What is the best course of action for a patient with indeterminate celiac (celiac disease) labs and symptoms consistent with celiac disease, such as abdominal pain, diarrhea, or fatigue?

Indeterminate Celiac Labs: Diagnostic Approach

In patients with indeterminate celiac serology and symptoms consistent with celiac disease, proceed directly to upper endoscopy with duodenal biopsies (at least 6 specimens from the second part of the duodenum) to establish or exclude the diagnosis, as biopsy remains the gold standard and serology alone cannot reliably diagnose or exclude celiac disease in this scenario. 1, 2

Confirm the Patient is Consuming Adequate Gluten

Before proceeding with any diagnostic testing, verify that the patient has been consuming at least 10g of gluten daily for 6-8 weeks prior to testing. 1, 2 Reduction or avoidance of gluten before diagnostic evaluation significantly reduces the sensitivity of both serology and biopsy, leading to false-negative results and diagnostic uncertainty. 1

• If the patient has already reduced gluten intake, they must resume a normal diet with at least three slices of wheat bread daily for 1-3 months before repeat serologic testing or biopsy. 1

Verify Total IgA Levels

Measure total IgA levels to exclude selective IgA deficiency, which occurs in 1-3% of celiac disease patients and causes falsely negative IgA-based antibody tests (tissue transglutaminase IgA, endomysial antibody IgA). 1, 2, 3

• If IgA deficiency is confirmed, repeat testing using IgG-based assays: IgG deamidated gliadin peptide (DGP-IgG) has superior diagnostic accuracy (93.6% sensitivity, 99.4% specificity) compared to IgG tissue transglutaminase. 2

Proceed to Upper Endoscopy with Duodenal Biopsies

The American Gastroenterological Association recommends proceeding with upper endoscopy and small bowel biopsy as the gold standard for establishing the diagnosis of celiac disease when serology is indeterminate or discordant. 2

Biopsy Protocol:

• Obtain at least 6 duodenal biopsy specimens from the second part of the duodenum or beyond, as mucosal changes can be patchy. 2, 3
• Include 2 oriented biopsies from the duodenal bulb in addition to 4 from the second portion of the duodenum. 1
• Ensure specimens are properly oriented for histologic analysis with Marsh classification. 2
• Request evaluation by a pathologist with gastroenterology expertise, as poorly oriented mucosa can lead to misinterpretation. 2

Diagnostic Histologic Criteria:

• Villous atrophy (partial to total) with crypt hyperplasia and increased intraepithelial lymphocytes (≥25 IELs per 100 enterocytes) confirm celiac disease. 2
• Lesser degrees of damage (≥25 IELs without villous atrophy) combined with positive serology may indicate probable celiac disease. 2

Consider HLA-DQ2/DQ8 Testing in Select Cases

HLA-DQ2 and HLA-DQ8 testing has limited diagnostic value but provides >99% negative predictive value—absence of both alleles essentially rules out celiac disease. 1, 2, 3

Use HLA testing only in specific scenarios: 1

• When serology is negative but clinical suspicion remains high
• When histologic results are equivocal
• In patients who did not have serologic confirmation at the time of diagnosis
• To rule out celiac disease in patients with a historic diagnosis made without modern serologic testing

Evaluate for Alternative Causes if Biopsy is Negative

If duodenal biopsies show villous atrophy but celiac serology remains indeterminate or negative, consider other causes of villous atrophy: 1

• Common variable immunodeficiency
• Autoimmune enteropathy
• Tropical sprue (characterized by folate/vitamin B12 deficiency, responds to folic acid and tetracycline)
• Medication-induced enteropathy
• HIV enteropathy
• Infectious causes (giardiasis, Whipple's disease, tuberculosis, Mycobacterium avium complex)

Post-Diagnosis Management if Celiac Disease is Confirmed

Initiate a strict lifelong gluten-free diet immediately after biopsy confirmation. 2

• Refer to a registered dietitian experienced in celiac disease management for comprehensive dietary education. 2, 3
• Repeat tissue transglutaminase IgA at 6 months after starting gluten-free diet, again at 12 months, and annually thereafter. 1, 3
• Persistently positive serology indicates ongoing intestinal damage and gluten exposure. 1
• Screen for nutritional deficiencies: complete blood count, iron studies, folate, vitamin B12, vitamin D, and bone mineral density (DXA scan). 1

Critical Pitfalls to Avoid

• Never start a gluten-free diet before completing the diagnostic workup, as this leads to false-negative serology and inconclusive biopsies. 1, 2, 3
• Do not rely on serology alone without biopsy confirmation in adults, especially with discordant or indeterminate results. 2, 3
• Do not confuse symptoms alone or symptom response to gluten-free diet as diagnostic, as this cannot differentiate celiac disease from non-celiac gluten sensitivity. 2
• Negative serology does not exclude celiac disease—seronegative celiac disease exists and requires biopsy for diagnosis. 1, 2

If Symptoms Persist Despite Negative Workup

If celiac disease is definitively excluded but symptoms persist, consider: 1

• Functional bowel disorders (irritable bowel syndrome)
• Lactose or fructose intolerance (breath testing)
• Microscopic colitis (requires colonoscopy with biopsies)
• Pancreatic insufficiency (treat with gluten-free pancreatic enzyme supplements)
• Small intestinal bacterial overgrowth (breath testing)
• Non-celiac gluten sensitivity (diagnosis of exclusion after celiac disease is ruled out)