What is the appropriate workup and treatment for a patient suspected of having celiac disease?

Celiac Disease Workup

Initial Serologic Testing

The first-line diagnostic test for celiac disease is IgA tissue transglutaminase antibody (tTG-IgA) combined with total IgA level measurement, which must be performed while the patient is consuming at least 10g of gluten daily (approximately 3 slices of wheat bread) for 6-8 weeks. 1, 2

Primary Screening Tests

• Order IgA tTG as the single most efficient serologic test, with sensitivity of 90-96% and specificity of 87.4-95% in adults 1, 2, 3
• Measure total IgA level simultaneously to identify IgA deficiency, which occurs in 1-3% of celiac patients and causes falsely negative IgA-based tests 1, 2
• No fasting is required for celiac serology testing 4

If IgA Deficiency is Present

• Switch to IgG-based testing immediately: order IgG deamidated gliadin peptide (DGP-IgG), which has superior diagnostic accuracy (93.6% sensitivity, 99.4% specificity) compared to IgG tTG 1, 2
• IgG tTG has limited utility with only 40.6-84.6% sensitivity and should not be relied upon 2

Confirmatory Serology

• Add IgA endomysial antibody (EMA) testing when tTG-IgA is positive, as EMA has excellent specificity of 99.6% in adults 1, 2, 4
• When tTG-IgA exceeds 10 times the upper normal limit combined with positive EMA in a second blood sample, the positive predictive value approaches 100% 2, 5

Confirmatory Biopsy

Upper endoscopy with small bowel biopsy remains essential for diagnosis in adults and cannot be replaced by serology alone, except in patients with coagulation disorders or pregnancy. 1

Biopsy Technique Requirements

• Obtain at least 6 biopsy specimens: 1-2 from the duodenal bulb and at least 4 from the second part of the duodenum or beyond 1, 2, 5
• Multiple biopsies are mandatory because mucosal changes can be patchy 1, 5
• Visual endoscopic examination alone is insufficient, as endoscopic appearance lacks adequate sensitivity 5

Diagnostic Histologic Criteria

• Definitive diagnosis requires villous atrophy (partial to total) with crypt hyperplasia and increased intraepithelial lymphocytes (≥25 IELs per 100 enterocytes) 1, 5
• "Probable celiac disease" may be diagnosed when lesser degrees of damage (≥25 IELs without villous atrophy) are combined with positive serology, warranting a trial of gluten-free diet 1, 5
• Ensure specimens are properly oriented by an experienced GI pathologist, as tangential sections can mimic villous atrophy 5

Ancillary Testing

HLA-DQ2/DQ8 Genetic Testing

HLA testing should NOT be performed routinely but is useful in select scenarios with a negative predictive value exceeding 99% when both DQ2 and DQ8 are absent. 1

When to Order HLA Testing:

• Patients with equivocal small-bowel histologic findings 1
• Patients already following a gluten-free diet in whom testing was not performed before diet initiation 1
• Patients with discrepant celiac-specific serology and histology 1
• First-degree relatives with Down syndrome or other high-risk conditions 1
• When the original diagnosis of celiac disease is in question 1

HLA Distribution:

• Approximately 95% of celiac patients have HLA-DQ2, and 5% have HLA-DQ8 5
• HLA-DQ2 is present in 25-30% of the white population, making it unsuitable as a primary diagnostic test 1

Critical Diagnostic Pitfalls to Avoid

Pre-Test Requirements

• Never allow patients to start a gluten-free diet before completing diagnostic workup, as this leads to false-negative serology and inconclusive biopsies 1, 2, 5
• Verify the patient consumed at least 10g of gluten daily for 6-8 weeks before both serology and biopsy 2, 5, 4
• Reduction or avoidance of gluten prior to testing significantly reduces sensitivity of both serology and biopsy 4

Common Diagnostic Errors

• Do not diagnose celiac disease based on serology alone without biopsy confirmation in adults 1, 5
• Do not rely on duodenal bulb biopsies alone, as they may miss patchy disease or be confounded by Brunner's glands or peptic changes 5
• Do not assume negative serology excludes celiac disease, as seronegative celiac disease represents up to one-third of cases in white patients 5
• Do not rely on subjective response to gluten-free diet alone for diagnosis, as this has very low positive predictive value and cannot differentiate celiac disease from non-celiac gluten sensitivity 1, 5

Tests NOT Recommended

• Stool studies 1
• Small-bowel follow-through 1
• Intestinal permeability testing 1
• D-xylose testing 1
• Salivary testing 1
• Capsule endoscopy for initial diagnosis (except in patients unable or unwilling to undergo upper endoscopy) 1

Differential Diagnosis of Villous Atrophy with Negative Serology

When biopsy shows villous atrophy but celiac serology is negative, seronegative celiac disease remains the most common cause (up to 33% of cases), but other etiologies must be systematically excluded. 5

Systematic Evaluation:

• Confirm total IgA level was measured to exclude IgA deficiency causing false-negative IgA-based tests 5
• Verify biopsy orientation by having an experienced GI pathologist review specimens to confirm true villous atrophy versus tangential sectioning artifact 5
• Check complete celiac serology panel including IgA DGP and IgA EMA in addition to IgA tTG 5
• Order HLA-DQ2/DQ8 testing: if positive, consider empiric trial of strict gluten-free diet for 6 months with clinical and histologic monitoring 5

Alternative Diagnoses to Consider:

• Medication-induced enteropathy: olmesartan, NSAIDs, mycophenolate mofetil, chemotherapy agents 1, 5
• Infectious causes: Giardiasis, Cryptosporidium (especially in AIDS), Whipple's disease, small bowel bacterial overgrowth 1, 5
• Immune-mediated disorders: common variable immunodeficiency, autoimmune enteropathy 5
• Inflammatory bowel disease: Crohn's disease with small bowel involvement 5
• Other causes: Helicobacter pylori infection, systemic autoimmune disorders 1

Management After Diagnosis

Initiate strict lifelong gluten-free diet immediately after biopsy confirmation and refer to a registered dietitian experienced in celiac disease management for comprehensive dietary education. 2, 5, 6

Follow-Up Monitoring Protocol

• Repeat tTG-IgA at 6 months after starting gluten-free diet, then at 12 months, and annually thereafter 2
• Persistently positive serology indicates ongoing intestinal damage and gluten exposure 2, 5
• Screen for nutritional deficiencies: iron deficiency anemia with CBC and iron studies, vitamin D, calcium, folate, vitamin B12 2
• Evaluate for associated autoimmune conditions: thyroid function tests, fasting glucose or HbA1c for type 1 diabetes 2
• Consider follow-up biopsy in 1-3 years to confirm mucosal healing, especially in patients with severe initial presentation 2

Non-Responsive Celiac Disease

• Review the original diagnosis to exclude alternative diagnoses 3, 7
• Reassess the gluten-free diet to ensure no obvious gluten contamination 3, 7
• Evaluate for coexisting conditions: microscopic colitis, pancreatic exocrine dysfunction 3
• Consider complications: enteropathy-associated lymphoma, refractory celiac disease 3, 8