Gluten-Free Diet Does Not Repair Intestinal Damage in Some Children With Celiac Disease

lack-of-recovery-in-celiac-childrenDespite following a gluten-free diet for a year, nearly 20% of children with celiac disease continue to show signs of intestinal damage on repeat biopsies, according to a new study.

“The findings point to the need for revisiting the criteria for monitoring mucosal recovery and managing pediatric celiac disease,”

  • says Maureen M. Leonard, MD, clinical director at the Center for Celiac Research & Treatment at Massachusetts General Hospital for Children in Boston, and colleagues.  published online November 3 in the Journal of Pediatric Gastroenterology and Nutrition.

In recent years, IgA tissue trans-glutaminase antibody (tTG) serologic testing has replaced routine follow-up biopsies to monitor intestinal healing in children with celiac disease who have been placed on a gluten-free diet. Although current guidelines endorse and recommend serology as a marker of dietary adherence and mucosal recovery, the evidence supporting their use for that purpose is lacking, the authors write.

The Study

Marsh-Score-Celiac-DiseaseIn light of the growing body evidence suggesting that adults with celiac disease have persistent enteropathy despite being symptom-free and having normal IgA tTG levels, the current study was designed to evaluate the rate of mucosal recovery in children with celiac disease on a gluten-free diet and to assess whether a correlation exists between tTG levels and mucosal damage.

The researchers reviewed the medical records of children and adolescents with celiac disease who received treatment at one of two medical centers between January 2012 and March 2015 or between January 2008 and December 2013. Patients were included in the study if they had a diagnosis of celiac disease confirmed by the presence of Marsh 3 lesions on diagnostic endoscopy and if they underwent a repeat endoscopy with duodenal biopsy at least 12 months after initiating a gluten-free diet.

Of 103 children included, 92 (89%) were IgA tTG positive at diagnosis. Eleven patients had a negative tTG test result at diagnosis, including 2 who were asymptomatic but at high genetic risk at diagnosis.

Despite excellent adherence to a gluten-free diet for most (91%) patients,

  • 43% experienced persistent symptoms,
  • 27% had new gastrointestinal symptoms
  • 34% had persistently elevated serology at the time of repeat endoscopy and biopsy.
  • Only 33% of the patients were asymptomatic at the time of repeat endoscopy.

The reasons for the repeat biopsy in the absence of celiac symptoms varied but included follow-up for another disease, persistently elevated serology, and “to assess for mucosal recovery and confirm the diagnosis of celiac disease in the setting of seronegative [celiac disease].”

  • Overall, 19% of patients showed persistent enteropathy consistent with a Marsh 3 lesion at the repeat endoscopy.

The authors note that the endoscopy results could not be predicted by the presence of symptoms or by IgA tTG. Of the patients with evidence of persistent enteropathy, 45% were asymptomatic at the time of repeat endoscopy.

The Findings

  • “In practice, IgA tTG was a poor predictor of Marsh 3 histology at repeat biopsy as sensitivity was 43%, specificity was 68%, the positive predictive value (PPV) was 25%, and the negative predictive value (NPV) was 83%,” the authors explained. They note that the poor predictability was not influenced by symptom status or the duration of the gluten-free diet.
  • Furthermore, IgA tTG was not an accurate measure of mucosal recovery in this population. The NPV was highest (87%) in patients following a gluten-free diet for more than 2 years, but the PPV was only 36% “Additionally, the NPV of tTG was not improved when correlated with the presence or absence of symptoms at the repeat endoscopy,” the authors write.
  • The findings demonstrate that neither the presence of symptoms nor a positive tTG result was a reliable measure of mucosal recovery in the study population. For example, tTG was elevated in 43% of patients with persistent enteropathy and in 32% of those with mucosal healing. In contrast, 84% of patients with mucosal recovery on repeat biopsy were symptomatic at the time of the repeat endoscopy, as were 55% with persistent enteropathy.

The findings “raise concerns” about using serologic tests as markers in pediatric celiac disease patients, the authors write,

  • “Despite the clinical practice and endorsement of using serological tests as markers of dietary adherence and mucosal recovery in pediatric patients with [celiac disease] on a [gluten-free diet], these serology tests have not been validated for this purpose.”

Although current practice guidelines — which were drafted more than 25 years ago and don’t reflect the transformation in clinical presentation of the disease over the past decades — do not recommend repeat endoscopy to assess mucosal recovery, it is currently the only objective way to confirm that enteropathy has resolved.

Future Considerations

  • “These findings suggest the need not only for a baseline endoscopy to confirm the diagnosis of celiac disease but also consideration of a repeat biopsy to evaluate for remission,” the authors write.

The long-term consequences of suboptimal mucosal healing in children with celiac disease are unclear. “However, malabsorption and ongoing inflammation in children may have negative repercussions on physical and cognitive development”…[P]ersistent enteropathy in adults has been associated with an increased risk of lymphoma, low bone density, and fracture,” they note.

Additional studies should be pursued to improve understanding of the intestinal response to the gluten-free diet in children and adolescents, the authors stress. “Furthermore, identifying minimally invasive accurate surrogate endpoints for patients is of utmost importance to identify patients who may benefit from potential for new therapeutic agents that may serve as adjuvant medications to the [gluten free diet].”

  • Study co-author Dr Alessio Fasano disclosed financial relationships with Alba Therapeutics, Mead Johnson Nutrition, Inova Diagnostics, Regeneron, and Pfizer. No other authors have disclosed any relevant financial relationships.
  • J Pediatr Gastroenterol Nutrition. Published online November 3, 2016