What Should Be Done When Celiac Serology and Biopsy Results Disagree?

Answer in brief: Discordant celiac testing should trigger diagnostic review rather than immediate labeling. Confirm that the patient was eating gluten, verify which serologic assay was used and whether IgA deficiency was considered, review biopsy number/orientation and pathology, and assess medications or diseases that can mimic villous atrophy. HLA-DQ2/DQ8 testing can be particularly useful because absence of both strongly argues against celiac disease.

Positive serology with normal biopsy

Possible explanations include inadequate or poorly oriented biopsies, patchy disease, early/potential celiac disease, false-positive serology or reduced gluten intake before endoscopy. Recheck the strength and specificity of the antibody result and confirm adequate sampling from bulb and distal duodenum.

Villous atrophy with negative serology

Consider IgA deficiency, insufficient gluten exposure, medication-related enteropathy, immune disorders, infections, Crohn’s disease, tropical sprue and other causes of seronegative villous atrophy. Seronegative celiac disease exists but is a diagnosis requiring careful exclusion of mimics.

Pathology quality matters

Orientation and sampling can substantially affect interpretation. Expert GI pathology review is valuable when Marsh-type changes are subtle or when the diagnosis will commit a patient to lifelong dietary treatment.

Use HLA as an exclusion tool

If neither HLA-DQ2 nor DQ8 is present, celiac disease becomes very unlikely and an alternative explanation should be pursued. Positive HLA supports possibility, not diagnosis.

Avoid empiric lifelong labeling

A symptomatic response to gluten withdrawal is not specific enough to resolve discordant testing. Establish the diagnosis as rigorously as possible before prescribing lifelong strict gluten avoidance and family screening.

What trainees should remember

When celiac tests conflict, re-open the diagnosis. Check gluten exposure, assay selection, IgA status, biopsy adequacy and mimics; use HLA to help exclude disease.

Frequently asked questions

Can PPIs or medications cause duodenal lymphocytosis?

Yes. Several medications and other conditions can create nonspecific histologic changes, which is why pathology must be interpreted clinically.

Should a patient with discordant testing start a gluten-free diet immediately?

Not unless clinically necessary. If stable, complete the diagnostic work-up first because gluten withdrawal can make later confirmation difficult.

References and further reading

1. Thomson ABR. Practice Review in Gastroenterology. CAPstone Academic Publishers; 2014.

2. Thomson ABR. Endoscopy and Diagnostic Imaging, Parts I-II. CAPstone Academic Publishers; 2012.

3. Rubio-Tapia A, et al. American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease. Am J Gastroenterol. 2023.