By Amy Ratner, Beyond Celiac Medical and Science News Analyst

One in five children with celiac disease may not heal despite following the gluten-free diet for at least a year, according to a new study that reexamines the idea that nearly all children recover almost completely on the diet.

The study suggests the way celiac disease is managed in children may need to be changed, including a return to use of a repeat biopsy, said Maureen Leonard, M.D., the lead author. But more research is being done to confirm the study’s findings, she added.

For parents of children with celiac disease, the study results shake confidence in the evidence they’ve relied on to determine how well their children are doing on the gluten-free diet, currently the only treatment for celiac disease. And they’re anxious for the additional research to be done.

Scientists from the Celiac Research Program at Harvard Medical School reviewed the charts of 103 pediatric patients who were diagnosed with celiac disease through a biopsy at Mass General Hospital for Children and Boston Children’s Hospital.

The children, who were seen between 2008 and 2015, also had a follow-up biopsy at least 12 months after starting a gluten-free diet. The study found that 19 percent had persistent intestinal damage when the second biopsy was done.

Blood tests and symptoms

The study, published in the Journal of Pediatric Gastroenterology and Nutrition, also found that the IgA anti-tissue transglutaminase (tTG) blood test commonly used to monitor how children are doing on the diet was not an accurate marker of whether the children had the intestinal recovery expected when the diet is followed. Likewise, the children’s symptoms did not accurately predict whether intestinal healing had occurred.

“Neither the presence of symptoms nor a positive tTG could be relied on as a measure of mucosal recovery in patients with celiac disease on a gluten-free diet,” the study said. “Our findings raise concerns about this monitoring approach.” A similar reevaluation of disease management for adults is being done as research shows a similar disconnect between test results, symptoms and gut damage.

“This study suggests that pediatric patients with celiac disease may need a repeat biopsy after at least a year on the gluten-free diet to ensure there has been healing in the small intestine,” Dr. Leonard, clinical director of the Center for Celiac Research and Treatment, said. But she added that a call for universal changes in the way children are treated would depend on further research confirming the study conclusions.

While generally considered safe, an endoscopy with a biopsy is an invasive procedure in which a narrow tube is inserted down the throat, through the stomach and into the intestine, allowing small pieces to be taken and later examined by a pathologist. For pediatric patients, it requires sedation and can be uncomfortable.

Current guidelines

Currently, the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) guidelines call for children to be diagnosed through both blood tests including tTG and a biopsy that shows damage to the small intestine. Children with a positive diagnosis then go on a gluten-free diet and are usually monitored through further tTG testing at six and 12 months to assess whether they are following the diet and whether the intestine is recovering. When tTG levels normalize, it is presumed that intestinal mucosal healing has occurred because of the diet.

Meanwhile, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines allow a diagnosis of celiac disease without any biopsy when a combination of certain diagnostic criteria has been met, such as a child having 10 times normal anti-tTG, a positive IgA endomysial antibody test, presence of the celiac disease genetic markers, resolution of symptoms and a return to normal antibody levels on a gluten-free diet.

Prior to development of tTG testing, three biopsies were used to diagnose celiac disease: initially, again after following the gluten-free diet and a third after a gluten challenge. Though the tTG test, which measures antibodies set off in an autoimmune response triggered by gluten, is highly reliable for diagnosis, it has not been validated for monitoring celiac disease and is only used because no other test exists. Celiac disease experts are searching for and testing other markers in blood, urine and stool that might do a better job.

Confirming healing

“While current guidelines do not suggest a repeat endoscopy (with a biopsy) to assess for mucosal recovery, it is the only way to confirm it,” the study noted.

At diagnosis, 89 percent of the children in the study had positive tTG blood test results. Of the 71 children who had repeat tTG testing within four months of the second biopsy, only 43 percent with persistent intestinal damage had positive tTG results. Meanwhile, 32 percent of those who had intestinal recovery also had positive tTG tests.

If a child has symptoms or is not growing properly, parents and physicians should not trust a low or negative tTG result, Dr. Leonard said.

But even children who don’t have symptoms can have gut damage, the study showed. Forty five percent of the 103 children who had persistent enteropathy were asymptomatic at the time of the repeat biopsy. “If nearly half of children with persistent enteropathy are asymptomatic, that means symptoms are not good indicators,” Dr. Leonard said.

While poor adherence to the diet could explain persistent gut damage, 91 percent of patients in the study were found to be following the diet strictly when evaluated by a dietitian or gastroenterologist.

Adults also have damage

Studies of adult celiac disease patients, including one done at the Mayo Clinic, have shown that even after two years on the gluten-diet, 30 to 60 percent have persistent gut damage. Data also suggests that this is true in more than 33 percent of adults regardless of having symptoms or positive blood tests. Persistent gut damage has been associated with an increased risk of lymphoma, low bone density and fracture.

The Harvard researchers decided to take a closer look at what is happening with children after noticing that those seen at the celiac center had tTG test results that did not correlate with evidence of intestinal healing. They noted that the long-term consequences of continuing damage in children are unclear, but say malabsorption and ongoing inflammation in children may have negative effects on physical and cognitive development.

“While the long-term effects are not known, persistent enteropathy may predispose pediatric patients with celiac disease to future complications and suboptimal growth,” the study said.

The study was retrospective, which means the researchers collected data from past records but did not follow up with the patients. Researchers at Mass General are currently doing a prospective study, in which they will follow patients in real time collecting and comparing tTG and other test results, symptoms and biopsy results.

Dr. Leonard said pediatric patients seen at Mass General are being advised to have a biopsy after at least a year on the gluten-free diet to determine if the intestine has healed.

“We are collecting all the data and hope to have more information in less than a year, looking at 100 to 200 patients,” she said. “At this time, the only way to assess whether the small intestine has healed is with a biopsy. Part of our ongoing research is to try to identify other markers in either the blood, urine or stool that can help predict healing so that one day a repeat biopsy will not be necessary.”

Parental dilemma

For parents, the study raises questions about how their children’s celiac disease should be monitored and managed.

Michael Paroda’s son, Miles, had extremely elevated tTG results when he was diagnosed, and it took years for them to fall into the normal range even though he was following a strict gluten-free diet. “Knowing there is a 20 percent risk he may not be healed concerns me. This is a big number,” said Paroda, a member of the Beyond Celiac Patient and Family Advisory Council. “It makes me feel that I have a false sense of security in his recovery and long-term health.”

Julie Kennedy’s 10-year-old daughter, Abbey, was diagnosed with celiac disease in 2014. Since then her tTG tests have all been positive, though the levels have been falling. Kennedy, also a council member, has been struggling with questions about what the test results mean because she has been doing everything possible to make sure her daughter is following the gluten-free diet. “Every positive test made me like a failure as a parent,” she explained. Now she wonders if the study results that show positive tTG does not always line up with intestinal damage might give her some answers.

Those answers, the study shows, would most reliably come from a repeat biopsy to evaluate intestinal recovery since tTG can be falsely elevated, Dr. Leonard said. Echoing the concerns of other parents, Kennedy said the biopsy is not an ideal solution because it means Abbey would have to be sedated, something she’s already been through more than half a dozen times.

In face of questions raised by the study and while research continues, Dr. Leonard said the most proactive thing concerned parents can do is make sure their children have follow-up care by both a pediatric gastroenterologist and dietitian who are knowledgeable about celiac disease. Growth, including stature and weight gain, and nutritional levels can also be used in determining how healthy a child with celiac disease is and should be monitored by a gastroenterologist.

Jessica Press, who has celiac disease and whose daughter was also diagnosed in 2014, is eager for researchers to conduct the additional related studies. “The report raises several important questions,” she said. “Namely, what should the final word on pediatric protocol be? I know I’ll be discussing these findings with my daughter’s gastroenterologist and watching future studies closely.”

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