What is the differential diagnosis for a patient with chronic abdominal pain in the epigastric area, associated with nausea, vomiting, and watery diarrhea, with negative Computed Tomography (CT) imaging, normal ultrasound, and normal laboratory results, including lipase, Complete Blood Count (CBC), liver enzymes, and analysis?

Differential Diagnosis for Chronic Epigastric Pain with Nausea, Vomiting, and Watery Diarrhea

Given the 4-week duration of epigastric pain with progression to vomiting and watery diarrhea, combined with repeatedly negative imaging and laboratory workup, the most likely diagnoses are functional gastrointestinal disorders (particularly functional dyspepsia or irritable bowel syndrome), infectious gastroenteritis with prolonged symptoms, or less commonly, eosinophilic gastroenteritis or early inflammatory bowel disease not yet detectable by standard biomarkers.

Primary Differential Considerations

Functional Gastrointestinal Disorders (Most Likely)

• Functional dyspepsia with overlapping irritable bowel syndrome is the leading consideration when epigastric pain, nausea, and diarrhea persist for 4 weeks with completely negative structural workup including CT, ultrasound, and normal laboratory values 1
• The absence of inflammatory biomarkers (normal CBC, liver enzymes) strongly suggests functional rather than organic disease, as studies show diagnostic yield of advanced testing is near 0% in patients with chronic abdominal pain and diarrhea without positive inflammatory markers 1
• Functional disorders characteristically present with chronic symptoms (>4 weeks), normal imaging, and normal laboratory parameters, which precisely matches this clinical presentation 2, 3

Infectious Gastroenteritis (Consider if Recent Onset)

• Acute gastroenteritis can present with nausea, vomiting, diarrhea, and abdominal pain, though symptoms typically resolve within 1-2 weeks 4
• The 4-week duration makes typical viral or bacterial gastroenteritis less likely unless there is persistent post-infectious functional disorder 4
• The absence of recent antibiotic use makes Clostridium difficile infection less probable, though it remains a consideration in any patient with prolonged diarrhea 4

Eosinophilic Gastroenteritis (Rare but Important)

• Serosal eosinophilic gastroenteritis can present with abdominal pain, nausea, and low-grade symptoms with normal endoscopy and CT findings 5
• This diagnosis requires specific testing: peripheral eosinophilia on CBC (which should be reviewed specifically) or ascitic fluid analysis showing eosinophils 5
• Ultrasound may show peritoneal nodules or ascites that were potentially missed on initial imaging 5

Early Inflammatory Bowel Disease

• Crohn's disease limited to small bowel can present with chronic abdominal pain and diarrhea with initially negative standard imaging 1
• However, the absence of elevated inflammatory markers (normal CBC, presumably normal CRP/ESR) makes active Crohn's disease unlikely, as studies show 0% diagnostic yield for Crohn's when inflammatory markers are negative 1
• Video capsule endoscopy is NOT recommended in this setting without positive biomarkers 1

Critical Diagnostic Steps to Pursue Now

Essential Laboratory Testing

• Check inflammatory markers immediately: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) if not already done, as these are critical for distinguishing organic from functional disease 1
• Review CBC differential carefully for eosinophilia, which would suggest eosinophilic gastroenteritis 5
• Stool studies: Comprehensive stool testing including bacterial culture, ova and parasites, Giardia antigen, and C. difficile toxin to exclude infectious causes 4
• Fecal calprotectin: If available, levels >100 mg/g would increase suspicion for inflammatory bowel disease and warrant further investigation 1

Imaging Reconsideration

• The negative CT and ultrasound effectively rule out: acute mesenteric ischemia, bowel obstruction, perforation, acute pancreatitis (with normal lipase), and biliary pathology 1
• No additional imaging is indicated unless new symptoms develop or inflammatory markers are elevated 1

What This Is NOT

Excluded Diagnoses Based on Negative Workup

• Acute pancreatitis: Ruled out by normal lipase on two occasions 1
• Peptic ulcer disease with complications: Would show findings on CT imaging or cause anemia/elevated inflammatory markers 1
• Biliary pathology: Excluded by normal ultrasound and liver enzymes 1
• Acute mesenteric ischemia: Completely excluded by negative CT imaging; this diagnosis requires CTA and presents with severe acute pain, not 4-week chronic symptoms 1, 6
• Celiac disease: Would not present with watery diarrhea as primary symptom and requires serologic testing, not imaging 1

Common Pitfalls to Avoid

• Do not pursue video capsule endoscopy without positive inflammatory biomarkers, as guidelines strongly recommend against this with a diagnostic yield of 0% in patients with only symptoms 1
• Do not repeat CT imaging without new clinical findings or positive inflammatory markers, as the yield will remain low 1
• Do not assume COVID-19 gastrointestinal manifestations unless there are respiratory symptoms or known exposure, as isolated GI symptoms occur in <10% of COVID-19 cases 1
• Do not overlook medication history: Review all medications, supplements, and over-the-counter agents that could cause these symptoms 7

Recommended Management Algorithm

1. Obtain inflammatory markers (CRP, ESR) and comprehensive stool studies immediately 1, 4
2. If inflammatory markers are elevated (CRP >10 mg/L, ESR >20 mm/hr): Consider upper endoscopy with biopsies and colonoscopy with ileoscopy to evaluate for inflammatory bowel disease 1
3. If inflammatory markers are normal and stool studies negative: Diagnose functional gastrointestinal disorder and initiate empiric treatment with dietary modification, prokinetics for nausea, and antispasmodics for pain 3, 7
4. If eosinophilia is present: Consider diagnostic paracentesis if ascites present, or empiric trial of corticosteroids for eosinophilic gastroenteritis 5
5. Reassess in 2-4 weeks: If symptoms persist despite treatment or worsen, reconsider diagnosis and pursue gastroenterology referral 2, 3