What are the likely causes and initial work‑up for a patient presenting with upper epigastric pain, elevated liver enzymes, and peripheral eosinophilia?

Differential Diagnosis and Initial Work-Up for Upper Epigastric Pain with Elevated Liver Enzymes and Eosinophilia

The most critical initial step is to exclude parasitic infections (particularly helminthic infections like Fasciola hepatica), followed by systematic evaluation for hypereosinophilic syndrome (HES), eosinophilic gastrointestinal disorders (EGIDs), and drug hypersensitivity reactions. 1, 2

Primary Differential Diagnoses to Consider

1. Parasitic Infections (Highest Priority)

• Helminthic infections, particularly Fasciola hepatica, can present with this exact triad of symptoms and represent a potentially treatable cause that must be excluded first 3
• Intestinal helminths are among the most common causes of eosinophilia after allergic disorders 1
• Fasciola hepatica specifically causes elevated liver enzymes, eosinophilia, and upper abdominal pain, with CT/MRI showing hepatic lesions 3

2. Hypereosinophilic Syndrome (HES)

• HES requires persistent eosinophilia >1,500 cells/μL with organ damage and can affect the gastrointestinal tract and liver 2
• Up to 38% of HES patients develop GI symptoms including epigastric pain 2
• Hepatic involvement can occur, causing elevated liver enzymes 4

3. Eosinophilic Gastrointestinal Disorders (EGIDs)

• Eosinophilic gastroenteritis (EGE) commonly presents with epigastric pain, nausea, and peripheral eosinophilia 5, 6
• EGE typically affects the stomach and duodenum, causing vague abdominal symptoms 5
• Peripheral eosinophilia occurs in 10-50% of adults with eosinophilic esophagitis, though EGE has higher rates 1
• Note: While eosinophilic esophagitis (EoE) can cause upper abdominal pain, it more commonly presents with dysphagia and food impaction 7

4. Drug Hypersensitivity Reactions

• Many medications can cause eosinophilia with hepatic involvement 7, 1

5. Inflammatory Pseudo-tumor of the Liver

• Rare but can present with elevated liver enzymes, eosinophilia, and abdominal symptoms 8

Structured Initial Work-Up Algorithm

Step 1: Immediate Laboratory Evaluation

• Complete blood count with differential to quantify absolute eosinophil count 1, 2
• Comprehensive metabolic panel to characterize liver enzyme pattern (AST, ALT, alkaline phosphatase, bilirubin)
• Serum vitamin B12 and tryptase levels to help distinguish primary (neoplastic) from secondary (reactive) HES 2
• Serum immunoglobulins to evaluate for IgG4-related disease 4

Step 2: Exclude Parasitic Infections (Critical)

• Stool examination for ova and parasites (three separate samples) 1, 2
• Strongyloides serology 1, 2
• Fasciola hepatica-specific antibody testing if patient has travel history or consumed watercress/contaminated water 3
• Consider other helminth serologies based on exposure history

Step 3: Comprehensive Medication Review

• Detailed review of all medications, supplements, and herbal products to identify potential drug-induced eosinophilia 1

Step 4: Imaging Studies

• Abdominal CT or MRI to evaluate for:
  • Hepatic lesions suggestive of parasitic infection 3
  • Duodenal/gastric wall thickening suggesting EGE 5
  • Lymphadenopathy (HES, IgG4-related disease) 4
  • Ascites (EGE can present with ascites) 5

Step 5: Endoscopic Evaluation with Biopsies

• Upper endoscopy (EGD) with multiple biopsies from esophagus, stomach, and duodenum 7, 5, 6
• Obtain at least 2-3 biopsies from proximal and distal esophagus if EoE suspected 7
• Look for ≥20 eosinophils/HPF in gastric or duodenal mucosa for EGE diagnosis 6
• Look for ≥15 eosinophils/HPF in esophageal mucosa for EoE diagnosis 7
• Endoscopy may appear grossly normal despite significant eosinophilic infiltration 6

Step 6: Assess for Allergic Conditions

• Detailed history of asthma, allergic rhinitis, eczema, and food allergies (allergic disorders account for ~80% of eosinophilia cases) 1
• Consider allergy testing if history suggests atopic diathesis 7

Step 7: Advanced Testing if Initial Work-Up Negative

• Bone marrow aspirate and biopsy with immunohistochemistry, cytogenetics, and FISH for tyrosine kinase fusion genes if HES suspected 2
• Flow cytometry with T-cell immunophenotyping to distinguish primary from secondary HES 2
• Liver biopsy if diagnosis remains unclear and hepatic involvement is prominent 4, 8

Critical Pitfalls to Avoid

• Do not assume GERD is the cause of epigastric pain without tissue diagnosis, as EGIDs can mimic GERD symptoms 7
• Do not overlook parasitic infections, especially in patients with travel history or specific dietary exposures (watercress, raw vegetables) 3
• Do not diagnose EoE based solely on symptoms and eosinophilia—endoscopic biopsies are mandatory 7
• Do not miss HES, as cardiac involvement can be life-threatening and requires urgent evaluation 2
• Recognize that normal-appearing endoscopy does not exclude EGIDs—histologic evaluation is essential 6

Special Considerations for PPI Trial

• Consider an empiric PPI trial (standard or double-dose for 8 weeks) before definitive diagnosis, as PPI-responsive esophageal eosinophilia is increasingly recognized 7
• If PPI trial is initiated, repeat endoscopy with biopsies after 8 weeks to assess response 7
• However, if parasitic infection is suspected based on exposure history, prioritize parasitic work-up before PPI trial 3