What is the management approach for a patient with celiac disease who is Immunoglobulin A (IgA) positive but anti-Tissue Transglutaminase (anti-TTG) negative?

Management of Celiac Disease with Positive IgA but Negative Anti-TTG

For patients with positive IgA but negative anti-TTG results, a comprehensive diagnostic evaluation is essential, including HLA testing, duodenal biopsy while on a gluten-containing diet, and consideration of seronegative celiac disease if villous atrophy is present. 1

Diagnostic Approach for Discordant Results

• Confirm that the patient is on a gluten-containing diet, as gluten avoidance can lead to false-negative serologic results 1, 2
• Measure total IgA levels to rule out IgA deficiency, which could explain negative anti-TTG IgA results 1
• Complete the full celiac serology panel including anti-TTG IgA, deamidated gliadin peptide (DGP) IgA, and endomysial antibody (EMA) IgA 1
• Test for HLA-DQ2 and HLA-DQ8 genetic markers, as negative results can effectively rule out celiac disease in seronegative patients 1
• Proceed with upper endoscopy and multiple duodenal biopsies (ideally 6 specimens) from the second part of the duodenum or beyond, regardless of serologic results if clinical suspicion is high 1, 2

Interpreting Discordant Results

• Normal IgA with negative anti-TTG suggests that the negative anti-TTG result is valid and not due to IgA deficiency 2, 3
• Isolated positive IgG anti-TTG with negative IgA anti-TTG has low utility (only 3% diagnostic yield) for confirming celiac disease 3
• Discordant results (such as positive EMA with negative anti-TTG, or vice versa) require careful evaluation as they may represent early or developing celiac disease 2, 4
• Different commercial anti-TTG assays show significant variability (28.5% to 77.7% agreement), which may explain discordant results 4

Management Algorithm

1. Confirm serologic testing accuracy:

   • Verify patient was consuming adequate gluten (at least 10g daily for 6-8 weeks) before testing 1
   • Review medication history for drugs that may affect results (e.g., immunosuppressants) 1

2. Proceed with endoscopy and biopsy:

   • Obtain multiple biopsy specimens (at least 6) from different parts of the duodenum 1, 2
   • Have specimens reviewed by an experienced GI pathologist 1

3. If biopsy shows villous atrophy:

   • With positive HLA-DQ2/DQ8: Consider seronegative celiac disease 1
   • With negative HLA-DQ2/DQ8: Consider other causes of enteropathy 1

4. If seronegative celiac disease is suspected:

   • Initiate a strict gluten-free diet 1
   • Perform follow-up endoscopy after 1-3 years to assess histologic improvement 1
   • Confirm diagnosis based on clinical and histologic improvement on gluten-free diet 1

Common Pitfalls and Caveats

• Relying solely on serologic testing without biopsy confirmation can lead to misdiagnosis, especially with discordant results 2, 4
• Initiating a gluten-free diet before completing diagnostic evaluation can lead to inconclusive results 2, 5
• Other causes of villous atrophy must be considered in seronegative patients, including medications (e.g., olmesartan), autoimmune enteropathy, and infections 1
• Patients with persistent symptoms who don't respond to a gluten-free diet, and for whom no etiology of enteropathy is identified, may benefit from budesonide treatment 1

Special Considerations

• Consider testing for other associated conditions, particularly in high-risk groups:
  • Iron deficiency anemia 1, 6
  • Premature osteoporosis 6
  • Autoimmune thyroid disease 6, 5
  • Type 1 diabetes 6, 5
  • First-degree relatives of patients with celiac disease 6, 5