What is the next step to evaluate celiac disease in a 30‑year‑old trans male with Ehlers–Danlos syndrome, postural orthostatic tachycardia syndrome, depression, obstructive sleep apnea, mast‑cell activation disorder, vitamin D deficiency, ADHD, and selective IgA deficiency (serum IgA 81 mg/dL) who has a negative tissue transglutaminase IgA test?

Celiac Disease Evaluation in IgA-Deficient Patient with hEDS

Order IgG-based celiac serology immediately—specifically IgG deamidated gliadin peptide (DGP-IgG) or IgG tissue transglutaminase—because your patient has selective IgA deficiency (serum IgA 81 mg/dL is below normal), which invalidates the negative TTG-IgA result. 1

Understanding the Diagnostic Problem

Your patient's serum IgA of 81 mg/dL falls below the normal range, creating a critical diagnostic pitfall: IgA deficiency occurs in 1–3% of celiac disease patients and causes falsely negative IgA-based antibody tests 1. The negative TTG-IgA (<2) cannot be trusted to exclude celiac disease in this context 1.

This is particularly important because:

• Celiac disease risk is elevated in patients with hEDS/HSDs compared to the general population 2
• The 2025 AGA Clinical Practice Update specifically recommends testing for celiac disease earlier in the diagnostic evaluation of patients with hEDS/HSDs who report a variety of GI symptoms, not only those limited to diarrhea 2
• Your patient has multiple comorbidities (POTS, mast cell disorder) that frequently overlap with hEDS and may share GI manifestations 2

Immediate Next Steps

1. Order IgG-Based Celiac Serology

• IgG deamidated gliadin peptide (DGP-IgG) is the preferred test for IgA-deficient patients, with superior diagnostic accuracy: 93.6% sensitivity and 99.4% specificity in adults 1
• IgG endomysial antibody (EMA-IgG) is also highly effective in IgA-deficient patients 1
• Do NOT rely on IgG tissue transglutaminase (TTG-IgG) as it has inferior performance: sensitivity only 40.6–84.6% and specificity 78.0–89.0% 1

2. Verify Adequate Gluten Intake

• Confirm the patient has been consuming at least 10g of gluten daily for 6–8 weeks before testing 1
• If the patient has already reduced gluten intake, gluten must be reintroduced for 1–3 months before repeat serologic testing or biopsy 1
• Insufficient gluten exposure is the leading cause of false-negative results 1

3. Proceed to Endoscopy Based on Serology Results

If IgG-based serology is positive:

• Proceed directly to upper endoscopy with at least 6 duodenal biopsy specimens from the second part of the duodenum or beyond 1
• Ensure specimens are properly oriented for histologic analysis using Marsh classification 1
• Do NOT initiate a gluten-free diet before completing the biopsy, as this invalidates histologic findings 1

If IgG-based serology is negative but clinical suspicion remains high:

• Consider HLA-DQ2/DQ8 testing: absence of both alleles has >99% negative predictive value and essentially rules out celiac disease 1
• If HLA-DQ2 or DQ8 is present and symptoms are highly suggestive, proceed to endoscopy despite negative serology to evaluate for seronegative celiac disease 1

Special Considerations in This Patient

hEDS and Celiac Disease Association

• Studies report elevated risk of celiac disease in patients with hEDS/HSDs 2
• The 2025 AGA guideline specifically addresses this population, recommending earlier serological testing followed by endoscopic biopsies in individuals with hEDS/HSDs who report a variety of GI symptoms 2

POTS and Gastric Motility

• In patients with hEDS/HSDs and comorbid POTS who report chronic upper GI symptoms, timely diagnostic testing of gastric motor functions should be considered after appropriate exclusion of anatomical and structural diseases 2
• Abnormal gastric emptying may be more common than in the general population 2

Mast Cell Disorder Considerations

• Testing for mast cell disorders should be considered in patients with hEDS/HSDs and GI symptoms who also present with episodic symptoms suggesting a more generalized mast cell disorder 2
• However, current data do not support the use of MCAS tests for routine evaluation of GI symptoms in all patients with hEDS/HSDs without clinical or laboratory evidence of a primary or secondary mast cell disorder 2

Critical Pitfalls to Avoid

• Never diagnose or exclude celiac disease based on IgA-based serology alone when total IgA is low 1
• Never start a gluten-free diet before completing the full diagnostic workup (serology + biopsy), as this invalidates subsequent testing 1
• Do not order multiple antibody panels simultaneously in low-risk individuals, as this reduces specificity 1
• Do not confuse elevated total IgA (which this patient does NOT have) with celiac disease risk—low IgA is the concern here 1

Diagnostic Algorithm Summary

1. Measure IgG DGP (preferred) or IgG EMA immediately 1
2. Verify adequate gluten intake (≥10g daily for 6–8 weeks) 1
3. If IgG serology positive → proceed to endoscopy with ≥6 biopsies 1
4. If IgG serology negative but high clinical suspicion → consider HLA-DQ2/DQ8 testing 1
5. If HLA positive or unavailable and symptoms persist → proceed to endoscopy 1
6. Only after biopsy confirmation, initiate strict gluten-free diet and refer to experienced dietitian 1