Children who are genetically predisposed to celiac disease and have too much gluten in early childhood are at greater risk of getting the condition, according to research published in the August 13 issue of the Journal of the American Medical Association. The study could spur more interest in testing for celiac disease, experts believe.
The new results come from the Environmental Determinants of Diabetes in the Young (TEDDY) trial, an international, observational birth cohort study of children genetically at risk for celiac disease and type 1 diabetes, due to their being carriers of the human leukocyte antigen (HLA) genotype.
Investigators used food records and regular tissue transglutaminase autoantibody tests of serum samples for 6,605 children who were followed from birth through age 5. They found a statistically significant 6.1% absolute risk increase in celiac disease autoimmunity associated with gluten intake of 1 gram per day more than average. They also reported a 7.2% increase in absolute terms for celiac disease with every gram increase of gluten intake per day.
"The 6% to 7% increase in risk for a small [1 gram per day] increase in gluten intake appears clinically important," wrote Dr. Daniel Agardh, PhD, a diabetes and celiac disease specialist at Lund University in Malmö, Sweden, and colleagues (JAMA, August 13, 2019, Vol. 322:6, pp. 514-523).
"Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children," they concluded.
Triggers for celiac disease
The TEDDY study was undertaken to elucidate the relationship between dietary gluten intake and the development of celiac autoimmunity and celiac disease, which often emerges in childhood.
"The timing of infant gluten exposure has not been consistently associated with celiac disease risk and this has led to changing recommendations for infant feeding," Agardh et al wrote. "It remains unclear whether the amount of gluten consumed triggers celiac disease."
In the study, the incidence of celiac autoimmunity and celiac disease peaked when children were between the ages of 2 and 3 years, they reported.
"The association of gluten intake with these risks was significantly increased if the child consumed more than [2 grams per day] of gluten at around 2 years of age, which corresponds to approximately 1 slice (35 g) of white bread or 1 portion of cooked pasta (150 g)," the researchers wrote. "The [hazard ratio] increased with subsequent higher gluten intake at the 2-year visit, further supporting the results that higher intakes of gluten were associated with higher risks of celiac disease autoimmunity and celiac disease."
However, Agardh and colleagues also noted limitations of the study, including the lack of information on gluten in food content databases, with variations in different countries. The calculations of gluten content were based on self-reported data.
"Different dietary assessment methods together with differences in methods of estimating gluten content are challenging when comparing results from previous studies," they wrote. "A randomized clinical trial of different amounts of gluten during early childhood in genetically at-risk individuals would be warranted to confirm our findings."
What other factors are at play?
In an accompanying editorial also published in JAMA on August 13, Dr. Maureen Leonard and Dr. Alessio Fasano, specialists at Massachusetts General Hospital's Center for Celiac Research and Treatment, described the results as "intriguing" and advised that more studies are needed to explore the findings.
"However, the amount of gluten ingested during the first 5 years after birth cannot completely explain the increased prevalence of celiac disease," Leonard and Fasano wrote. "Previous work examining the relationship between HLA genetics, gluten consumption, and celiac disease prevalence found no significant relationship between the amount of gluten ingested and the prevalence of celiac disease."
They also noted that celiac prevalence does not correlate with different cultural trends in wheat consumption. Consequently, other factors must be at play, including genetic predisposition, exposure to infectious agents, vitamin D levels, and interaction with pets, they concluded.
"Based on these considerations, there is a fine balance between the possible advantage of reducing the intake of gluten-containing grains in at-risk children to prevent celiac disease and the potential increased risk of chronic health problems by further reducing the whole grain and fiber intake in the Western diet, which is already inadequate," Leonard and Fasano wrote. "Thus, additional studies are needed before a recommendation is made to change the current practice of gluten introduction into a child's diet."
CAP weighs in
The study is likely to increase interest in testing for celiac disease, which is found in an estimated 1% of the population in the U.S., commented Dr. Michael Misialek, speaking on behalf of the College of American Pathologists (CAP) in an interview.
This is the first study to demonstrate that increased intake of gluten in the diet is associated with celiac disease -- and this can be recognized by earlier testing, said Misialek, associate chair of pathology at Newton-Wellesley Hospital in Newton, MA.
"It's going to draw even more attention to the disease and likely result in patients asking their providers: 'Can I be tested? Should I be tested? And how about my kids? Are they at risk and what can we do to get the appropriate diagnosis and intervention?' " he said.
While celiac is often thought of as a childhood disease, it may not be diagnosed until adulthood because symptoms can go unreported and there are many presentations of the disease, he noted. Screening has been problematic because a number of tests are frequently ordered a la carte, without knowledge of what the assays can do or any logic about the sequence of testing.
In addition, physicians who order tests may not interpret the results correctly, Misialek added. CAP offers an algorithm to members to help guide the workup of celiac disease, which the organization acknowledges has been the subject of debate.
Misialek advised that a "pretty firm" diagnosis of celiac can be made based on just two tests on one blood draw. First, a test should be done for total immunoglobulin A (IgA) to rule out IgA deficiency, which can result in false negatives. That should be followed by a test for antitransglutaminase antibodies. If the results are positive, a gastroenterologist then decides whether patients should go on to receive a follow-up endoscopy, the gold standard test for celiac disease; however, an endoscopy is more invasive and requires light sedation.
Not everybody needs an endoscopy -- rather, in a typical clinical scenario, patients may be treated based on the serum tests.
As for other available diagnostic methods, Misialek said that assays for endomysial antibodies can be viewed as second-tier tests and may be overused. He added that genetic HLA haplotype tests should be third-line tests and should not be ordered upfront.
"I definitely have seen it ordered inappropriately and earlier in a workup than it should be," Misialek said.
"While HLA testing is not recommended for routine [celiac disease (CD)] testing due to its low positive predictive value, it may be helpful to rule out CD in a narrowly defined set of clinical circumstances (for example, testing in patients who refuse to discontinue a gluten-free diet) due to its high negative predictive value," CAP has advised its members.
Opportunities for public outreach
With rising public interest in celiac disease, there is room for pathologists to reach out to referring physicians, notably pediatricians, primary care doctors, and gastroenterologists, Misialek said.
"This is one example where pathologists can really leverage opportunities here and make themselves visible, and in doing so help our clinical colleagues and, ultimately, the patients," he explained.
Some people have advocated for mass screening for celiac disease, but such screening may not be cost-effective, he said. Following publication of the TEDDY results, more work is needed to determine which populations should be the focus of screening efforts, such as those with a genetic predisposition for the disease. The U.S. Preventive Services Task Force currently does not recommend screening for asymptomatic individuals.
Those with a family history of celiac disease should ask their healthcare provider, in consultation with pathologists, if testing is appropriate, he said. The diagnostic algorithm CAP developed has value for patients of all ages who might fit the picture of celiac disease, Misialek advised.