What is the management plan for a patient with elevated tryptase levels and Ehlers-Danlos syndrome?

Management of Elevated Tryptase and Ehlers-Danlos Syndrome

For a patient with elevated tryptase (>11 ng/mL) and Ehlers-Danlos syndrome, first determine if the patient has hereditary alpha-tryptasemia (HαT) with baseline elevated tryptase versus mast cell activation syndrome (MCAS) with episodic elevations during symptom flares, as this distinction fundamentally changes management—HαT requires treatment of EDS and comorbid conditions (POTS, GI symptoms) rather than mast cell-directed therapy, while MCAS requires both mast cell stabilization and EDS management. 1

Initial Diagnostic Clarification

Distinguish Between Hereditary Alpha-Tryptasemia vs MCAS

• Hereditary alpha-tryptasemia (HαT) presents with baseline tryptase persistently >8 ng/mL (often >11 ng/mL), and notably, many affected individuals do NOT have MCAS despite elevated tryptase 1
• MCAS diagnosis requires episodic multisystem symptoms (≥2 organ systems: cardiovascular hypotension/tachycardia/syncope, dermatologic urticaria/flushing/angioedema, respiratory wheezing/dyspnea, gastrointestinal cramping/diarrhea/nausea) PLUS acute tryptase elevation >baseline × 1.2 + 2 ng/mL during symptom flares on ≥2 occasions 1
• Critical distinction: Patients with HαT can have concomitant EDS and POTS, but these manifestations are NOT caused by MCAS—they require independent evaluation and treatment 1

What to Look For Clinically

• For MCAS: Document recurrent episodes of flushing, urticaria, wheezing, hypotension, tachycardia, syncope, abdominal cramping, diarrhea with ≥2 systems involved simultaneously 1
• For HαT without MCAS: Baseline elevated tryptase without episodic multisystem anaphylactic symptoms 1
• Triggers to assess: Hot water, alcohol, drugs, stress, exercise, hormonal fluctuations, infection, physical stimuli (pressure/friction) 1

Management Algorithm

Step 1: If MCAS Criteria Are Met (Episodic Multisystem Symptoms + Documented Acute Tryptase Elevations)

Initiate mast cell-directed pharmacotherapy with layered approach:

• First-line: Second-generation H1 antihistamine (cetirizine, levocetirizine, fexofenadine, or loratadine) 1
• Add H2 receptor antagonist: Famotidine, nizatidine, or ranitidine 1
• Add mast cell stabilizer: Cromolyn sodium or ketotifen (not FDA-approved but can be compounded) 1
• Consider leukotriene receptor antagonist: Montelukast 1
• Refer to allergy/immunology or mast cell specialist for refractory cases or consideration of corticosteroids/immunoglobulins 1

Environmental and dietary modifications:

• Avoid identified triggers (temperature extremes, UV radiation, specific antigens) 1
• Consider trial of low-histamine diet, gluten-free diet, or dairy-free diet based on clinical experience, though formal studies are lacking 1

Step 2: Manage EDS-Specific Manifestations (Regardless of MCAS Status)

Gastrointestinal management (affects up to 98% of hypermobile EDS patients):

• For upper GI symptoms with comorbid POTS: Obtain gastric emptying studies after excluding structural disease 1
• For constipation/incomplete evacuation: Perform anorectal manometry, balloon expulsion test, or defecography given high prevalence of pelvic floor dysfunction 1
• Pharmacologic options: Neuromodulators (TCAs, SSRIs, SNRIs, anticonvulsants) for visceral hypersensitivity 1
• Brain-gut behavioral therapies: Cognitive behavioral therapy, hypnotherapy, relaxation therapies for anxiety and psychological distress 1
• Avoid opioids for chronic pain management, especially with GI manifestations 1

POTS management (common comorbidity):

• Conservative measures first: Increase fluid intake (2-3 liters/day), increase salt intake (6-10 grams/day), exercise training (recumbent initially), compression garments 1
• Pharmacologic options if conservative measures fail: Volume expansion agents, heart rate control medications, vasoconstrictors 1
• Monitor for QT prolongation when using multiple therapeutic agents 1

Musculoskeletal management:

• Physical therapy and occupational therapy with bracing are most effective (70% report improvement) 2
• Neuropathic modulators for pain, though 47% report adverse effects requiring careful monitoring 2
• Complementary/alternative treatments are commonly used (88% of patients) 2

Step 3: Screen for Celiac Disease

• Obtain celiac serologies earlier in EDS patients with any GI symptoms (not just diarrhea), as risk is elevated compared to general population 1
• Perform endoscopic biopsies if serologies positive 1

Step 4: Exclude Vascular EDS (Critical Safety Issue)

• If not already genetically confirmed as hypermobile EDS, urgently obtain COL3A1 gene testing to exclude vascular EDS, which carries catastrophic risk of arterial/organ rupture 3
• Avoid invasive vascular procedures until vascular EDS is definitively excluded 3

Common Pitfalls to Avoid

• Do NOT diagnose MCAS based solely on elevated baseline tryptase—this likely represents HαT, which does not require mast cell-directed therapy 1
• Do NOT perform routine MCAS testing in all EDS patients with isolated GI symptoms without multisystem episodic features 1
• Do NOT use opioids for chronic pain management in EDS patients with GI manifestations 1
• Do NOT assume elevated tryptase automatically means MCAS requires treatment—many HαT patients do not have MCAS and treating EDS/POTS manifestations is the priority 1
• Do NOT delay COL3A1 testing if vascular EDS is clinically suspected, as this is a medical emergency with median survival of 48 years 3

When to Refer

• Allergy/immunology or mast cell specialist: If MCAS diagnosis is supported by clinical and laboratory criteria (tryptase elevation during flares) 1
• Gastroenterology: For refractory GI symptoms despite appropriate management 1
• Cardiology/autonomic specialist: For POTS evaluation if lifestyle modifications fail 1
• Medical genetics: If genetic confirmation of EDS subtype not yet obtained 3