditary alpha-tryptasemia (HαT) as the first-line investigation. 1, 3
• HαT is present in 4–6% of the general population and results from germline duplications or triplications of the TPSAB1 gene encoding alpha-tryptase. 1, 3
• Baseline tryptase values in HαT typically range 8–20 ng/mL, occasionally reaching 25 ng/mL. 1, 3
• Bone marrow biopsy is not indicated in this range unless red-flag features are present (see below). 1, 3

Tryptase 20–200 ng/mL

• A baseline tryptase ≥20 ng/mL fulfills a minor WHO diagnostic criterion for systemic mastocytosis. 1, 3
• Proceed to bone marrow evaluation if any red-flag features are present; otherwise, consider HαT genetic testing first, as more than 50% of cases in this range are non-malignant. 1, 3
• Approximately 75% of patients with systemic mastocytosis have baseline tryptase >20 ng/mL, reinforcing the utility of this threshold for case-finding. 1

Tryptase >200 ng/mL

• This level indicates high mast cell burden and strongly suggests advanced systemic mastocytosis or mast cell leukemia. 1, 3
• Urgent hematology referral and possible hospitalization are required. 1, 3

Identify Red-Flag Features Mandating Bone Marrow Biopsy

Regardless of tryptase level, bone marrow evaluation is mandatory if any of the following are present: 1, 3

• Urticaria pigmentosa skin lesions (small red-brown macules/papules with positive Darier's sign, present in 89–94% of cutaneous mastocytosis) 1, 2
• Unexplained hepatomegaly, splenomegaly, or lymphadenopathy 1, 3
• Unexplained cytopenias (anemia, thrombocytopenia, neutropenia) 1, 3
• History of severe Hymenoptera (bee/wasp) sting anaphylaxis 1, 3
• Unexplained osteoporosis or pathologic fractures 1, 3

Bone Marrow Evaluation Protocol

When indicated, bone marrow work-up must include: 1, 3

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

WHO diagnostic criteria for systemic mastocytosis require either the major criterion (≥15 mast cells in aggregates in bone marrow) plus one minor criterion, or three minor criteria. 1, 3

Assess for Mast Cell Activation Syndrome (MCAS)

• MCAS is diagnosed when acute tryptase rises exceed (1.2 × baseline) + 2 ng/mL on at least two separate occasions, accompanied by episodic symptoms affecting ≥2 organ systems. 1, 2, 4
• MCAS does not present with persistently elevated baseline tryptase alone; documented acute rises during symptomatic episodes are required. 1, 3
• If the patient has episodic symptoms, obtain serum tryptase during acute episodes: initial sample as soon as feasible, second at 1–2 hours after symptom onset, and third at 24 hours or in convalescence. 2

Evaluate for Non-Mast Cell Causes

Consider alternative causes of elevated baseline tryptase: 5, 6, 7

• Chronic kidney disease (especially end-stage renal failure) 5, 6, 7
• Hematologic malignancies (acute myelocytic leukemia, myelodysplastic syndromes) 6, 7
• Hypereosinophilic syndrome with FIP1L1-PDGFRA mutation 6, 8

Immediate Safety Measures for All Patients

Regardless of the underlying cause, all patients with confirmed baseline tryptase elevation require: 1, 3

• Two epinephrine auto-injectors to carry at all times, even if asymptomatic
• Medic Alert identification documenting elevated tryptase and anaphylaxis risk
• Trigger avoidance education: extreme temperatures, physical trauma to skin, alcohol, NSAIDs, opioids (especially morphine/meperidine), certain antibiotics (vancomycin), contrast media, general anesthesia without premedication, stress, vigorous exercise, hot water exposure 1, 3

Symptomatic Management

For patients with symptoms of mast cell mediator release: 1, 2

• H1 antihistamines (cetirizine, loratadine, fexofenadine) for urticaria, pruritus, flushing; may increase up to four-fold for refractory symptoms 1
• H2 antihistamines (famotidine, ranitidine) for gastrointestinal symptoms (diarrhea, cramping, nausea, bloating) 1, 2
• Cromolyn sodium for additional gastrointestinal and cutaneous symptom control 1, 2
• Leukotriene receptor antagonists (montelukast) as adjunctive therapy 1, 2
• Omalizumab may be considered for recurrent anaphylaxis insufficiently controlled by conventional therapy 2

Ongoing Monitoring and Follow-Up

• Annual tryptase monitoring is recommended for patients with confirmed systemic mastocytosis to assess disease burden. 1, 3
• Routine annual tryptase monitoring is not required for HαT unless symptoms worsen or new red-flag features develop. 3
• Establish multidisciplinary care with allergy/immunology and hematology for ongoing symptom management and disease monitoring. 1
• Instruct the patient to maintain a detailed symptom diary documenting episodic symptoms, timing, potential exposures, and activities to identify previously unrecognized triggers. 1

Critical Pitfalls to Avoid

• Normal tryptase does not exclude anaphylaxis, as reactions can occur via basophil or complement pathways without tryptase elevation. 1, 3
• Do not rely on a single elevated tryptase measurement; obtain both acute (if symptomatic) and baseline values to calculate the diagnostic ratio. 1, 3
• Avoid reflex bone marrow biopsy for tryptase 20–25 ng/mL; first rule out HαT with genetic testing when no red-flag features are present. 1, 3
• Never withhold epinephrine auto-injectors from patients with confirmed baseline elevation; all require two devices and Medic Alert identification. 1, 3

Special Perioperative Considerations

If a patient with elevated baseline tryptase requires surgery: 1

• Notify the anesthesia team and document elevated tryptase in the medical record
• Obtain baseline coagulation studies
• Use fentanyl or sufentanil rather than morphine or meperidine
• Avoid ketorolac
• Have emergency anaphylaxis protocols immediately available