What is the best course of action for an adult patient with elevated trypase levels, no identifiable triggers, and symptoms such as flushing, itching, or gastrointestinal issues, with no known medical history of allergic disorders?

Management of Elevated Tryptase Without Identifiable Triggers

For an adult patient with elevated tryptase but no identifiable triggers, you must first confirm whether this is a true baseline elevation by repeating the measurement when completely asymptomatic (at least 24 hours after any symptoms), and if the baseline tryptase remains >20 ng/mL, proceed directly to bone marrow evaluation to assess for systemic mastocytosis. 1, 2

Initial Diagnostic Steps

Confirm True Baseline Elevation

• Repeat tryptase measurement when the patient is completely asymptomatic (>24 hours after any symptoms) to establish a true baseline, as acute measurements may reflect recent mast cell degranulation even without recognized symptoms 1, 2, 3
• If the initial measurement was taken during or within 1-4 hours of any symptoms (flushing, pruritus, gastrointestinal distress, lightheadedness), this represents acute degranulation rather than baseline elevation 3, 4
• A persistently elevated baseline tryptase >20 ng/mL meets a minor diagnostic criterion for systemic mastocytosis and mandates bone marrow evaluation 1, 2, 3

Risk Stratification by Tryptase Level

• Tryptase 20-200 ng/mL: Proceed with outpatient bone marrow evaluation and comprehensive workup 1, 2
• Tryptase >200 ng/mL: This indicates high mast cell burden requiring urgent hematology referral and possible hospitalization, as it strongly suggests advanced systemic mastocytosis or mast cell leukemia 1, 2, 3

Comprehensive Clinical Assessment

Detailed Symptom Documentation

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

• Cutaneous: Episodic flushing, pruritus, urticaria, or angioedema occurring without obvious cause 1, 2
• Gastrointestinal: Diarrhea, abdominal cramping, nausea, vomiting, or bloating 1, 2
• Cardiovascular: Palpitations, presyncope, syncope, tachycardia, or unexplained hypotensive episodes 1, 2
• Neurologic: Headache, poor concentration, memory problems, or "brain fog" 1
• Respiratory: Wheezing, throat swelling, or bronchospasm 1

Physical Examination Priorities

• Thoroughly examine all skin surfaces for urticaria pigmentosa (small red-brown macules or papules) or mastocytoma lesions, which may be subtle 3
• Test for Darier's sign by stroking suspected lesions to elicit wheal formation (positive in 89-94% of cutaneous mastocytosis) 2
• Assess for hepatosplenomegaly, which may indicate higher disease burden 3

Historical Red Flags

• History of severe anaphylaxis to Hymenoptera (bee/wasp) stings, which is strongly associated with underlying mastocytosis 1, 3, 5
• Unexplained osteoporosis or fractures (mast cell mediators affect bone metabolism) 3
• Recurrent "idiopathic" anaphylaxis 1, 5

Mandatory Bone Marrow Evaluation (if baseline tryptase >20 ng/mL)

Required Testing Components

The bone marrow evaluation must include all of the following 1, 3:

• Bone marrow aspiration and core biopsy to assess for multifocal dense infiltrates of ≥15 mast cells in aggregates (major diagnostic criterion)
• Immunohistochemistry for CD117, CD25, and CD2 expression on mast cells (aberrant expression is a minor criterion)
• KIT D816V mutation testing (present in >80% of adult systemic mastocytosis cases; a minor criterion) 1
• Flow cytometry to assess mast cell immunophenotype
• Evaluation for associated hematologic neoplasms (present in up to 71% of advanced cases) 3

WHO Diagnostic Criteria for Systemic Mastocytosis

Diagnosis requires either the major criterion plus one minor criterion, OR three minor criteria 1, 3:

Major criterion:

• Multifocal dense infiltrates of ≥15 mast cells in aggregates in bone marrow or other extracutaneous organs 1, 3

Minor criteria:

• 25% spindle-shaped or atypical mast cells in bone marrow or other extracutaneous organs 1, 3

• KIT D816V mutation detected 1, 3
• CD25 and/or CD2 expression on mast cells 1, 3
• Baseline serum tryptase >20 ng/mL (unless there is an associated clonal myeloid disorder) 1, 3

Consider Hereditary Alpha-Tryptasemia

• Approximately 4-6% of the general population carry germline TPSAB1-α copy number gains, resulting in elevated baseline tryptase without systemic mastocytosis 1, 5
• This condition (hereditary alpha-tryptasemia, HαT) is associated with symptoms including flushing, pruritus, dysautonomia, gastrointestinal symptoms, chronic pain, and joint hypermobility 1, 5
• TPSAB1 genotyping should be included in the diagnostic workup, particularly if bone marrow evaluation is negative for systemic mastocytosis 5
• HαT is more common in patients with severe anaphylaxis, idiopathic anaphylaxis, and mast cell activation syndromes 5

Immediate Safety Measures (Implement Before Diagnosis is Complete)

Prescribe Emergency Medications

• All patients with confirmed elevated baseline tryptase require two epinephrine auto-injectors (0.3-0.5 mg for adults) to carry at all times, even if asymptomatic 1, 2, 3, 6
• Epinephrine is first-line treatment for anaphylaxis without absolute contraindications 2, 6
• Provide Medic Alert identification documenting elevated tryptase and anaphylaxis risk 1, 2, 3

Trigger Avoidance Education

Even without identified triggers, educate on common precipitants to aid in future trigger identification 1, 2, 3:

• Temperature extremes (hot showers, saunas, cold exposure)
• Physical stimuli (friction, pressure, vigorous exercise)
• Medications: NSAIDs, opioids (especially codeine and morphine), vancomycin, contrast media 1, 3
• Alcohol consumption 2, 3
• Emotional stress 1, 2
• Insect stings (particularly Hymenoptera) 1

Initiate Antimediator Therapy

Start prophylactic treatment to reduce symptom burden and potentially prevent severe reactions 1, 2, 3:

• H1 antihistamines (e.g., cetirizine 10 mg daily or loratadine 10 mg daily) for urticaria, pruritus, and flushing
• H2 antihistamines (e.g., famotidine 20 mg twice daily) for gastrointestinal symptoms
• Cromolyn sodium (200 mg four times daily) for gastrointestinal, cutaneous, and neurologic symptoms 1
• Leukotriene receptor antagonists (e.g., montelukast 10 mg daily) for refractory skin and gastrointestinal symptoms 1

Ongoing Monitoring Strategy

Serial Tryptase Measurements

• If initial baseline tryptase is 15-20 ng/mL (borderline), repeat measurement in 3-6 months 2
• For confirmed systemic mastocytosis, obtain annual tryptase monitoring to assess disease burden 1, 2

Symptom Diary

• Instruct the patient to maintain a detailed diary documenting any episodic symptoms, timing, potential exposures, and activities to help identify previously unrecognized triggers 1, 2

Multidisciplinary Follow-up

• Establish care with allergy/immunology for ongoing symptom management and trigger identification 1, 3
• If systemic mastocytosis is confirmed, involve hematology for disease monitoring and consideration of cytoreductive therapy if indicated 1, 3
• Schedule follow-up every 6-12 months for patients with confirmed mast cell disorders 3

Critical Pitfalls to Avoid

• Do not assume normal tryptase excludes mast cell disorders: Anaphylaxis can occur through basophil or complement activation pathways without tryptase elevation 1, 3, 4
• Do not rely on a single elevated measurement: Obtain both acute (if symptoms occur) and baseline values separated by >24 hours 2, 3
• Do not delay bone marrow evaluation if baseline tryptase is >20 ng/mL, as this is a minor diagnostic criterion requiring definitive assessment 1, 2, 3
• Do not withhold necessary medications (including analgesics) from patients with mast cell disorders, but exercise caution with direct mast cell degranulators like morphine or codeine 1, 2
• Do not perform skin testing as a screening tool in patients with suspected mastocytosis, as some drugs directly degranulate mast cells in vivo 3

Special Considerations for Procedures

If the patient requires surgery or procedures before diagnosis is complete 3:

• Notify the anesthesia team about elevated tryptase
• Obtain baseline coagulation studies
• Use fentanyl or sufentanil rather than morphine or meperidine
• Avoid ketorolac
• Have emergency anaphylaxis protocols immediately available
• Consider premedication with H1 and H2 antihistamines