Certain Factors Predict Celiac Disease Risk in Children With Positive Serology but Negative Biopsy

By Marilynn Larkin

April 22, 2019

NEW YORK (Reuters Health) - In children with "potential" celiac disease - positive serology but negative biopsy - who are not on gluten-free diets, factors that may help predict risk for eventual villous atrophy include age at diagnosis, gamma delta lymphocytes and HLA haplotype, researchers say.

"Potential celiac disease is characterized by positive results from serologic tests for tissue transglutaminase antibodies (anti-TG2) but normal duodenal architecture (Marsh stages 0-1)," note Dr. Renata Auriccio of the University Frederico II in Naples, Italy and colleagues. Because management of affected children is controversial, the team investigated risk factors associated with development of villous atrophy - i.e., clearly defined celiac disease.

"The most relevant message from our research in potential celiac disease is that this is a very heterogenous group of patients," Dr. Auriccio told Reuters Health. "They have to be carefully managed by expert pediatric gastroenterologists."

"Concerns in their management are both (whether) to start a gluten-free diet for symptoms that are not really gluten-dependent or to leave them on a gluten-containing diet without a careful clinical, serological and histological follow-up," she said by email. "Clinicians should be very careful at diagnosis, repeating serology after a few months and performing a correct histological analysis (good orientation of the fragment and morphometry)."

Dr. Auriccio and colleagues enrolled 280 children ages two to 18 years with potential celiac disease and followed them for up to 12 years. Participants had two consecutive positive results from tests for anti-TG2, tested positive for the endomysial antibody (anti-EMA), had total serum levels of IgA in the normal range, normal duodenal architecture (Marsh stages 0-1) in five biopsies, and HLA DQ2- or DQ8-positive haplotypes.

Clinical analyses of serologic tests were done every six months and a small bowel biopsy was taken every two years. Two hundred ten of the original cohort were assessed at the 9-year follow-up evaluation.

As reported online April 9 in Gastroenterology, 42 of 280 children (15%) developed villous atrophy during follow-up, while 89 (32%) no longer tested positive for anti-TG2 or anti-EMA. The cumulative incidence of progression to villous atrophy was 43% at 12 years.

Factors most strongly associated with development of villous atrophy were numbers of gamma delta intraepithelial lymphocyte cells, followed by age at diagnosis and homozygosity for the HLA DQB1-02. In discriminant analysis, these baseline factors identified 80% of the children who developed baseline atrophy.

More specifically, children who developed flat mucosa over time showed an increased number of gamma delta lymphocytes in the first biopsy compared with those who remained "potential" cases (mean value, 11.9 vs. 6.4). However, as the authors state, "we are conscious that this assay is not available in routine diagnostics."

Further, only 7% of younger children (<3 years of age) developed flat mucosa compared with 51% of those diagnosed between 3 and 10 years of age and 55% of those diagnosed after age 10.

Children who developed villous atrophy had positive anti-TG2 deposits more often during follow-up. Those with clear deposits in the small intestine mucosa were more than twice as likely to develop flat mucosa compared with children who did not.

The effect of HLA risk classes was significant in the three to 10-year old group, but lost its significance in those diagnosed after age 10.

There was no significant difference between sexes, and a family history of autoimmunity (e.g., celiac disease, type 1 diabetes) did not affect risk.

The researchers' next step will be to identify factors that differentiate patients who become seronegative from those who develop villous atrophy, Dr. Auriccio said.

Dr. Joseph Picoraro, assistant professor of pediatrics at Columbia University Irving Medical Center and Director of Pediatric GI Inpatient Services at NewYork-Presbyterian Morgan Stanley Children's Hospital in New York City, commented, "This study provides useful predictors of children with potential celiac disease...for future evolution to clearly defined celiac disease or, alternately, normalization of autoantibody. Incorporating these predictors into the clinical decision-making of clinicians with families will aid the decision to continue a gluten-containing diet or not."

"The full discriminant score is not actionable until clinical assays are developed," he told Reuters Health by email. "However, some of the predictors can be utilized in decision-making now."

"'Potential celiac disease' is a useful framework for the expectant management in the face of uncertainty," he said. "Genetic markers and lymphocyte characterization of histologic specimens may guide clinical decisions in future."

However, he noted, "the risks of consuming a gluten-containing diet in children with potential celiac disease (e.g., growth potential, weight gain, bone density, etc.) were not examined."

SOURCE: http://bit.ly/2GASdEn

Gastroenterology 2019.

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