Can you have celiac disease with a negative duodenal biopsy and only positive serologies, such as endomysial antibody (EMA) and tissue transglutaminase antibody (tTGA) tests?

Can You Have Celiac Disease with Negative Duodenal Biopsy and Only Positive Serologies?

Yes, celiac disease is possible with positive serology and negative duodenal biopsy, but this scenario requires repeat biopsies and careful evaluation before making a definitive diagnosis. 1

Primary Diagnostic Approach

In patients with strongly suspected celiac disease and negative biopsies, positive tissue transglutaminase-IgA (tTG-IgA) should still be performed, and repeat biopsies should be considered either immediately or in the future. 1 This recommendation directly addresses your clinical scenario and represents the most current expert guidance from the American Gastroenterological Association.

Key Considerations for Negative Biopsy with Positive Serology

• Inadequate biopsy sampling is the most common reason for false-negative histology. 2 At least 6 specimens must be obtained from the second part of the duodenum or beyond, as celiac lesions are patchy and can be missed with fewer samples. 1, 2

• Duodenal bulb biopsies alone are insufficient and may miss disease. 2 While bulb sampling can detect celiac disease in many cases 3, relying exclusively on bulb biopsies without distal duodenal sampling increases the risk of false-negative results.

• Gluten avoidance prior to testing is a critical pitfall. 1 Patients must consume at least 10g of gluten daily (approximately three slices of wheat bread) for 6-8 weeks before biopsy to avoid false-negative results. 1, 4

Serologic Thresholds That Support Diagnosis

When tTG-IgA levels exceed 10 times the upper normal limit combined with positive endomysial antibody (EMA) in a second blood sample, the positive predictive value for celiac disease is virtually 100%. 1 In this specific scenario:

• Endoscopy and duodenal biopsies may be performed primarily for differential diagnosis purposes rather than to confirm celiac disease. 1
• The extremely high serologic levels correlate strongly with the degree of intestinal villous atrophy. 2, 4
• However, even with these highly positive serologies, biopsy remains essential in adults to exclude other causes of villous atrophy and confirm the diagnosis. 2

Algorithm for Managing Discordant Results

Step 1: Verify Testing Conditions

• Confirm the patient was consuming adequate gluten (≥10g daily) for at least 6-8 weeks when biopsies were performed. 1, 4
• Measure total IgA levels to exclude IgA deficiency, which occurs in 1-3% of celiac patients and causes falsely negative IgA-based tests. 1, 2

Step 2: Assess Biopsy Quality

• Review whether at least 6 specimens were obtained from the second part of the duodenum or beyond. 1, 2
• Ensure specimens were properly oriented for histologic analysis with Marsh classification. 1, 2
• Consider pathologist expertise, as poorly oriented mucosa or inexperienced interpretation can lead to missed diagnoses. 2, 5

Step 3: Determine Next Steps Based on Serologic Levels

For tTG-IgA >10x upper normal limit with positive EMA:

• Repeat endoscopy with meticulous biopsy technique (6+ specimens from distal duodenum). 1
• Consider HLA-DQ2/DQ8 testing, which has >99% negative predictive value—absence of both alleles virtually excludes celiac disease. 1, 2

For lower positive tTG-IgA levels:

• Repeat biopsies are strongly recommended, as sensitivity of serology alone is insufficient (90.7% in adults). 4
• Consider timing of repeat biopsy—either immediately with improved technique or after continued gluten consumption. 1

Seronegative Celiac Disease Considerations

While your question focuses on positive serology with negative biopsy, it's important to note that the reverse scenario (seronegative celiac disease with positive biopsy) does exist. 5 However:

• Positive serology with negative biopsy is NOT the same as seronegative celiac disease. 2, 5
• In your scenario, the positive serology suggests active disease, making inadequate biopsy sampling or early/patchy disease the most likely explanations. 1, 3

Critical Pitfalls to Avoid

• Never diagnose celiac disease based on serology alone without biopsy confirmation in adults, even with extremely high antibody levels. 2 The exception would be patients with coagulation disorders or pregnancy where biopsy poses significant risk.

• Do not start a gluten-free diet before completing the diagnostic workup, as this leads to false-negative serology and inconclusive biopsies. 1, 2

• Capsule endoscopy is not recommended for making the initial diagnosis of celiac disease, even with positive serology and negative standard endoscopy. 1 Meta-analyses show that despite positive serology, no patients with negative endoscopy and histology showed mucosal changes compatible with celiac disease on capsule endoscopy in multiple studies. 1

Differential Diagnosis for Positive Serology

If repeat biopsies remain negative despite adequate sampling and gluten consumption, consider:

• Medication-induced enteropathy (olmesartan, NSAIDs, mycophenolate mofetil) can produce villous atrophy but would not typically cause positive celiac serology. 2, 5
• Early or developing celiac disease where serologic changes precede histologic changes. 4
• Review for immunosuppressant medications that could affect biopsy findings or serologic results. 5

Monitoring Strategy

• If diagnosis remains uncertain after repeat biopsies, follow-up tTG-IgA testing at 3-6 months while maintaining gluten intake. 2, 4
• Persistently positive serology usually indicates ongoing intestinal damage and warrants continued investigation. 1
• Consider trial of gluten-free diet with follow-up biopsy in 1-3 years to assess histologic improvement, which would support the diagnosis retrospectively. 2, 5