What is the recommended treatment for individuals with hereditary elevated tryptase (HET)?

Hereditary Elevated Tryptase (Hereditary Alpha-Tryptasemia)

Primary Management Strategy

For individuals with hereditary alpha-tryptasemia (HαT), treatment focuses on symptom control with H1 and H2 antihistamines as first-line therapy, mast cell stabilizers for gastrointestinal and neuropsychiatric symptoms, and mandatory carriage of two epinephrine auto-injectors due to increased risk of severe anaphylaxis. 1, 2

Diagnostic Confirmation

Before initiating treatment, confirm the diagnosis through:

• Baseline serum tryptase measurement when asymptomatic (typically >8 ng/mL in HαT, though can be normal range) 1, 3
• TPSAB1 gene copy number testing via droplet digital PCR to identify alpha-tryptase gene duplications or triplications 3, 4
• Exclude systemic mastocytosis if baseline tryptase >20 ng/mL through bone marrow biopsy with KIT D816V mutation testing 5, 1

This diagnostic approach is critical because HαT prevalence is 12-21% in systemic mastocytosis patients, and distinguishing between these conditions avoids unnecessary bone marrow examinations in confirmed HαT cases. 3, 6

Symptom-Directed Pharmacotherapy

First-Line Daily Prophylaxis

• Combined H1 and H2 antihistamines for baseline symptom control (superior to either agent alone) 2, 3
  • H1 blockers address flushing (47% of patients), pruritus (69%), and urticaria (37%) 7
  • H2 blockers provide additional benefit for gastrointestinal symptoms including irritable bowel (30-60%), nausea (51%), and reflux (49-77%) 7

Additional Symptom-Specific Agents

• Leukotriene antagonists for respiratory and atopic manifestations 3, 4
• Cromolyn sodium (cromoglicic acid) for gastrointestinal symptoms (30-60% prevalence) and neuropsychiatric manifestations including exhaustion (85%), depressive episodes (59%), and memory impairment (59-68%) 3, 7
• Omalizumab (anti-IgE monoclonal antibody) is especially successful for urticaria and anaphylaxis in HαT patients who fail conventional therapy 3

Emergency Preparedness (Non-Negotiable)

All HαT patients must carry two epinephrine auto-injectors at all times due to 14-28% prevalence of anaphylaxis and increased severity risk. 1, 2, 7

Dosing by Age:

• >12 years: 500 μg (0.5 mg) IM 2
• 6-12 years: 300 μg (0.3 mg) IM 2
• <6 years: 150 μg (0.15 mg) IM 2

Acute Anaphylaxis Management:

• Immediate IM epinephrine into anterolateral thigh (no absolute contraindications) 2, 8
• Multiple doses may be required for severe hypotension or bronchospasm 2
• Aggressive IV fluid resuscitation with normal saline or lactated Ringer's at 5-10 mL/kg boluses 2, 8
• Measure serum tryptase at 1-2 hours post-symptom onset to document acute elevation 1, 2

Trigger Avoidance Strategy

Counsel patients to avoid specific triggers that precipitate mast cell degranulation:

• Extreme heat and hot water 1, 2
• Alcohol consumption 5, 2
• Physical stimuli including pressure, friction, and vibration 5
• Exercise postprandially if food-associated exercise-induced anaphylaxis suspected 1
• Stress, hormonal fluctuations, and infections 5, 2

Critical Medication Review

Review and potentially discontinue beta-blockers and ACE inhibitors as these medications increase anaphylaxis risk and severity in HαT patients. 1, 2 Coordinate with cardiology before making changes in patients with cardiovascular disease.

Safety Measures

• Medic Alert identification is mandatory because syncope can occur during episodes 1
• Patient and family education on proper epinephrine auto-injector technique 2
• Referral to specialized Allergy/Immunology center for comprehensive evaluation and long-term management 1

Monitoring Protocol

• Serial tryptase levels every 3-6 months once diagnosis established 1
• Complete allergologic workup including skin tests or specific IgE antibodies to identify concurrent IgE-mediated hypersensitivity 1
• Screen first-degree relatives with anaphylactic reactions or mast cell mediator release symptoms for HαT after measuring baseline tryptase 3

Important Clinical Pitfalls

Do not assume HαT is benign or asymptomatic. While approximately two-thirds of HαT carriers appear asymptomatic, the condition is a significant risk factor for severe anaphylaxis, particularly with insect venom or unknown triggers. 3, 4, 6 HαT shows a gene-dose effect where higher TPSAB1 copy numbers correlate with elevated basal tryptase and more severe symptoms. 7, 9

Do not confuse HαT with mast cell activation syndrome (MCAS). HαT patients can develop MCAS, but many do not. 5 MCAS requires episodic symptoms affecting at least 2 organ systems concurrently with documented acute mediator elevation on 2 or more occasions, whereas HαT is defined by persistently elevated baseline tryptase from genetic alpha-tryptase overproduction. 5

Recognize that concomitant conditions are common. HαT frequently coexists with Ehlers-Danlos syndrome (joint hypermobility in 28%), postural orthostatic tachycardia syndrome (POTS), and autonomic dysfunction, though these are not caused by mast cell activation. 5, 7