Study Suggests Non-Biopsy Diagnosis May Be Accurate for a Select Group of Adults with Celiac Disease

Findings from a large, multicenter study — recently presented during the Digestive Disease Week conference — suggest that a non-biopsy diagnosis of celiac disease may be accurate in a small subset of U.S. adults with highly elevated tissue transglutaminase immunoglobulin A (TTG-IgA) levels.

The research, led by Claire Jansson-Knodell, MD, of the Cleveland Clinic’s Department of Gastroenterology, Hepatology & Nutrition, included over 11,000 adult patients across six U.S. sites and explored whether the same non-invasive diagnostic approach used in European pediatric guidelines could be applied to adult patients.

Background and Motivation

In the United States, celiac disease in adults is typically diagnosed using a combination of serologic testing and confirmatory small bowel biopsy during upper endoscopy. Comparatively, European pediatric guidelines have permitted a non-biopsy diagnosis since 2012 for selected children with high TTG-IgA antibody levels — a strategy reaffirmed in their 2020 update, according to Dr. Jansson-Knodell.

“Currently, there’s no equivalent approach for adults in the U.S., but the TTG-IgA test is so strong that we wondered if the pediatric strategy might be applicable to adults as well,” she notes, while discussing the rationale behind her team’s research.

In this large, multicenter, observational study, the investigators aimed to evaluate whether a non-biopsy diagnostic strategy using a TTG-IgA threshold greater than 10 times the upper limit of normal (ULN)—the same cutoff used in European pediatric guidelines — could accurately identify incident cases of adult celiac disease.

The study population included adults (≥18 years) who underwent a duodenal biopsy during esophagogastroduodenoscopy and had TTG-IgA levels drawn within three months before or one month after the procedure. Individuals with a prior diagnosis of celiac disease, total IgA lower than the reference range, or those already following a gluten-free diet were excluded.

Celiac disease was defined histologically by the presence of villous atrophy. Statistical analyses, including receiver operating characteristic (ROC) analysis, were used to assess the diagnostic performance.

Key Findings

Of 11,282 adult patients evaluated across six U.S. centers, a majority were female (7,739; 68.7%) and Non-Hispanic White (8,925; 81.2%). Investigators observed an abnormal TTG-IgA in 1,884 (16.7%) of study participants and villous atrophy was found in 1,800 (16.0%) of patients. Individuals with higher TTG-IgA values were more likely to have villous atrophy.

“For any elevated TTG-IgA the sensitivity was 73% and specificity was 94%. The positive predictive value (PPV) was 71% and the negative predictive value (NPV) was 95% for a diagnosis of celiac disease,” Dr. Jansson-Knodell and colleagues report. “The test accuracy was 91% with an overall false positive rate of 6%. The AUC of the ROC curve was 0.88 (95% CI, 0.87-0.89).”

Among study participants, 155 patients (8.2%) had TTG-IgA levels greater than 10 times the upper limit of normal. “When using this cutoff, the TTG-IgA test performed incredibly well with a specificity of 99.9% and a positive predictive value of 95.5%,” Dr. Jansson-Knodell explains, while noting that a cutoff of TTG-IgA >5x ULN also performed well with a specificity of greater than 99% and a positive predictive value greater than 93%.

Only seven of the 155 patients with TTG-IgA levels >10x ULN did not exhibit villous atrophy on biopsy, according to the researchers, who found that these patients were more likely to have a history of other autoimmune conditions (p=0.024).

Implications and next steps

While the findings of this large, multicenter study offer valuable insights into non-biopsy diagnosis of celiac disease, researchers emphasized that ongoing exploration is needed. TTG-IgA levels above 10 times the upper limit of normal were highly specific for celiac disease; however, this threshold applied to fewer than 10% of adults with biopsy-confirmed disease and just about 1% of all patients undergoing evaluation at tertiary care centers.

The researchers stressed that biopsy would remain a necessary diagnostic tool for the vast majority of adult patients with celiac disease, particularly those who are seronegative or IgA deficient. “The big takeaway is that the TTG-IgA test is very strong at high levels, with excellent specificity,” Dr. Jansson-Knodell says. “But according to this data, a biopsy will still be needed for confirmation for around 90% of patients.”

A key next step will be conducting a prospective cohort study to further evaluate the safety, accuracy, and practical application of high TTG-IgA thresholds in adult populations, according to Dr. Jansson-Knodell, who also highlights the importance of including a broader and more varied patient base to ensure that any diagnostic strategy is both equitable and effective.

Dr. Jansson-Knodell also underscores that diagnosis is only the beginning of a longer journey. “Celiac disease is a lifelong condition. Making the diagnosis is just the first step. After that comes education about a gluten-free diet, referral to a dietitian, and long-term follow-up with a gastroenterologist,” she notes. “This research focuses on just one important piece of the overall patient journey.”

The study adds to the evolving conversation around non-invasive diagnostic strategies and sheds light on a potential pathway toward more individualized care in the future. “We’re still in a phase where we’re looking to confirm these findings,” Dr. Jansson-Knodell concludes. “That’s why prospective validation is so important — this is exciting work, but it needs to be solidly backed before it can shape clinical practice.”

DDW Presentation: “Non-biopsy diagnosis of celiac disease appears highly accurate but would not apply to most U.S. adults”