What are the next steps for a patient with a negative anti-TTG (Tissue Transglutaminase) IgA result but suspected coeliac disease?

Management of Negative Anti-TTG IgA Results in Suspected Coeliac Disease

With a negative anti-TTG IgA result but elevated IgA levels, further investigation for coeliac disease is generally not warranted unless there are specific gastrointestinal symptoms suggestive of significant pathology.

Interpretation of Current Test Results

• The patient has a negative anti-TTG IgA (<1.9 CU) with slightly elevated total IgA (4.2 g/L), which effectively rules out coeliac disease in most cases 1
• The negative likelihood ratio for the TTG antibody test using human recombinant TTG is 0.06, meaning that with a negative test, the post-test probability of coeliac disease is only 0.3%, which is less than in the general population 1
• The elevated IgA level confirms that the negative anti-TTG IgA is a true negative result and not due to IgA deficiency 2

When to Consider Further Testing Despite Negative Serology

Clinical Scenarios Warranting Additional Investigation:

• Presence of specific gastrointestinal symptoms such as:

  • Chronic diarrhea with weight loss
  • Steatorrhea
  • Postprandial abdominal pain and bloating 1

• High-risk clinical features:

  • Family history of coeliac disease
  • Personal history of other autoimmune disorders
  • Persistent unexplained iron deficiency anemia 1

Recommended Next Steps When Clinical Suspicion Remains High:

1. HLA-DQ2/DQ8 Testing:

   • Consider testing for HLA-DQ2/DQ8 haplotypes which have a high negative predictive value (>99%) 1
   • If negative, coeliac disease can be effectively ruled out 2

2. Upper Endoscopy with Duodenal Biopsy:

   • Should be pursued if clinical suspicion remains high despite negative serology 1
   • Multiple duodenal biopsies (one or two of the bulb and at least four of the distal duodenum) are recommended 1
   • This is particularly important if symptoms persist without other explanation 1

Important Considerations

• The pretest probability of coeliac disease in those with iron deficiency anemia alone is approximately 5%, but with a negative anti-TTG IgA, the post-test probability drops to 0.3% 1
• Duodenal biopsy samples would need to be taken from approximately 330 TTG antibody-negative patients to detect one extra patient with coeliac disease, at an estimated additional cost of £35,000 1
• Reduction or avoidance of gluten prior to diagnostic testing can reduce the sensitivity of both serology and biopsy testing 1

Pitfalls to Avoid

• Initiating a gluten-free diet before completing diagnostic evaluation can lead to inconclusive results 2
• Relying solely on symptom improvement after gluten restriction has a very low positive predictive value for coeliac disease 1
• Failing to consider other causes of gastrointestinal symptoms that may mimic coeliac disease, such as non-celiac gluten sensitivity, which has been reported in patients with negative coeliac serology 3

Follow-up Recommendations

• If clinical suspicion persists despite negative serology, consider:
  • Maintaining gluten in the diet (at least three slices of wheat bread daily) for 1-3 months before repeat testing 1
  • Referral to a gastroenterologist for consultation if symptoms continue without explanation 2
  • Evaluation for other causes of similar symptoms 1