What is the interpretation of EGD (Esophagogastroduodenoscopy) results showing preserved villous architecture and locally increased intraepithelial lymphocytes in the duodenal mucosa, with a negative H. pylori (Helicobacter pylori) status?

Interpretation of EGD Findings: Preserved Villous Architecture with Locally Increased Intraepithelial Lymphocytes

Your biopsy shows increased intraepithelial lymphocytes (IELs) without villous atrophy, which is NOT diagnostic of celiac disease but requires systematic evaluation to determine the underlying cause. 1

Key Diagnostic Principle

Villous atrophy is required for definitive diagnosis of celiac disease in adults—increased IELs alone (without villous atrophy) should not be considered diagnostic of celiac disease on their own. 1, 2 However, this finding warrants investigation as it can represent early celiac disease or numerous other conditions. 3, 4

Most Likely Differential Diagnoses

H. pylori-Associated Gastritis (Most Common Non-Celiac Cause)

• Despite your negative H. pylori duodenal biopsy, H. pylori gastritis is the most common cause of duodenal intraepithelial lymphocytosis with preserved villi. 5, 6
• 44% of patients with H. pylori gastritis demonstrate duodenal IEL elevations (ranging 3-42 IELs/100 epithelial cells), even when H. pylori organisms are not visualized in the duodenal tissue itself. 5
• The lymphocyte distribution patterns and numbers overlap significantly with those seen in celiac disease, making this a critical diagnostic consideration. 5
• If H. pylori eradication is achieved, duodenal IEL counts decrease significantly (from median 73 to 28 per 100 epithelial cells within 2 months). 6

Early or Latent Celiac Disease

• Approximately 9-10% of patients with increased IELs and normal villi have gluten sensitivity as the underlying cause. 3, 4
• Lesser degrees of intestinal damage (≥25 IELs per 100 enterocytes without villous atrophy) may indicate celiac disease, representing early-stage disease. 1, 2
• Three of 14 patients (21%) with raised IELs and normal villi had positive celiac serology in one study. 4

Autoimmune and Immune Dysregulation Disorders

• 14% of patients with increased IELs have disorders of immune regulation including Hashimoto's thyroiditis, Graves' disease, rheumatoid arthritis, psoriasis, and multiple sclerosis. 3
• Common variable immunodeficiency and autoimmune enteropathy should be considered. 1

Medication-Induced

• 14% of cases are associated with NSAIDs, compared to only 2.2% of controls. 3
• Other medications including PPIs, olmesartan, and mycophenolate mofetil can cause this pattern. 1, 2

Other Infectious and Inflammatory Causes

• Post-infectious enteropathy, giardiasis, small intestinal bacterial overgrowth, Crohn's disease, and microscopic colitis are recognized causes. 1, 3

Required Diagnostic Workup

Immediate Serologic Testing

• Obtain IgA tissue transglutaminase antibodies (tTG-IgA) with total IgA level to rule out IgA deficiency (occurs in 1-3% of celiac patients). 2, 7
• If IgA deficient, obtain IgG-based tests (IgG-DGP or IgG-tTG). 2, 7
• Consider IgA endomysial antibodies (EMA) for additional specificity. 2

Confirm H. pylori Status

• Verify H. pylori status in gastric biopsies (antrum and body), not just duodenal tissue, as H. pylori organisms are typically not visualized in duodenal biopsies even when causing duodenal lymphocytosis. 5, 6
• Consider urea breath test or stool antigen if gastric biopsies were not obtained. 6

HLA Typing

• HLA-DQ2 and HLA-DQ8 testing has >99% negative predictive value—absence of both alleles virtually excludes celiac disease. 2, 7
• Approximately 95% of celiac patients have HLA-DQ2, and 5% have HLA-DQ8. 2

Review Medications

• Document all current medications, particularly NSAIDs, PPIs, olmesartan, and immunosuppressants. 1, 3

Screen for Autoimmune Conditions

• Thyroid function tests, rheumatoid factor, ANA, and immunoglobulin levels if not already obtained. 3

Management Algorithm

If Celiac Serology is Positive

• Patients with positive celiac serology and increased IELs (≥25 IELs per 100 enterocytes) may be classified as having "probable celiac disease" and should be offered a trial of gluten-free diet. 2
• Refer to registered dietitian for comprehensive gluten-free diet education. 2, 7
• Repeat duodenal biopsy in 12-24 months to assess for progression to villous atrophy. 8

If Celiac Serology is Negative and H. pylori is Positive

• Treat H. pylori infection and repeat duodenal biopsy 2-3 months after confirmed eradication to document resolution of lymphocytosis. 6
• This approach avoids unnecessary gluten-free diet in patients whose lymphocytosis is H. pylori-related. 6

If Both Celiac Serology and H. pylori are Negative

• Consider trial of gluten-free diet for 6 months if clinical suspicion for seronegative celiac disease remains high, particularly if HLA-DQ2/DQ8 positive. 2, 8
• Monitor clinical response and repeat serology. 8
• Investigate other causes: stool studies for giardiasis, evaluate for SIBO, review autoimmune workup. 1, 8

Pathology Review

• Confirm proper orientation of biopsy specimens with an experienced GI pathologist to ensure accurate assessment of villous architecture. 1, 8
• Request formal IEL count if not already performed (threshold ≥25 IELs per 100 enterocytes is significant). 1

Critical Pitfalls to Avoid

• Do not diagnose celiac disease based on increased IELs alone without villous atrophy in adults. 1
• Do not assume negative H. pylori in duodenal tissue excludes H. pylori gastritis as the cause—check gastric biopsies. 5, 6
• Do not start gluten-free diet before completing celiac serologic workup, as this leads to false-negative results. 2, 7
• Do not dismiss this finding as clinically insignificant—it warrants investigation and follow-up, as 6 of 10 patients in one study had ongoing GI symptoms one year later. 4

Follow-Up Strategy

• If diagnosis remains unclear after initial workup, repeat duodenal biopsy in 12-24 months to assess for progression. 8, 4
• Consider jejunal biopsies if celiac disease remains suspected, as lesions can be patchy. 1, 8
• The finding of increased IELs with normal villous architecture is of sufficient clinical importance to warrant highlighting in pathology reports and systematic follow-up. 4