Gene testing best for CD screening in high-risk children under age 2

Celiac disease (CD) is an immune-based reaction to gluten — a protein in wheat, rye and barley — that results in damage to the small intestine mucosa. It occurs in genetically predisposed children and adults and usually responds to a gluten-free diet.

CD is one of the most common causes of malabsorption; progressive villous atrophy limits both production of digestive enzymes and absorption of iron and some vitamins, including folic acid and vitamin B-12. Although many children with CD-associated intestinal damage are asymptomatic, others may present with poor growth in addition to gastrointestinal symptoms.

Screening is currently recommended for all children who have a first-degree relative with CD and sometimes for others at higher risk due to Down, Turner or Williams syndrome or insulin-dependent diabetes. The preferred screening test is immunoglobulin A (IgA) anti-tissue transglutaminase (TTG) antibody, which has high sensitivity and specificity — more than 95 percent in most studies. Total IgA is measured when there is a good probability of CD and suspected IgA deficiency. The diagnosis is confirmed with intestinal biopsy.

Until very recently, testing for IgG-deamidated gliadin peptides was instead recommended for children younger than 2 years because they had limited exposure to gluten. But Imad Absah, M.D., a pediatric gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota, says the publication of two influential studies in the New England Journal of Medicine in 2014 changed that thinking. "Those two very good trials found that the age at which gluten is introduced into a child's diet has little or no association with the risk of CD," he explains.

In one trial, children with either a standard-risk or high-risk human leukocyte antigen (HLA) genotype were randomly assigned to receive gluten at 6 months or 12 months of age. At five years, there was no significant difference between the two groups for autoimmunity or overt disease, but at 10 years, the risk of both autoimmunity and CD was far greater among the children with high-risk HLA. The researchers concluded that neither late introduction of gluten nor breast-feeding — long thought to modify CD risk — was a significant predictor of disease, whereas a high-risk HLA genotype was.

The second trial, which compared nearly 1,000 children who received gluten from16 to 24 weeks of age, again found that the timing of gluten exposure didn't affect the development of CD. All children in the study were positive for either HLA-DQ2 or HLA-DQ8 — the haplotypes that confer genetic susceptibility.

"These findings seem to indicate that the new recommendation would be to screen children younger than 2 who are at high risk due to having a family member with celiac disease by assessing the presence of the permissive genes. If they carry the permissive genotype, then they need to be screened every 3 to 5 years," Dr. Absah says. "Deamidated gluten can still be used in lower-risk children under 2. For children older than 2, we would continue to use TTG testing. It's simple, straightforward and much more affordable."

He notes that new guidelines issued by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition in 2012 suggest a confirmatory biopsy isn't necessary for a subset of young patients who have symptoms of celiac disease, the HLA genotype and TTG levels 10 times higher than normal. "Others still need a biopsy to confirm the diagnosis, especially since many kids are asymptomatic, and there is a very poor correlation between what is seen on a biopsy and symptoms," he says.

New thoughts on pathogenesis

The recent studies not only call into question the way infants are screened for CD but also the factors believed to contribute to disease development.

"There is increased incidence in both children and adults that is very confusing to us," Dr. Absah says. "For the longest time, we thought it had to do with the timing of gluten exposure during infancy. In the 1980s and 1990s, there was an epidemic in Sweden, where the incidence of celiac disease quadrupled, and we thought it was the result of a large amount of gluten exposure, especially in the absence of breast-feeding. But these studies show that's not the case, so it's more likely something environmental, such as perinatal antibiotic use or vital wheat gluten — a concentrated form of gluten added to breads and pastries. Some epidemiologic studies have suggested a relationship with proton pump inhibitors, which are now used very early in children, but that needs to be looked at in a more scientific way."

Going gluten-free

Gluten-free eating has become a worldwide phenomenon. About 17 percent of people now avoid gluten, most of them without diagnosed celiac disease or gluten sensitivity.

"If people want to limit gluten to treat chronic headache or autism spectrum disorder or other health problems, that's a personal choice," Dr. Absah says. "The problem is that celiac serology must be performed before starting a gluten-free diet. For parents and children seeking a diagnosis, we have a dedicated pediatric celiac disease clinic that operates in conjunction with the adult clinic, and we are more than happy to answer any questions patients and providers may have."

For more information

Lionetti E, et al. Introduction of gluten, HLA status, and the risk of celiac disease in children. The New England Journal of Medicine. 2014;371:1295.

Liu E., et al. Risk of pediatric celiac disease according to HLA haplotype and country. The New England Journal of Medicine. 2014;371:42.