What is the best management approach for a patient with hypermobile Ehlers-Danlos Syndrome (hEDS) and Postural Orthostatic Tachycardia Syndrome (POTS)-like symptoms, currently taking mirtazapine (30mg nightly) and propranolol (10mg twice daily), presenting with early satiety, abdominal pain, nausea, constipation, occasional diarrhea, and heartburn?

Management of GI Symptoms in hEDS with POTS-like Features

This patient requires immediate diagnostic testing for gastroparesis with gastric emptying scintigraphy, followed by symptom-directed treatment with prokinetics, dietary modifications, and optimization of POTS management, while screening for mast cell activation syndrome. 1

Immediate Diagnostic Workup

Prioritize gastric motor function testing given the constellation of early satiety, nausea, and abdominal pain in the setting of hEDS with POTS-like symptoms, as abnormal gastric emptying is significantly more common in this population than the general population. 1

• Obtain 4-hour gastric emptying scintigraphy after excluding anatomical/structural disease (if not already done with upper endoscopy). 1
• Test for celiac disease earlier in the diagnostic evaluation, as it should be considered with this variety of GI symptoms, not just diarrhea. 1
• Perform anorectal manometry, balloon expulsion test, or defecography for the constipation symptoms, given the high prevalence of pelvic floor dysfunction (especially rectal hyposensitivity) in hEDS. 1

Screen for mast cell activation syndrome (MCAS) given the multisystem symptoms involving GI and cardiac systems:

• Obtain baseline serum tryptase level. 1, 2
• If symptoms flare, collect tryptase 1-4 hours after symptom onset—an increase of 20% above baseline plus 2 ng/mL indicates mast cell activation. 1, 2
• If MCAS is supported, refer to an allergy specialist or mast cell disease research center for additional testing (urinary N-methylhistamine, leukotriene E4, 11b-prostaglandin F2). 1

Medication Management

Current Medication Review

The propranolol 10mg twice daily is appropriate for POTS heart rate control but may be contributing to gastroparesis symptoms, as beta-blockers can slow gastric emptying. 3 However, given the low dose and need for heart rate management, continue it while addressing GI symptoms directly. 3

Mirtazapine 30mg nightly is reasonable for appetite stimulation but recognize it may not overcome mechanical gastroparesis if present. 4

Add Symptom-Directed Pharmacotherapy

For nausea and early satiety (presumed gastroparesis):

• Start metoclopramide 5-10mg three times daily before meals as first-line prokinetic, or consider domperidone, erythromycin, or prucalopride as alternatives. 1, 3
• Add ondansetron 4-8mg as needed for breakthrough nausea. 1, 3

For heartburn:

• Initiate proton pump inhibitor (omeprazole 20-40mg daily or equivalent) for acid suppression. 1, 3

For constipation:

• Trial osmotic laxatives (polyethylene glycol 3350 17g daily) as first-line. 1, 3
• If inadequate response, add stimulant laxatives (bisacodyl) or consider prescription agents (linaclotide 145-290mcg daily, prucalopride 2mg daily, or lubiprostone 24mcg twice daily). 1, 3

For abdominal pain (neuromodulation):

• Consider low-dose tricyclic antidepressant (amitriptyline 10mg at bedtime, titrating slowly to 30-50mg) as a gut-brain neuromodulator. 4, 3
• Critical: Avoid opioids entirely—they worsen GI dysmotility and are contraindicated for chronic abdominal pain in this population. 1, 4, 3

POTS Optimization

Intensify conservative POTS management as inadequately controlled POTS worsens GI symptoms:

• Increase fluid intake to 2-3 liters daily and salt intake to 10-12 grams daily for volume expansion. 1, 3
• Recommend lower body compression garments (20-30 mmHg) to reduce venous pooling. 1, 3
• Implement supervised exercise training program (recumbent exercise initially). 1

If orthostatic symptoms remain inadequately controlled:

• Consider adding fludrocortisone 0.1-0.2mg daily for volume expansion. 3
• Midodrine 5-10mg three times daily can be added for vasoconstriction if significant orthostatic hypotension develops. 3
• Coordinate care with cardiology or neurology for integrated management. 1

Dietary Interventions

Implement gastroparesis diet immediately:

• Small, frequent meals (5-6 per day) with small particle size. 1, 4, 3
• Low fat (<50g/day), low fiber diet initially. 4, 3
• Avoid insoluble fiber (wheat bran) as it exacerbates bloating. 4

Consider trial of low FODMAP diet as second-line therapy if initial measures fail, particularly for the bloating and alternating bowel symptoms. 4, 3

If MCAS is confirmed, trial low-histamine diet while avoiding triggers (alcohol, strong smells, temperature extremes, mechanical friction, emotional stress). 1, 3

Ensure nutritional counseling to prevent restrictive eating patterns and nutritional deficiencies. 1, 4

MCAS Treatment (if confirmed)

• Start H1 receptor antagonist (cetirizine 10mg daily or fexofenadine 180mg daily). 3
• Add H2 receptor antagonist (famotidine 20mg twice daily) for GI symptoms. 3
• Consider mast cell stabilizer (cromolyn sodium 200mg four times daily) for refractory cases. 1, 3

Critical Pitfalls to Avoid

• Never prescribe NSAIDs—they worsen GI symptoms in hEDS and are MCAS triggers. 4, 3
• Never use opioids for chronic abdominal pain—they cause narcotic bowel syndrome and worsen gastroparesis and constipation. 1, 4, 3
• Do not implement restrictive diets without nutritional guidance—this population is vulnerable to disordered eating patterns. 1, 4
• Avoid excessive testing without symptom-directed approach—follow positive symptom-based diagnostic strategy similar to general DGBI evaluation. 1

Multidisciplinary Coordination

• Maintain integrated care with cardiology/neurology for POTS management. 1, 3
• Consider referral to allergy specialist if MCAS is confirmed. 1
• Provide psychological support with brain-gut behavioral therapies, as anxiety and psychological distress are common and may be mediated by autonomic dysfunction. 1, 3
• Refer to physical therapy for pelvic floor dysfunction if anorectal testing is abnormal. 1