What does an elevated tissue transglutaminase IgG (TTG‑IgG) with a negative tissue transglutaminase IgA (TTG‑IgA) indicate, and how should I proceed?

Elevated TTG IgG with Negative TTG IgA: Interpretation and Management

An isolated positive TTG IgG with negative TTG IgA has extremely limited diagnostic utility for celiac disease and does not warrant further celiac-specific workup in most cases, but you must first measure total IgA levels to rule out selective IgA deficiency, which would render the negative TTG IgA result unreliable. 1, 2

Immediate Next Step: Measure Total IgA

• Check total serum IgA levels immediately to determine whether the negative TTG IgA result is valid or represents a false negative due to IgA deficiency. 1, 2
• Selective IgA deficiency occurs in 1-3% of celiac disease patients (10-15 times higher than the general population) and causes falsely negative IgA-based antibody tests. 1, 2
• If total IgA is normal, the negative TTG IgA effectively excludes celiac disease in most cases, and the isolated positive TTG IgG should be disregarded. 1

If Total IgA is Normal (IgA Sufficient)

The isolated positive TTG IgG has minimal diagnostic value and celiac disease is effectively ruled out. 1, 3

• TTG IgG demonstrates poor diagnostic accuracy when total IgA is normal, with sensitivity ranging only 40.6-84.6% and specificity 78.0-89.0%. 1, 2
• A retrospective study of 233 patients with isolated positive TTG IgG and negative TTG IgA found that only 3% (6/178) had confirmed celiac disease on biopsy. 3
• The negative TTG IgA has a negative predictive value approaching 100% when the patient has consumed adequate gluten, making celiac disease highly unlikely. 4

Consider Alternative Diagnoses

• Investigate other causes of gastrointestinal symptoms if present (chronic infections, inflammatory bowel disease, irritable bowel syndrome, medication effects). 5
• Do not initiate a gluten-free diet based on this serologic pattern alone, as it can lead to nutritional deficiencies and unnecessary dietary restrictions. 1

If Total IgA is Low or Deficient (IgA Deficiency Confirmed)

Immediately order IgG deamidated gliadin peptide (DGP-IgG) testing, as this is the preferred and most accurate IgG-based test for celiac disease in IgA-deficient patients. 1, 2

• IgG DGP demonstrates superior diagnostic accuracy compared to TTG IgG, with 93.6% sensitivity and 99.4% specificity in adults. 1, 2
• The TTG IgG result you already have is not reliable for excluding celiac disease due to its poor performance characteristics. 2
• IgG endomysial antibody (EMA) testing is also highly effective in IgA-deficient patients and can serve as confirmatory testing. 1

If DGP-IgG is Positive

• Proceed directly to upper endoscopy with duodenal biopsy to confirm the diagnosis. 2
• 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
• Request evaluation by an experienced gastrointestinal pathologist to assess for villous atrophy using Marsh classification or Corazza-Villanacci grading. 1, 2

If DGP-IgG is Also Negative

• Consider HLA-DQ2/DQ8 genetic testing if clinical suspicion remains high, as absence of both alleles has >99% negative predictive value and effectively rules out celiac disease. 1, 2
• If HLA testing is negative for both DQ2 and DQ8, celiac disease is excluded and alternative diagnoses should be pursued. 1

Critical Pre-Test Requirements

Verify that the patient was consuming adequate gluten at the time of testing (at least 10g daily for 6-8 weeks prior), as insufficient gluten intake causes false-negative serologic results. 1, 4

• If the patient had already reduced or eliminated gluten before testing, all serologic results are unreliable. 1
• Gluten must be reintroduced for 1-3 months before repeat testing if celiac disease remains a consideration. 1

Common Pitfalls to Avoid

• Never rely on TTG IgG alone as a screening test when total IgA is normal—it lacks the specificity needed for diagnosis. 1, 2
• Do not proceed to endoscopy based solely on isolated positive TTG IgG without first confirming IgA status and considering more accurate IgG-based tests if deficient. 1, 3
• Never start a gluten-free diet before completing the diagnostic workup, as this renders subsequent testing inconclusive. 1
• Traditional gliadin antibody assays (IgA or IgG) are outdated and should not be used, as they have inferior diagnostic accuracy compared to modern tests like DGP-IgG. 2

Additional Screening in IgA-Deficient Patients

If IgA deficiency is confirmed, screen for other autoimmune conditions commonly associated with both IgA deficiency and celiac disease:

• Type 1 diabetes (fasting glucose or HbA1c). 2
• Autoimmune thyroid disease (TSH, thyroid antibodies). 2