What is the most likely diagnosis for a patient who has brief, self‑limited episodes of nausea, vomiting, and diarrhea occurring every three to four weeks, with mild transaminase elevation, no abdominal pain, and no cannabis use?

Cyclic Vomiting Syndrome (CVS)

This clinical presentation is most consistent with Cyclic Vomiting Syndrome (CVS), characterized by stereotypical episodes of nausea, vomiting, and diarrhea occurring every 3-4 weeks, with complete wellness between episodes. 1

Diagnostic Criteria Supporting CVS

Your patient meets the Rome IV diagnostic criteria for CVS:

• Stereotypical episodic pattern: Episodes lasting <1 day (well under the 7-day maximum) occurring every 3-4 weeks 1
• Frequency requirement: With episodes occurring roughly every 3-4 weeks, the patient likely has ≥3 discrete episodes annually 1
• Symptom-free intervals: Complete wellness between episodes separated by weeks 1
• Associated gastrointestinal symptoms: Diarrhea occurs in CVS patients, particularly those with co-existing irritable bowel syndrome features 2

The mild liver function test elevation is consistent with CVS, as basic laboratory abnormalities can occur during or between episodes 1.

Critical Differential: Ruling Out Cannabinoid Hyperemesis Syndrome

You must screen for cannabis use ≥4 times weekly for >1 year, as this pattern would shift the diagnosis from CVS to cannabinoid hyperemesis syndrome (CHS). 1, 3 While you state the patient does not use cannabis, confirm this explicitly, as CHS presents identically to CVS with cyclic vomiting episodes 3. Hot-water bathing behavior, if present, does not distinguish between the two conditions—it occurs in 71% of CHS patients but also in 48% of CVS patients without cannabis exposure 3.

Distinguishing Clinical Features Present in Your Patient

• Absence of abdominal pain: While abdominal pain occurs in most CVS patients and should not exclude the diagnosis 3, its absence is not atypical and may represent a variant presentation 1
• Brief episode duration (<1 day): CVS episodes typically last hours to days, and your patient's brief episodes fit within this spectrum 1, 4
• Regular 3-4 week interval: The stereotypical timing between episodes is characteristic—CVS patients demonstrate remarkably consistent patterns 4, 5

Recommended Diagnostic Workup

Complete the following initial evaluation to exclude structural and metabolic causes:

• Laboratory tests: Complete blood count, serum electrolytes, glucose, liver function tests (already showing mild elevation), lipase, and urinalysis 1
• One-time esophagogastroduodenoscopy: Exclude obstructive lesions, peptic ulcer disease, or malignancy 1
• Avoid repeated imaging or endoscopy unless new symptoms develop 1

Consider gastric emptying scintigraphy only if gastroparesis is suspected, though this is not routine in CVS 1. Notably, 59% of CVS patients demonstrate rapid gastric emptying, 27% normal, and only 14% delayed emptying 2.

Disease Severity Classification and Treatment Strategy

Classify your patient's CVS severity to determine treatment intensity:

• Mild CVS (<4 episodes/year, each <2 days, no ED visits): Requires abortive therapy only 3
• Moderate-severe CVS (≥4 episodes/year, lasting >2 days, requiring ED visits): Requires both prophylactic amitriptyline AND abortive therapy 3

Given episodes every 3-4 weeks, your patient likely experiences 12-17 episodes annually, placing them in the moderate-severe category requiring prophylactic treatment 3.

Prophylactic Treatment (First-Line)

Initiate amitriptyline 25 mg at bedtime, titrating by 10-25 mg every 2 weeks to a target of 75-150 mg nightly (1-1.5 mg/kg). 3 This achieves a 67-75% response rate 1, 3.

• Obtain baseline ECG before starting due to QTc prolongation risk 1, 3
• Administer at night to minimize daytime sedation and anticholinergic effects (dry mouth, blurred vision, constipation, weight gain) 3
• Slow titration improves tolerability compared to rapid dose escalation 3

Abortive Therapy Education

Educate the patient to recognize prodromal symptoms (present in ~65% of CVS patients) such as impending sense of doom, panic, fatigue, mental fog, restlessness, anxiety, diaphoresis, or flushing 1, 3. The probability of aborting an episode is highest when medications are taken immediately at prodrome onset 3.

Standard abortive regimen:

• Sumatriptan 20 mg intranasal spray (can repeat once after 2 hours, maximum 2 doses/24 hours) 1, 3
• Ondansetron 8 mg sublingual every 4-6 hours during the episode 1, 3

Essential Comorbidity Screening

Screen for anxiety, depression, and panic disorder—present in 50-60% of CVS patients—as treating underlying anxiety decreases episode frequency 1, 3. Also assess for:

• Migraine history: Present in 20-30% of CVS patients, indicating shared pathophysiology 3
• Postural orthostatic tachycardia syndrome (POTS): Observed in a substantial CVS subgroup, suggesting overlapping autonomic dysfunction 3

Lifestyle Modifications

All patients require:

• Regular sleep schedule and avoiding sleep deprivation 1, 3
• Avoiding prolonged fasting 1
• Stress management techniques 1
• Identifying and avoiding individual triggers (found in 70-80% of patients) 3

Critical Pitfalls to Avoid

• Missing the prodromal window dramatically reduces abortive therapy effectiveness 3
• Avoid opioids—they worsen nausea and carry high addiction risk 6, 3
• Do not perform repeated endoscopy unless new symptoms develop 1
• Monitor for QTc prolongation with ondansetron, especially with electrolyte abnormalities 1

Alternative Diagnosis Consideration

If the patient has diabetes mellitus, narcotic use, or confirmed regular cannabis use, the 14% subset of CVS patients with delayed gastric emptying becomes more likely 2. However, the clinical presentation and absence of these risk factors make classic CVS with rapid or normal gastric emptying most probable 2.