Can We Improve Diagnosis for Celiac Disease in Children?

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Celiac disease is still widely underdiagnosed among children. Doctors, Gilaad Kaplan and Jocelyn Silvester, discuss current research and how to move forward.

Reported incidence rates of celiac disease (CeD) have increased by 7.5% annually in the Western world in recent decades, according to a meta-analysis that included 50 studies. The findings showed a substantially higher incidence rate in children compared with adults, with a rate of 21.3 vs 12.9 per 100,000 person-years, respectively, in the 21st century.1

Despite these trends and vast improvements in screening capabilities for CeD, a 2021 study found that up to 91% of pediatric cases are missed by clinicians, with the greatest disparities observed among children from lower socioeconomic backgrounds.2

To discuss ways to improve diagnosis and other aspects of care for children with CeD, we interviewed Gilaad Kaplan, MD, MPH, FRCPC, AGAF, FCAHS, professor of medicine in the division of gastroenterology and hepatology at the Cumming School of Medicine at the University of Calgary in Alberta, Canada, and Jocelyn Silvester, MD, PhD, FRCPC, director of research for the Celiac Disease Program at Boston Children’s Hospital and assistant professor of pediatrics at Harvard Medical School in Boston, Massachusetts.

CeD is prevalent across race and ethnicity and socioeconomic status, and thus awareness of the disease needs to be raised in clinicians.

According to a 2021 study from the European Journal of Pediatricsapproximately 83% to 91% of children with CeD remain undiagnosed despite improved and readily available serological testing.2 Can you elaborate on some of the most common signs and symptoms that clinicians should be on the lookout for when determining whether a patient is a candidate for further CeD screening and diagnostics? 

Dr. Kaplan: CeD can be challenging to diagnose because symptoms can vary from classic chronic diarrhea and weight loss to asymptomatic iron deficiency anemia. The index of suspicion for CeD should be raised in patients at higher risk, such as those with a family history of CeD or a concomitant immune disorder such as hypothyroidism.

Dr. Silvester: Identifying children based on symptoms is difficult and has not been shown to detect undiagnosed patients. In the ASK study in Colorado, which involved screening a general pediatric population, symptoms were not predictive of seropositivity.3 Similar findings have been reported in adults.

The same aforementioned study concluded that children from socioeconomically underserved backgrounds were more likely to be underdiagnosed with CeD.2 What measures can clinicians take to ensure that patients from racially and ethnically diverse backgrounds have proper access to care and testing?

Dr. Kaplan: CeD is prevalent across race and ethnicity and socioeconomic status, and thus awareness of the disease needs to be raised in clinicians. CeD can be screened by a blood test — tissue transglutaminase (TTG) — allowing the opportunity for public health organizations to create screening programs for those who are socioeconomically disadvantaged or living in underserviced regions.

Can you expound on common serological and genetic testing options available to patients? How do clinicians determine which test might be most appropriate for a given patient?

Dr. Kaplan: The gold standard for diagnosing CeD is a positive serological TTG antibody test and an upper endoscopy with duodenal biopsies showing pathological evidence of CeD.4 When duodenal biopsies show pathological evidence of CeD but TTG levels are normal, then genetic testing with HLA-DQ2/DQ8 is considered. A negative genetic test rules out the diagnosis of CeD, though a positive test is not confirmatory.  

Dr. Silvester: The first-line screening test is TTG IgA in all age groups, with a total IgA so that those who are IgA deficient can be tested using deamidated gliadin peptide (DGP) IgG or TTG IgG.5 The incremental benefit of more serologic tests such as DGP or endomysial antibody (EMA) is not clear, but certainly some patients with CeD who do not have TTG IgA antibodies screen positive on a different assay. It is also important to remember that assays are not standardized and do perform differently even on the same blood sample.

Is there an advantage to more invasive forms of screening for CeD, such as video capsule endoscopy (VCE) vs less invasive forms of screenings, such as IgA endomysial antibody (EMA)?

Dr. Kaplan: VCE is typically not required to diagnose CeD. VCE may be performed when ruling out other causes of small bowel pathology that are not detected by small bowel endoscopy and imaging. TTG assays are more routinely used for testing because they are widely accessible, accurate, and cost-efficient as compared to the EMA. However, the choice of screening test may be directed by lab-specific practices that vary geographically.

Dr. Silvester: IgA EMA involves tissue immunofluorescence and has been replaced by recombinant TTG as a first-line test; EMA antibodies recognize TTG. VCE has been used in research but is not suitable for diagnostic purposes as there are no established criteria. As well, both villus-crypt architecture and infiltration of lymphocytes into the epithelium must be assessed.

A 2023 study published in the American Journal of Gastroenterology found that the incidence of CeD among children can vary by geographical region across the United States and from one country to another.6 Can you discuss how environmental and even epigenetic factors may play a role in the development of CeD? 

Dr. Kaplan: This study followed children at higher risk of CeD because they tested positive for HLA DQ2 or DQ8. The authors discovered that the risk of developing CeD by the age of 10 years varied by geography — for example, 0.9% in Washington vs 3% in Sweden. These data suggest that genes increase susceptibility to CeD, but genetic risk alone is not sufficient to explain all the cases of CeD. The study was not designed to identify the environmental determinates that drive the pathogenesis of CeD; but, the authors speculate that variation in CeD risk may be explained by environmental factors such as diet.

Dr. Silvester: This is an exciting area, and we are fortunate in CeD to have several international prospective birth cohorts, including TEDDY and CD-GEMM, that enrolled at-risk children and collected biospecimens prior to disease onset.6,7 The environmental factors that trigger those genetically at-risk for CeD to react to gluten are likely many, with infections — particularly viral infections — currently topping the list.8

Studies designed specifically to evaluate the roles of early infant feeding practices, such as breast-feeding and the timing of gluten introduction, have not found a link despite epidemiologic associations during the “Swedish Celiac Epidemic.”9 Of course, there is also lots of interest in the role of the microbiome. Data regarding the impact of the amount of gluten is conflicting.

In a 2019 study published in Nutrients, researchers found that gluten-free products are 183% more expensive than gluten-containing food.10 What resources can clinicians provide their patients to help address the financial burden of a costly gluten-free diet? Are there any modifications patients can make to their diet beyond gluten-free choices? 

Dr. Kaplan: Individuals diagnosed with CeD should consider joining local CeD foundations, as they are a wealth of information designed to navigate the complex world of living with the disease. Living with CeD can be costly, but resources exist to support these individuals. For example, the Canada Revenue Agency allows a tax deduction when buying gluten-free food.  

Dr. Silvester: Specialty gluten-free processed foods tend to be more expensive than gluten-containing versions. Convenience foods are also more limited and often more expensive. There is some data that otherwise food-secure families struggle to afford gluten-free foods. Food banks and food pantries are highly variable regarding their provision of gluten-free food and may stock items that are gluten-free even though they may not be labelled as such — for example, every fruit and vegetable is born gluten-free! Gluten-free diet education should involve more than just avoiding gluten; a diet rich in processed gluten-free foods should not be the goal.


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