How is celiac disease diagnosed and treated?

Celiac Disease: Diagnosis and Treatment

Celiac disease is diagnosed through a combination of serologic testing (tissue transglutaminase IgA with total IgA level) while consuming gluten, followed by confirmatory duodenal biopsy showing villous atrophy, and treated exclusively with lifelong strict adherence to a gluten-free diet. 1

Diagnostic Algorithm

Step 1: Initial Serologic Screening (Patient Must Be Consuming Gluten)

• Order tissue transglutaminase IgA (tTG-IgA) plus total IgA level as the first-line screening test, with sensitivity of 90.7% and specificity of 87.4% in adults at 15 U/mL threshold. 2, 3
• The total IgA measurement is mandatory because IgA deficiency occurs in 1-3% of celiac patients and causes falsely negative IgA-based antibody tests. 1, 2
• Patients must consume at least 10g of gluten daily for 6-8 weeks before testing to avoid false-negative results—this is the most common cause of missed diagnoses. 1, 2, 3

Step 2: Confirmatory Serology

• When tTG-IgA is positive, add endomysial antibody (EMA) testing which has superior specificity of 99.6% in adults. 2, 3
• If tTG-IgA exceeds 10 times the upper limit of normal AND EMA is positive in a repeat sample, the positive predictive value approaches 100%. 2, 3

Step 3: Special Populations—IgA Deficiency

• If total IgA is low or absent, switch to IgG-based testing using IgG deamidated gliadin peptide (DGP-IgG), which demonstrates 93.6% sensitivity and 99.4% specificity in adults. 2, 3
• IgG tTG has poor performance (sensitivity 40.6-84.6%) and should not be used as a primary screen when total IgA is normal. 3

Step 4: Duodenal Biopsy (Gold Standard)

• Proceed to upper endoscopy with at least 6 duodenal biopsy specimens from the second part of the duodenum or beyond, as mucosal changes can be patchy. 1, 3
• Visual endoscopic appearance alone is insufficient—endoscopists should not regard the absence of visual features as sufficient to rule out celiac disease. 1
• Diagnostic histology requires villous atrophy (partial to total) with crypt hyperplasia and increased intraepithelial lymphocytes (≥25 IELs per 100 enterocytes). 3
• Specimens must be properly oriented and evaluated using Marsh classification by an experienced pathologist. 3

Step 5: HLA Testing (Selective Use Only)

• HLA-DQ2/DQ8 testing should NOT be used as a primary diagnostic tool—it is reserved for exclusionary purposes when diagnosis is unclear. 1
• Approximately 95% of celiac patients have HLA-DQ2 and 5% have HLA-DQ8; absence of both alleles provides nearly 100% negative predictive value (essentially excludes celiac disease). 1, 2
• Use HLA testing only when: serology and biopsy are equivocal, the patient is already on a gluten-free diet, or for family screening with genetic counseling available. 1, 3

Critical Diagnostic Pitfalls to Avoid

• Never initiate a gluten-free diet before completing the full diagnostic workup—this invalidates both serologic and histologic testing and is the most common diagnostic error. 1, 2, 3
• Do not diagnose celiac disease based on serology alone without biopsy confirmation in adults. 3, 4
• Do not rely on isolated positive TTG IgG when total IgA is normal—this generates frequent false-positives and has no diagnostic value. 3
• Avoid ordering multiple antibody panels simultaneously in low-risk individuals, as this reduces specificity without meaningful sensitivity gains. 3

High-Risk Populations Requiring Screening

• First-degree relatives of celiac patients (10% prevalence). 2
• Type 1 diabetes (5-10% prevalence). 2
• Autoimmune thyroid disease or autoimmune liver disease. 2, 3
• Unexplained iron-deficiency anemia (celiac disease present in 2-6% of cases). 2, 3
• Down syndrome or Turner syndrome. 3

Treatment: Strict Lifelong Gluten-Free Diet

The only proven treatment for celiac disease is lifelong adherence to a strict gluten-free diet (daily gluten intake <10 mg). 1, 3

Essential Treatment Components

• Immediate referral to an experienced registered dietitian for comprehensive dietary education—this is mandatory, not optional. 1, 2
• Referral to a celiac disease support group to improve long-term adherence. 1
• Treatment of nutritional deficiencies (iron, folate, vitamin B12) is essential at diagnosis. 1
• Bone mineral density assessment to screen for osteoporosis, which occurs in 1.7-42% of untreated patients. 2

Expected Benefits of Gluten-Free Diet

• Compliance with a gluten-free diet is protective against non-Hodgkin's lymphoma in celiac disease and dermatitis herpetiformis. 1
• Fracture risk normalizes after the first year on a gluten-free diet, even though bone mineral density may remain persistently low. 2
• Improvements in bone mineral density are greatest in the first years of treatment. 1
• Treatment for at least 12 months results in increased body weight, body mass index, fat mass, bone mass, and improved nutritional parameters. 1

Follow-Up and Monitoring

• Evaluate patients at regular intervals with a physician and dietitian to assess compliance by history and reinforce adherence. 1
• Monitor adherence with tTG-IgA or EMA serology at 6 months, 12 months, then annually—these tests are sensitive for major dietary indiscretions but not minor transient ones. 1, 3
• In children, histologic improvement occurs quickly; in adults, the small intestinal mucosa heals more slowly and less completely. 1
• A negative serologic test in adults does not necessarily mean improvement beyond severe villous atrophy. 1
• Persistently positive serology indicates ongoing intestinal damage and gluten exposure. 2, 3

Non-Responsive Celiac Disease

When symptoms persist despite a gluten-free diet and negative serology, evaluate for:

• Review the original diagnosis to exclude alternative diagnoses. 4
• Review the gluten-free diet to ensure no obvious gluten contamination—inadvertent exposure is the most common cause. 4
• Associated disorders: microscopic colitis, pancreatic exocrine dysfunction. 4
• Complications: enteropathy-associated lymphoma or refractory celiac disease. 4, 5
• Consider follow-up biopsy in 1-3 years to confirm mucosal healing, especially in patients with severe initial presentation. 3

Extraintestinal Manifestations

Celiac disease should be considered in patients presenting with:

• Iron deficiency anemia (48% of adults at presentation), often resistant to oral iron supplementation. 2
• Osteopenia/osteoporosis with increased fracture risk (60-100% higher than general population before diagnosis). 2
• Depression and psychiatric disorders (24% of adults). 2
• Dermatitis herpetiformis (pathognomonic skin manifestation with granular IgA deposits on direct immunofluorescence). 2
• Infertility, recurrent miscarriages, and adverse pregnancy outcomes. 2
• Elevated liver enzymes. 2, 4
• Epilepsy and seizures. 2