How should I evaluate and manage a patient with persistently elevated serum tryptase (>20 ng/mL) and no identified trigger?

Evaluation and Management of Persistently Elevated Serum Tryptase (>20 ng/mL) Without Identified Triggers

A baseline tryptase >20 ng/mL meets a minor WHO diagnostic criterion for systemic mastocytosis and mandates bone marrow evaluation with aspiration, biopsy, immunohistochemistry (CD117, CD25, CD2), and KIT D816V mutation testing. 1

Initial Diagnostic Confirmation

Verify that the elevated tryptase represents a true baseline elevation:

• Repeat the tryptase measurement when the patient is completely asymptomatic and at least 24 hours after any symptoms, as acute measurements may reflect recent mast cell degranulation even without recognized symptoms. 1, 2
• If the repeat baseline tryptase remains >20 ng/mL, proceed directly to bone marrow evaluation. 1

Risk Stratification by Tryptase Level

The magnitude of elevation determines urgency and approach:

Tryptase Level (ng/mL)	Clinical Action
20–200	Outpatient bone marrow evaluation and comprehensive workup [1]
>200	Urgent hematology referral and possible hospitalization; strongly suggests advanced systemic mastocytosis or mast cell leukemia [1,2]

Comprehensive Clinical Assessment for Red-Flag Features

Before proceeding to bone marrow biopsy, systematically assess for features that strongly suggest systemic mastocytosis:

Cutaneous Findings

• Urticaria pigmentosa lesions: Small red-brown macules or papules with positive Darier's sign (wheal formation when stroking the lesion), present in 89–94% of cutaneous mastocytosis. 1, 2

Systemic B-Findings (Organ Involvement)

• Unexplained hepatomegaly, splenomegaly, or lymphadenopathy 1
• Unexplained osteoporosis or pathologic fractures 1

Systemic C-Findings (Organ Dysfunction)

• Unexplained cytopenias (anemia, thrombocytopenia, neutropenia) 1
• Malabsorption or liver dysfunction 1

Historical Red Flags

• History of severe anaphylaxis to Hymenoptera (bee/wasp) stings 1, 2
• Recurrent "idiopathic" anaphylaxis 2

Mandatory Bone Marrow Evaluation Protocol

The bone marrow workup must include: 1

• 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:

• Major criterion: ≥15 mast cells in aggregates in bone marrow or other extracutaneous organs, plus one minor criterion, OR
• Three minor criteria: (1) >25% spindle-shaped or atypical mast cells, (2) KIT D816V mutation, (3) CD25 and/or CD2 expression on mast cells, (4) baseline tryptase >20 ng/mL 1

Alternative Diagnosis: Hereditary Alpha-Tryptasemia (HαT)

If bone marrow evaluation is negative for systemic mastocytosis, consider HαT:

• HαT is present in 4–6% of the general population and results from TPSAB1 gene duplications or triplications. 1, 3
• Typical baseline tryptase values range from 8–20 ng/mL, with occasional values up to 25 ng/mL. 1, 3
• Order TPSAB1 genetic testing (buccal swab DNA analysis) if bone marrow is negative and tryptase is in the 20–25 ng/mL range without red-flag features. 1

HαT is associated with a benign symptom complex:

• Cutaneous flushing, pruritus, dysautonomia, functional gastrointestinal complaints (IBS-type), chronic pain, and joint hypermobility 1, 3
• This does not indicate malignancy or clonal mast cell disease. 3

Systematic Symptom Assessment

Even without identified triggers, systematically review for subtle manifestations of mast cell mediator release: 2

Cutaneous

• Episodic flushing, urticaria, pruritus, angioedema 2

Gastrointestinal

• Diarrhea, abdominal cramping, nausea, vomiting, bloating 2

Cardiovascular

• Hypotension, tachycardia, syncope, near-syncope, palpitations, vasomotor instability 2

Respiratory

• Bronchospasm, wheezing, throat swelling 2

Neurologic

• Headache, brain fog, cognitive dysfunction 1

Instruct the patient to maintain a detailed symptom diary documenting timing, potential exposures, and activities to identify previously unrecognized triggers. 2

Immediate Safety Measures (Regardless of Final Diagnosis)

All patients with confirmed baseline tryptase >20 ng/mL require: 1, 3

1. Two epinephrine auto-injectors to carry at all times, even if asymptomatic
2. Medic Alert identification documenting elevated tryptase and anaphylaxis risk
3. Trigger avoidance education covering:
   • Extreme temperatures (hot or cold)
   • Physical trauma to skin, vigorous exercise
   • Alcohol consumption
   • NSAIDs (especially ketorolac)
   • Opioids (morphine, codeine, meperidine)
   • Certain antibiotics (vancomycin, fluoroquinolones)
   • Radiocontrast media
   • General anesthesia without premedication
   • Emotional stress
   • Hot water exposure 1, 2

Symptomatic Management Pending Diagnosis

Initiate antimediator therapy for symptom control: 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 1
• Cromolyn sodium (oral or topical) for cutaneous, gastrointestinal, and neurologic symptoms refractory to antihistamines 1
• Leukotriene receptor antagonists (montelukast) for skin and gastrointestinal symptoms not controlled by antihistamines 1

Ongoing Monitoring Strategy

• Annual tryptase monitoring to assess disease burden in patients with confirmed systemic mastocytosis 1, 2
• Multidisciplinary care with allergy/immunology and hematology for ongoing symptom management and disease monitoring 1
• Repeat tryptase at 3–6 months to confirm stability of the level 1

Critical Pitfalls to Avoid

• Do not assume normal tryptase excludes anaphylaxis: Reactions can occur via basophil or complement pathways without tryptase elevation. 1
• Do not rely on a single elevated tryptase measurement: Obtain both acute (if symptomatic) and baseline values separated by >24 hours. 1
• Do not withhold epinephrine auto-injectors: All patients with confirmed baseline elevation require two devices and Medic Alert identification, even if asymptomatic. 1, 3
• Do not perform reflex bone marrow biopsy for tryptase 20–25 ng/mL without red-flag features: First rule out HαT with genetic testing. 1
• Do not withhold analgesics: When opioid analgesia is needed, use fentanyl or sufentanil rather than morphine or meperidine to minimize mast cell activation. 1

Special Considerations for Procedures

If the patient requires surgery or procedures: 1

• Notify the anesthesia team of elevated tryptase
• Obtain baseline coagulation studies
• Premedicate with H1 and H2 antihistamines plus corticosteroids
• Avoid ketorolac and morphine/meperidine
• Have emergency anaphylaxis protocols ready