What are the steps for testing and treating celiac disease?

Celiac Disease Testing and Treatment

Initial Screening Test

Begin with IgA tissue transglutaminase antibody (tTG-IgA) as the first-line screening test, which has 90-96% sensitivity and >95% specificity. 1, 2

Critical Pre-Testing Requirement

• The patient must be consuming gluten (at least 10g daily for 6-8 weeks) before testing, as positive serologic results resolve and histologic findings improve with gluten removal. 1, 2 Starting a gluten-free diet before completing diagnostic testing is one of the most common pitfalls leading to false-negative results. 2

Simultaneous IgA Level Measurement

• Measure total IgA levels at the same time as tTG-IgA to identify IgA deficiency, which occurs more frequently in celiac disease and causes false-negative results. 1, 2 However, routine IgA measurement is not warranted as a first step unless IgA deficiency is strongly suspected. 3

Confirmatory Testing Algorithm

For Positive tTG-IgA Results

If tTG-IgA is >10× upper limit of normal:

• Perform IgA endomysial antibody (EMA-IgA) as confirmatory test, which has 99.6% specificity. 1, 2
• In adults with both tTG-IgA >10× ULN and positive EMA-IgA, the positive predictive value approaches 100%, though biopsy may still be performed for differential diagnosis. 2

Intestinal biopsy remains the gold standard for diagnosis in adults:

• Obtain multiple specimens—ideally 6 biopsies total: 1-2 from the duodenal bulb and at least 4 from the second part of the duodenum or beyond. 3, 2 Mucosal changes can be patchy, and Brunner's glands or peptic changes may hamper examination if specimens are obtained only from the duodenal bulb. 3
• Characteristic histologic findings include a spectrum from partial to total villous atrophy, crypt lengthening with increased lamina propria, and increased intraepithelial lymphocytes. 3, 4
• Important caveat: Increased intraepithelial lymphocytes without architectural changes should not be considered diagnostic of celiac disease and requires consideration of other causes. 3, 1

For Negative Serology with High Clinical Suspicion

Follow this stepwise approach: 2

1. Confirm the patient is consuming adequate gluten
2. Verify total IgA level is normal
3. Perform HLA-DQ2 and HLA-DQ8 testing—if positive, proceed to biopsy

HLA testing has >99% negative predictive value—absence of both DQ2 and DQ8 alleles essentially rules out celiac disease. 1, 2 HLA testing is also useful in patients with equivocal biopsy findings or those already on a gluten-free diet who were never properly tested. 2

Special Population Testing

IgA-Deficient Patients

• 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, as they are markedly less accurate in that setting. 2

Children Under 2 Years

• Combine tTG-IgA with IgG and IgA deamidated gliadin peptides for improved sensitivity. 1, 2

Biopsy-Avoidance in Children

• In children with tTG-IgA ≥10× upper limit of normal, positive EMA-IgA, and positive HLA-DQ2/DQ8, biopsy may be avoided according to pediatric guidelines. 1, 2

High-Risk Groups Requiring Testing

Test these populations, especially when symptoms compatible with celiac disease are present: 3, 2

Strongly Recommended (symptomatic or not):

• Unexplained iron deficiency anemia 3, 2
• Premature onset of osteoporosis 3, 2
• Down syndrome 3, 2
• Unexplained liver transaminase elevations 3, 2
• Primary biliary cirrhosis 3
• Autoimmune hepatitis 3
• First-degree relatives of celiac disease patients 3, 2

Selectively Consider (especially if symptoms present):

• Type 1 diabetes mellitus 3, 2
• Autoimmune thyroid disease 3, 2
• Sjögren's syndrome 3
• Unexplained recurrent fetal loss 3
• Unexplained delayed puberty 3
• Selective IgA deficiency 3
• Irritable bowel syndrome 3
• Turner's syndrome 3
• Peripheral neuropathy 3
• Cerebellar ataxia 3
• Recurrent migraine 3
• Children with short stature 3

Treatment Approach

The only treatment is a strict lifelong gluten-free diet. 2

Initial Management:

• Refer patients to a dietitian experienced in celiac disease management. 2
• Gluten-free diet leads to improvement in quality of life, ameliorating symptoms, and preventing complications including refractory celiac disease, ulcerative jejunoileitis, and small intestinal adenocarcinoma and lymphoma. 5

Follow-Up Testing:

• Perform follow-up serology at 6 and 12 months after diagnosis, then yearly thereafter. 1, 2
• Critical limitation: Negative serology after treatment does not guarantee intestinal mucosal healing. 1, 2 In fact, serum tTG-IgA and EMA-IgA tests have only 50% and 45% sensitivity respectively for detecting persistent villous atrophy in patients on a gluten-free diet. 6
• Persistently positive serology usually indicates ongoing intestinal damage and continued gluten exposure. 1, 2
• For patients with persistent or relapsing symptoms, perform repeat endoscopic biopsies to determine healing, even with negative tTG-IgA. 2

Common Pitfalls to Avoid

• Never initiate a gluten-free diet before completing diagnostic testing—this leads to false-negative results. 1, 2
• Do not rely solely on serology without biopsy confirmation in adults—this can lead to misdiagnosis. 1, 2
• Do not use IgA antigliadin antibody testing—its diagnostic performance is poor compared to tTG-IgA and EMA-IgA. 3
• Do not use IgG-based tests in patients with normal IgA levels—they are not specific in this setting. 2
• Recognize that seronegative celiac disease can occur and requires biopsy for diagnosis. 2
• For patients already on a gluten-free diet without prior testing: Resume normal diet with three slices of wheat bread daily for 1-3 months before repeat testing; some patients may require several years of gluten challenge for histologic relapse to occur. 2
• Improvement of symptoms after starting a gluten-free diet has low positive predictive value for celiac disease and should not be used for diagnosis without supportive evidence. 1