What is the best management approach for a 26-year-old patient with Hypermobile Ehlers-Danlos Syndrome (hEDS), Postural Orthostatic Tachycardia Syndrome (POTS) symptoms, thrombocytosis, borderline hepatomegaly, presenting with early satiety, abdominal pain, nausea, and constipation?

Management of a 26-Year-Old with hEDS, POTS Symptoms, Thrombocytosis, Hepatomegaly, and Upper GI Symptoms

Begin with gastric emptying scintigraphy and celiac disease serological testing while simultaneously optimizing POTS management with increased fluid/salt intake and compression garments, then treat the most prominent GI symptoms with prokinetics for gastroparesis or acid suppression for dyspepsia. 1

Immediate Diagnostic Priorities

Essential GI Testing

• Gastric emptying scintigraphy is the priority test given early satiety, nausea, and abdominal pain, as abnormal gastric emptying is more common in hEDS/POTS than the general population 1
• Celiac disease serological testing should be performed earlier than usual in hEDS patients with any GI symptoms, as celiac disease risk is elevated in this population 1, 2
• Anorectal manometry or balloon expulsion testing should be obtained to evaluate constipation, given high prevalence of pelvic floor dysfunction in hEDS 3
• Upper endoscopy is appropriate to exclude structural disease before attributing symptoms to dysmotility, though perforation risk is not increased in hEDS (unlike vascular EDS) 1

Critical Hematology Workup for Thrombocytosis

• Baseline serum tryptase level must be obtained urgently to distinguish between reactive thrombocytosis and mast cell activation syndrome (MCAS), as elevated tryptase is common in myeloproliferative variants 2
• Complete blood count with differential to evaluate for cytopenias or eosinophilia suggesting systemic involvement 2
• The pending hematology assessment should include JAK2 mutation testing and bone marrow evaluation if primary myeloproliferative disorder is suspected 2

Hepatomegaly Investigation

• Comprehensive metabolic panel including liver function tests is essential 2
• Consider abdominal ultrasound or MRI to characterize hepatomegaly and exclude structural causes
• The combination of thrombocytosis and hepatomegaly raises concern for myeloproliferative disorder, which must be excluded before attributing symptoms solely to hEDS/POTS 2

POTS Optimization (Must Be Done Concurrently)

First-Line Non-Pharmacologic Interventions

• Increase fluid intake to 2-3 liters daily and salt intake to 10-12 grams daily for volume expansion 3
• Lower body compression garments (30-40 mmHg) should be worn during upright activities to reduce venous pooling 3
• Supervised recumbent exercise training (starting with rowing or recumbent cycling) should be initiated to improve orthostatic tolerance 1, 3

When to Add Pharmacologic POTS Treatment

• If conservative measures fail after 2-4 weeks, consider referral to cardiology or neurology for pharmacologic management with volume expanders (fludrocortisone), heart rate control (beta-blockers), or vasoconstrictors (midodrine) 1

Symptom-Directed GI Management

For Early Satiety and Nausea (Likely Gastroparesis)

• Metoclopramide 5-10mg three times daily before meals as first-line prokinetic if gastric emptying is delayed 3
• Ondansetron 4-8mg as needed for breakthrough nausea 3
• Gastroparesis diet: small, frequent meals (5-6 per day), low fat (<40g/day), low fiber, with liquid calories prioritized 1, 3

For Abdominal Pain

• Avoid NSAIDs completely as they worsen GI symptoms in hEDS and are MCAS triggers 3
• Never use opioids for chronic abdominal pain, as they cause narcotic bowel syndrome and worsen gastroparesis and constipation 1, 3
• Consider neuromodulators such as mirtazapine 7.5-15mg at bedtime, which can increase food tolerance and body weight 1

For Constipation

• Polyethylene glycol 3350 17g daily as first-line osmotic laxative 3
• Add stimulant laxatives (bisacodyl or senna) if osmotic therapy insufficient 3
• If pelvic floor dysfunction confirmed on testing, refer for pelvic floor physical therapy 3

MCAS Evaluation and Treatment (If Indicated)

When to Suspect MCAS

• MCAS should be suspected if patient has multisystem symptoms including flushing, urticaria, wheezing, or anaphylaxis-like episodes 1
• Do not perform MCAS testing for isolated GI symptoms alone without evidence of generalized mast cell disorder 1, 2

MCAS Treatment Protocol (If Confirmed)

• H1 receptor antagonist: cetirizine 10mg daily 3
• H2 receptor antagonist: famotidine 20mg twice daily for GI symptoms 3
• Mast cell stabilizer: cromolyn sodium 200mg four times daily for refractory cases 3
• Avoid triggers: certain foods, alcohol, strong smells, temperature changes, mechanical friction, emotional distress, opioids, NSAIDs 1

Dietary Interventions with Nutritional Safeguards

Structured Dietary Approach

• Start with gastroparesis diet as described above 1, 3
• Low-FODMAP diet may be trialed as second-line for bloating and alternating bowel symptoms 3
• Low-histamine diet only if MCAS is confirmed 3

Critical Pitfall to Avoid

• All dietary interventions must include nutritional counseling to avoid restrictive eating patterns and development of avoidant/restrictive food intake disorder (ARFID), which has significant overlap with hEDS/DGBI 1
• Screen for ARFID using validated tools, as this population is highly vulnerable to disordered eating 1

Multidisciplinary Coordination

Essential Specialist Involvement

• Hematology (already pending): to definitively diagnose cause of thrombocytosis and hepatomegaly
• Gastroenterology: for ongoing management of dysmotility and DGBI 1
• Cardiology or Neurology: if POTS symptoms persist despite conservative measures 1
• Nutrition: mandatory for dietary interventions to prevent ARFID 1
• Pain management: if chronic pain develops, but with strict avoidance of opioids 1

Avoid Parenteral Nutrition

• Parenteral nutrition should be avoided in hEDS/POTS except in life-threatening malnutrition as a temporary bridge to rehabilitative therapies, as catheter-related bloodstream infections are more frequent in this population 1

Common Pitfalls in This Clinical Scenario

• Do not attribute all symptoms to hEDS/POTS until thrombocytosis and hepatomegaly are fully explained, as myeloproliferative disorders can cause similar GI symptoms 2
• Do not perform routine genetic testing for hEDS, as no causative genes have been identified 2
• Do not delay gastric emptying testing while waiting for hematology workup, as these evaluations should proceed in parallel 1
• Recognize that opioid use is contraindicated and will worsen all GI symptoms through opioid bowel dysfunction 1, 3