What are the diagnostic criteria and management recommendations for celiac disease?

Celiac Disease: Diagnostic Criteria and Management

Diagnostic Approach

Celiac disease diagnosis requires both positive serology and duodenal biopsy confirmation in adults—serology alone is insufficient. 1, 2 The diagnostic workup must be completed while the patient consumes at least 10g of gluten daily for 6-8 weeks to avoid false-negative results. 1, 3

Initial Serologic Testing

• Measure IgA tissue transglutaminase (tTG-IgA) as the first-line test (sensitivity 90.7%, specificity 87.4% in adults at 15 U/mL threshold). 2, 3, 4
• Always measure total IgA level simultaneously to detect IgA deficiency, which occurs in 1-3% of celiac patients and causes falsely negative IgA-based tests. 1, 2, 3
• If IgA deficient, order IgG deamidated gliadin peptide (DGP-IgG) as the preferred alternative test (sensitivity 93.6%, specificity 99.4%). 2, 3

Confirmatory Serology

• When tTG-IgA is positive, confirm with IgA endomysial antibody (EMA) testing for superior specificity (99.6% in adults). 2, 3, 4
• tTG-IgA levels >10 times the upper limit of normal combined with positive EMA in a second sample have virtually 100% positive predictive value for celiac disease. 2, 3

Endoscopic Biopsy Requirements

Obtain at least 6 duodenal biopsy specimens: 1-2 from the duodenal bulb and minimum 4 from the second portion of duodenum or beyond, as mucosal changes can be patchy. 1, 2, 4 Visual endoscopic appearance alone is inadequate—histologic confirmation is mandatory. 2

Histopathologic Criteria

• Definitive diagnosis requires villous atrophy (partial to total) with crypt hyperplasia and ≥25 intraepithelial lymphocytes per 100 enterocytes. 1, 2, 4
• "Probable celiac disease" may be diagnosed when biopsies show ≥25 IELs without villous atrophy combined with positive serology (IgA-EMA, tTG, or IgG-DGP). 1, 2
• Ensure specimens are properly oriented by an experienced GI pathologist, as tangential sections can mimic villous atrophy. 2, 3

HLA Genetic Testing

• HLA-DQ2 and HLA-DQ8 testing has >99% negative predictive value—absence of both alleles virtually excludes celiac disease. 2, 4
• Approximately 95% of celiac patients have HLA-DQ2; 5% have HLA-DQ8. 1, 2
• Use HLA testing to rule out disease in equivocal cases or when patients have already started a gluten-free diet before testing. 2, 4

Differential Diagnosis of Villous Atrophy

When serology is negative but villous atrophy is present, systematically exclude:

• Medication-induced enteropathy: olmesartan, NSAIDs, mycophenolate mofetil, chemotherapy agents. 2, 3
• Infectious causes: Giardiasis, Cryptosporidium (especially in AIDS), Whipple's disease. 2, 3
• Autoimmune enteropathy: Look for absent/reduced plasma cells in lamina propria. 3
• Seronegative celiac disease: Represents up to 33% of seronegative enteropathy cases in White populations. 3

Management

Immediate Post-Diagnosis Actions

Initiate strict lifelong gluten-free diet immediately after biopsy confirmation as the only effective treatment. 1, 2, 3 Refer to a registered dietitian experienced in celiac disease management for comprehensive dietary education. 2, 3, 4

Gluten-Free Diet Specifications

• Patients must consume <10 mg gluten per day. 1
• Gluten-free oats may be commenced at diagnosis in adults. 1
• The diet must be nutritionally complete to support healthy growth in children and prevent deficiencies in adults. 5

Follow-Up Protocol

Annual monitoring should include: 1

• Complete blood count, ferritin, serum folate, vitamin B12, calcium, alkaline phosphatase (assess absorption)
• Thyroid-stimulating hormone and thyroid hormones (screen for autoimmune thyroid disease)
• Serum glucose (screen for type 1 diabetes)
• Aspartate aminotransferase/alanine aminotransferase (assess liver disease)
• Anti-TG2 or EMA/DGP (assess dietary adherence)

Repeat tTG-IgA testing schedule: 3

• At 6 months after starting gluten-free diet
• At 12 months after diagnosis
• Annually thereafter

Follow-Up Biopsy Considerations

The 2024 guidelines acknowledge controversy regarding universal follow-up biopsy. 1

• Follow-up biopsies may be considered to identify patients at increased risk of lymphoma, particularly after 1-2 years on gluten-free diet. 1
• Follow-up biopsies are not mandatory if the patient is asymptomatic on gluten-free diet with no features suggesting increased risk of complications. 1
• Follow-up biopsies should be undertaken in patients whose condition does not respond to gluten-free diet. 1

Non-Responsive Celiac Disease

When symptoms persist despite gluten-free diet (occurs in 4-30% of patients): 1

1. Confirm original diagnosis by reviewing serology, biopsy, and HLA status. 1
2. Review dietary adherence with expert dietitian—inadvertent or deliberate gluten exposure is the most frequent cause. 1
3. Perform follow-up biopsy to assess for ongoing enteropathy. 1
4. Exclude associated conditions: microscopic colitis, pancreatic exocrine insufficiency, small intestinal bacterial overgrowth, lactose intolerance. 1
5. Consider refractory celiac disease (type I or II) if symptoms persist with confirmed adherence and negative serology. 1

Critical Pitfalls to Avoid

• Never diagnose celiac disease based on serology alone without biopsy confirmation in adults (biopsy remains essential except in coagulation disorders or pregnancy). 2, 4
• Never initiate gluten-free diet before completing diagnostic workup—this leads to false-negative serology and inconclusive biopsies. 2, 3
• Never rely on duodenal bulb biopsies alone—they may miss patchy disease or be confounded by Brunner's glands or peptic changes. 2
• Never assume negative serology excludes celiac disease—seronegative celiac disease is common. 3
• Never overlook IgA deficiency—always check total IgA level with IgA-based tests. 2, 3

Prognosis and Complications

• Strict gluten-free diet decreases excess risk of adverse fetal outcomes and lymphoma. 1
• Persistent villous atrophy despite gluten-free diet is associated with statistically significant increased risk of lymphoma compared to those with mucosal healing. 1
• Most patients (57-76%) achieve full histological recovery on diet, though up to 30% will have symptomatic exacerbations due to gluten exposure over time. 1