By Amy Ratner, Beyond Celiac Medical and Science News Analyst
Children who have symptoms and certain definitive blood test results do not need a biopsy to be diagnosed with celiac disease, a large, international study has found.
More than half the children with celiac disease worldwide could avoid the risks and costs of having an endoscopy and anesthesia, according to the authors of the study, which was published in the journal, Gastroenterology.
Researchers looked at data collected from 2011 to 2014 from 33 pediatric gastroenterology centers in 21 countries and found that patients 18 years old or younger can be accurately diagnosed without an intestinal biopsy when they have at least one symptom of celiac disease, very high TGA-IgAlevels and confirming positive results from an anti-endomysial test (EMA).
Anti-endomysial antibody (EMA-IgA) - a test that is very specific for celiac disease. It's estimated that a person with an elevated titer of EMA is almost assured of having celiac disease. However, the EMA test isn't as sensitive as the tTG-IgA test; about 5 to 10 percent of celiac disease patients do not have a positive EMA test.
Tissue transglutaminase antibody (TGA or tTG), IgA class — the primary test ordered to screen for celiac disease. It is the most sensitive and specific blood test for celiac disease and is the single test preferred by the American College of Gastroenterology, according to its 2013 guidelines.
Positive predictive value – the probability that patients with a positive screening test truly have the disease.
Negative predictive value – the probability that patients with a negative screening test truly don't have the disease.
The main strength of the study is its use of many participants “recruited in a variety of clinical centers in different countries and settings, which truly reflect clinical practice,” the authors wrote. They also noted that the study showed “the complexity and pitfalls occurring in the diagnostic work-up of children with suspected celiac disease.”
European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPHGAN) guidelines allow diagnosis of celiac disease without a biopsy if a child has the genes associated with celiac disease, symptoms and a TGA-IgA blood test that is 10 times the upper limit of normal, along with a positive EMA. The ESPHGAN recommendations, made in 2012, were based on mostly retrospective data or small single-center studies, authors of the international study noted. "There were major doubts whether omitting biopsies would result in false diagnoses and unnecessary therapies," the Dr. von Hauner Children's Hospital, Munich, Germany, which coordinated the study, said in a press release.
The study was conducted by the Prospective Celiac Disease Diagnostic Evaluation (ProCeDE) group, which brings together an array of celiac disease researchers to investigate the performance of the ESPGHAN diagnostic criteria. The primary aim was to determine whether, in a multi-center setting, the non-biopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99 percent in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified.
"The results are reassuring and provide strong support for the non-biopsy approach suggested by the European pediatric gastroenterology society," Sibylle Koletzko, head of pediatric gastronenerology at Dr. van Hauner hopsital and a study author, said.
Meanwhile, the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) continues to call for a biopsy to confirm of a diagnosis of celiac disease in all children. Additionally, the group’s guidelines don’t rely as heavily on the EMA test, saying that while it “may also be reliable” it is subject to errors of interpretation and adds cost. If tTG blood tests are positive but biopsy results are negative, NASPGHAN says the EMA test should be considered.
Alessio Fasano, M.D., a pediatric gastroenterologist and director of the Center for Celiac Research and Treatment at MassGeneral Hospital for Children, said it’s unlikely NASPHGHAN will review its guidelines anytime soon. “While the tTG antibodies are a robust and well-validated tool to screen for celiac disease, they are not infallible, carrying the risk of both false negative and false positive results,” he said.
Fasano noted that while the proposed ESPGHAN approach would provide a clear benefit to a subgroup of children, it is based on the premise that this group should have tTG antibodies 10 times higher than normal. “Unfortunately, this test is limited by the variability among different kits that are commercially available, making comparison from one lab to another difficult and not strongly reliable,” he said.
Since celiac disease is a chronic condition that requires following a gluten-free diet for life, an intestinal biopsy showing the actual autoimmune insult of celiac disease has been recommended as the ultimate proof to justify the lifelong commitment, Fasano said, pointing to the effect the diet has on a patient’s quality of life. “Therefore, it is extremely important to be as accurate as possible in diagnosing this lifelong condition in children,” he said.
Lack of a biopsy could also become a problem in the future if a drug to be taken along with the gluten-free diet becomes available, according to Fasano. “It is likely that health insurances will cover these new drugs only in those celiac patients who had their diagnosis validated by an intestinal biopsy,” he said.
Diagnosis without biopsy
The international study included 707 children, 645 who were diagnosed with celiac disease, 46 who were not and 16 who had inconclusive results. All the children also had biopsies, allowing researchers to compare diagnosis results when only ESPGHAN criteria was used and when a biopsy was also part of the process.
When the children had a tTG-IgA test that was at least 10 times the upper limit of normal, a positive EMA and any symptom of celiac disease, the test results without a biopsy were 99.75 percent accurate in predicting celiac disease, the study showed. When only children with diarrhea, weight loss or insufficient gain, failure to grow or anemia were considered, the tests were 100 percent accurate. Although ESPHGAN guidelines call for positive results on test for the genes associated with celiac disease, HLA-DQ2/DQ8, the study concluded HLA analysis is not required for accurate diagnosis. HLA-typing “does not improve accuracy of celiac disease diagnosis without biopsies and can be omitted,” the study said.
The perfomance of the tests themselves was also taken into account, with researchers looking at results from 16 antibody tests from five different manufactures. The reliability of diagnosis without a biopsy was independent of country and the type of tTGA test used. the study found.
However, the study noted that if a child is missing any of the three conditions -- symptoms, high tTG blood test results or EMA blood test confirmation -- a biopsy should be done to confirm a celiac disease diagnosis. Additionally, Kletzko recommended that children be evaluated for celiac disease by a physician knowledgeable about the condition because of the complexity of diagnosis and the pitfalls in interpretation of test results. She noted that more study is needed to determine if the biopsy can be omitted in children without symptoms or adults.
Use of the biopsy as the so-called "gold standard" for diagnosis of celiac disease remains a hotly debated topic. Check back for our ongoing coverage of reaction to this study.
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