No Validated Blood Test for Non-Celiac Gluten Sensitivity
There is no blood test to diagnose non-celiac gluten sensitivity (NCGS) after a negative celiac panel. The diagnosis of NCGS is made by exclusion after properly ruling out celiac disease with both serology and duodenal biopsies, followed by documented symptom improvement on a gluten-free diet and symptom recurrence with gluten reintroduction 1.
Confirm Celiac Disease Has Been Properly Excluded
Before considering NCGS, you must verify that celiac disease was adequately ruled out:
Ensure the patient was consuming adequate gluten (at least 10g daily for 6-8 weeks) when serologic testing was performed, as testing on a gluten-free or reduced-gluten diet yields false-negative results 2, 3
Verify total IgA level was measured alongside IgA tissue transglutaminase (tTG-IgA), since selective IgA deficiency occurs 10-15 times more frequently in celiac patients and causes falsely negative IgA-based testing 1
Confirm upper endoscopy with duodenal biopsies was performed, not just serology alone—multiple biopsies (ideally 6 total: 1-2 from duodenal bulb and at least 4 from second part of duodenum) are required to properly exclude celiac disease 1, 2, 3
If biopsies were not obtained, the diagnosis of celiac disease has not been properly excluded, and upper endoscopy should be performed before labeling this as NCGS 3
Consider HLA-DQ2/DQ8 Genetic Testing
HLA-DQ2 and HLA-DQ8 testing has a negative predictive value exceeding 99%—absence of both alleles essentially rules out celiac disease 1. This testing is particularly useful when:
- Celiac disease is strongly suspected despite negative serology 1
- The patient has equivocal small-bowel histologic findings 1
- The patient started a gluten-free diet before testing was completed 1
- There are discrepant celiac-specific serology and histology results 1
However, HLA testing cannot diagnose NCGS—it can only help rule out celiac disease. Approximately 25-30% of the white population carries HLA-DQ2, so a positive result does not confirm any diagnosis 1.
Diagnostic Approach to Non-Celiac Gluten Sensitivity
Once celiac disease is properly excluded, NCGS is diagnosed clinically through a structured elimination and rechallenge protocol:
Document symptom improvement on a gluten-free diet for 6-8 weeks 1, 4
Perform a gluten rechallenge to confirm symptom recurrence with gluten reintroduction 1, 4
Rule out wheat allergy through appropriate testing before confirming NCGS 4
Symptoms alone or symptom response to a gluten-free diet cannot reliably differentiate celiac disease from NCGS, as there is substantial overlap in clinical presentations 1. The positive predictive value of symptom improvement with gluten avoidance is very low and should not be used as diagnostic evidence in isolation 1, 3.
Critical Pitfalls to Avoid
Never diagnose NCGS without first properly excluding celiac disease with both serology and duodenal biopsies performed while the patient is consuming gluten 1, 3
Do not rely on negative serology alone to exclude celiac disease—seronegative celiac disease occurs, and biopsy remains the gold standard 1, 3
Avoid initiating a gluten-free diet before completing the diagnostic workup, as this leads to false-negative results and makes subsequent testing unreliable 1, 2
If the patient has already started a gluten-free diet, they should resume a normal diet with three slices of wheat bread daily for 1-3 months before repeat testing 1, 2
Why Differentiation Matters
Distinguishing celiac disease from NCGS has important clinical implications 1:
- Celiac disease patients are at risk for nutritional deficiencies and serious complications including lymphoma
- First-degree relatives of celiac patients require screening
- The degree and duration of adherence to a gluten-free diet differs between conditions
- Celiac disease requires lifelong strict gluten avoidance and ongoing monitoring