Can you have celiac disease with negative blood laboratory results?

Can You Have Celiac Disease with Negative Blood Labs?

Yes, celiac disease can occur with negative serologic testing, and if clinical suspicion remains high despite negative serology, you should proceed directly to upper endoscopy with duodenal biopsies. 1

Understanding Seronegative Celiac Disease

Seronegative celiac disease is a recognized entity where patients have characteristic intestinal damage but negative antibody testing. This occurs in a small but clinically important subset of patients and requires a different diagnostic approach. 1

Key Scenarios Where Negative Serology Occurs

IgA Deficiency (Most Common Cause)

• Selective IgA deficiency occurs in 1-3% of celiac disease patients—10-15 times more frequently than in the general population 1, 2, 3
• IgA deficiency causes falsely negative results on all IgA-based antibody tests (IgA tissue transglutaminase, IgA endomysial antibody, IgA deamidated gliadin peptide) 1, 3
• You must measure total IgA levels alongside celiac serology in all patients to identify this critical pitfall 1
• If IgA deficiency is confirmed, repeat testing using IgG-based assays (IgG deamidated gliadin peptide or IgG tissue transglutaminase) 1

Inadequate Gluten Intake Before Testing

• Patients must consume at least 10g of gluten daily (approximately 3 slices of wheat bread) for 6-8 weeks prior to testing 1, 4
• Reduction or avoidance of gluten significantly reduces sensitivity of both serology and biopsy, creating false-negative results 1, 4
• This is one of the most common reasons for missed diagnoses in clinical practice 1

True Seronegative Celiac Disease

• Even with adequate gluten intake and normal IgA levels, some patients with biopsy-proven celiac disease have persistently negative serology 1
• The sensitivity of IgA tissue transglutaminase is 90.7% in adults, meaning approximately 9-10% of celiac disease patients will have negative results despite active disease 1, 4

Diagnostic Algorithm for Suspected Celiac Disease with Negative Serology

Step 1: Verify Testing Was Performed Correctly

• Confirm the patient was consuming adequate gluten (≥10g daily for 6-8 weeks) when tested 4
• Verify total IgA level was measured to exclude IgA deficiency 1, 4
• Review medication history for immunosuppressants that may affect antibody production 5

Step 2: Proceed to Endoscopy if High Clinical Suspicion

When to pursue biopsy despite negative serology: 1

• Symptoms of malabsorption (chronic diarrhea with weight loss, steatorrhea, postprandial abdominal pain and bloating) 1
• Unexplained iron deficiency anemia (celiac disease present in 2-6% of these patients) 6
• First-degree relative with celiac disease 1, 4
• Type 1 diabetes or autoimmune thyroid disease 4, 5
• Unexplained osteoporosis or elevated liver enzymes 5

Biopsy technique: 1

• Obtain at least 6 duodenal biopsy specimens (1-2 from the bulb and at least 4 from the distal duodenum) 1
• Multiple biopsies are essential because celiac disease can have patchy distribution 1
• Ensure specimens are properly oriented for histologic analysis with Marsh classification 4

Step 3: Consider HLA-DQ2/DQ8 Genetic Testing

When HLA testing is useful: 1

• HLA-DQ2 and HLA-DQ8 are present in almost all patients with celiac disease (>99% negative predictive value when both are absent) 1
• If HLA-DQ2 and HLA-DQ8 are both negative, celiac disease is effectively ruled out 1, 4
• This prevents unnecessary gluten challenges and further invasive testing 1

Important caveats about HLA testing: 1

• HLA-DQ2 is present in 25-30% of the white population, so positive results do not confirm celiac disease 1
• HLA testing should not be used as a primary diagnostic tool, only to rule out disease in specific scenarios 1
• Carefully review all alleles tested—laboratories may not report all celiac-associated variants (DQ2.5, DQ8, DQ2.2, DQ7.5) 1

Step 4: Interpret Biopsy Results in Context

If biopsy shows villous atrophy with negative serology: 1

• Confirm HLA-DQ2/DQ8 is positive (if negative, celiac disease is excluded) 1, 5
• Consider seronegative celiac disease as the diagnosis 1, 5
• Rule out other causes of villous atrophy: Helicobacter pylori infection, small bowel bacterial overgrowth, systemic autoimmune disorders, medications (especially olmesartan), tropical sprue, Whipple disease, common variable immunodeficiency, autoimmune enteropathy 1, 5

If biopsy shows only lymphocytic infiltration without villous atrophy: 1

• This is NOT specific for celiac disease 1
• Most patients with lymphocytic duodenosis are not in the spectrum of celiac disease 1
• Consider other causes after ruling out celiac disease 1

Management of Confirmed Seronegative Celiac Disease

Initiate strict gluten-free diet immediately after biopsy confirmation 4, 5

Perform follow-up endoscopy after 1-3 years on gluten-free diet to assess histologic improvement 1, 5

Diagnosis is confirmed based on clinical and histologic improvement on gluten-free diet 1, 5

Refer to registered dietitian experienced in celiac disease management 4, 5

Critical Pitfalls to Avoid

Never rely on symptoms alone or symptom response to gluten-free diet for diagnosis 1

• Improvement of symptoms after gluten-free diet or symptom exacerbation after gluten reintroduction has very low positive predictive value for celiac disease 1
• This approach cannot differentiate celiac disease from non-celiac gluten sensitivity 1, 7

Never start gluten-free diet before completing diagnostic workup 1, 4

• This leads to false-negative serology and inconclusive biopsies 4
• If patient has already started gluten-free diet, they must resume normal diet with at least 10g gluten daily for 1-3 months before repeat testing 1

Do not use obsolete tests 1

• Antibodies against native gliadin are no longer recommended 1
• Stool studies, small-bowel follow-through, intestinal permeability testing, D-xylose testing, and salivary testing should not be used 1

Ensure pathologist has gastroenterology expertise 4, 5

• Poorly oriented mucosa can lead to misinterpretation 4
• Subtle histologic changes may be missed by general pathologists 5

Differentiating from Non-Celiac Gluten Sensitivity

Non-celiac gluten sensitivity should only be considered after celiac disease has been ruled out by appropriate testing 1

Patients with negative celiac serology who lack symptoms of malabsorption (weight loss, diarrhea, nutrient deficiencies) and celiac disease risk factors (personal history of autoimmune diseases, family history of celiac disease) are highly likely to have non-celiac gluten sensitivity rather than celiac disease 7

The positive likelihood ratio for non-celiac gluten sensitivity in patients with gluten-responsive symptoms and negative IgA tissue transglutaminase or IgA/IgG deamidated gliadin peptide on regular diet is 9.6, increasing to 80.9 when malabsorption symptoms and risk factors are absent 7