What is the diagnosis and treatment of celiac disease?

Diagnosis and Management of Celiac Disease

Diagnostic Approach

The diagnosis of celiac disease requires IgA tissue transglutaminase antibody (tTG-IgA) testing followed by duodenal biopsy confirmation, both performed while the patient is consuming a gluten-containing diet, with treatment consisting of a strict lifelong gluten-free diet. 1, 2

Initial Serologic Testing

• Order tTG-IgA as the first-line test with simultaneous measurement of total IgA level to identify IgA deficiency (which occurs 10-15 times more frequently in celiac patients and causes false-negative results). 1, 3
• The patient must be consuming at least 10g of gluten daily for 6-8 weeks before testing—gluten-free or gluten-reduced diets yield false-negative results. 1
• tTG-IgA has sensitivity of 90-96% and specificity >95%. 1

Confirmatory Serologic Testing

• If tTG-IgA is >10 times the upper limit of normal, obtain IgA endomysial antibody (EMA-IgA) as confirmatory testing with excellent specificity of 99.6%. 1
• The combination of tTG-IgA >10x upper limit plus positive EMA-IgA approaches 100% positive predictive value for celiac disease. 1

IgA Deficiency Protocol

• If IgA is low or absent, use IgG-based tests: IgG deamidated gliadin peptide (DGP-IgG) or IgG tissue transglutaminase (tTG-IgG). 1, 2
• Do not use IgG-based tests in patients with normal IgA levels—they are markedly less accurate in this setting. 1

Biopsy Confirmation

Upper endoscopy with duodenal biopsy remains mandatory for diagnosis in adults, even with highly positive serology. 4, 1

Biopsy Technique

• Obtain at least 6 biopsy specimens total: 1-2 from the duodenal bulb and at least 4 from the second part of the duodenum or beyond. 1, 2
• Taking fewer than 4 biopsies reduces diagnostic yield by 50%. 4
• Proper orientation of specimens by laboratory technicians is essential for accurate assessment of villous height-to-crypt depth ratio. 4, 2

Histologic Criteria

• Definitive diagnosis requires villous atrophy (Marsh 3 lesion) combined with positive serology. 4
• Lesser degrees of damage (≥25 intraepithelial lymphocytes per 100 enterocytes without villous atrophy) plus positive serology may represent "probable celiac disease" and warrant a trial of gluten-free diet. 4
• Characteristic findings include villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes. 1

Exceptions to Biopsy Requirement

• Biopsy may be deferred in patients with coagulation disorders or during pregnancy. 4
• In children (not adults) with tTG-IgA ≥10x upper limit, positive EMA-IgA, and positive HLA-DQ2/DQ8, biopsy may be avoided. 1

HLA Testing

HLA-DQ2 and HLA-DQ8 testing has >99% negative predictive value—absence of both alleles essentially rules out celiac disease. 4, 1

Indications for HLA Testing

• Celiac disease strongly suspected despite negative serology. 4, 1
• Equivocal small bowel histologic findings. 4
• Patients already on gluten-free diet who were never properly tested. 4, 1
• First-degree relatives with Down syndrome. 4
• Discrepant serology and histology results. 4

Differential Diagnosis of Villous Atrophy

When biopsy shows villous atrophy but serology is negative, consider these alternative diagnoses:

Medication-Induced

• Olmesartan, NSAIDs, mycophenolate mofetil, chemotherapy. 4, 2

Infectious Causes

• Giardiasis (common), Helicobacter pylori gastritis, small intestinal bacterial overgrowth, tropical sprue, HIV, Whipple's disease. 4, 2

Autoimmune Disorders

• Autoimmune enteropathy, common variable immunodeficiency, systemic lupus erythematosus, Sjögren's syndrome. 4

Other Causes

• Crohn's disease, eosinophilic gastroenteritis, lymphoma, post-infectious enteropathy. 4, 2

Treatment

Initiate a strict, lifelong gluten-free diet immediately after biopsy confirmation. 4, 2

Initial Management

• Refer to a registered dietitian experienced in celiac disease management for comprehensive dietary education. 4, 1, 2
• Screen for nutritional deficiencies (iron, folate, vitamin D, calcium, vitamin B12). 2
• Evaluate for associated autoimmune conditions (type 1 diabetes, autoimmune thyroid disease, autoimmune liver disease). 2

Follow-Up Protocol

• Perform follow-up serology at 6 months, 12 months, then yearly thereafter. 1
• Negative serology after treatment does not guarantee intestinal mucosal healing. 1
• Persistently positive serology usually indicates ongoing intestinal damage from continued gluten exposure. 1

Management of Persistent Symptoms

In patients with persistent or relapsing symptoms, perform repeat endoscopic biopsies to determine healing status, even if tTG-IgA is negative. 1

• Review the original diagnosis to exclude alternative diagnoses. 5
• Conduct dietary review to ensure no obvious gluten contamination. 5
• Evaluate for complications: refractory celiac disease, enteropathy-associated lymphoma, microscopic colitis, pancreatic exocrine dysfunction. 5

High-Risk Groups Requiring Screening

Screen asymptomatic individuals from these high-risk groups, as celiac disease frequently occurs without gastrointestinal symptoms:

• First-degree relatives (7.5% risk). 1, 3
• Type 1 diabetes mellitus (5-10% prevalence). 1, 3
• Autoimmune thyroid disease. 1, 3
• Down syndrome or Turner syndrome. 1, 3
• Unexplained iron deficiency anemia. 1
• Premature osteoporosis. 1
• Unexplained liver transaminase elevations. 1
• Autoimmune liver disease. 3

Critical Pitfalls to Avoid

Pre-Diagnostic Errors

• Never initiate a gluten-free diet before completing diagnostic workup—this leads to false-negative serology and inconclusive biopsies. 1, 2
• For patients already on gluten-free diet, resume normal diet with three slices of wheat bread daily for 1-3 months (sometimes up to several years) before repeat testing. 1

Testing Errors

• Do not rely solely on serology without biopsy confirmation in adults—this leads to misdiagnosis. 1
• Do not use IgG-based tests in patients with normal IgA levels—they lack specificity in this setting. 1
• Do not perform HLA testing routinely—it should be reserved for specific clinical scenarios outlined above. 4

Biopsy Errors

• Taking fewer than 4 biopsy specimens reduces diagnostic accuracy by 50%. 4
• Failure to biopsy the duodenal bulb misses patchy disease distribution. 1
• In patients with persistently positive serology but normal duodenal mucosa, consider repeat biopsy including jejunal specimens, as the lesion may be present only in the jejunum. 4

Diagnostic Confusion

• Seronegative celiac disease can occur and requires biopsy for diagnosis. 1
• Lymphocytic infiltration without villous atrophy is not specific for celiac disease—most patients with lymphocytic duodenosis do not have celiac disease. 4
• Improvement of symptoms on gluten-free diet or exacerbation with gluten reintroduction has very low positive predictive value and should not be used for diagnosis without other supportive evidence. 4

Clinical Presentation Spectrum

• Celiac disease affects approximately 1% of the population, but only 24% are diagnosed—creating a "celiac iceberg" of undiagnosed cases. 3
• Many patients present with only extraintestinal manifestations or remain completely asymptomatic ("silent celiac disease"). 3
• Left undiagnosed and untreated, even asymptomatic celiac disease leads to higher risk of osteoporosis, infertility, and small bowel cancer. 3