High gluten intake during the first 5 years of life was a statistically significant, independent risk factor for both celiac disease (CD) autoimmunity and CD in genetically predisposed children, according to TEDDY study results published in JAMA.1

CD is a chronic, autoimmune disorder of the digestive system that is triggered by the ingestion of gluten in genetically predisposed individuals.2,3 Attention to the gluten-consumption component of the disease has been increasing in recent years as diagnoses for gluten sensitivity and CD have been rising.2,3  According to the Celiac Disease Foundation, roughly 1 in 100 people worldwide are estimated to have the disease and approximately 200 million may not be aware that they have it. If left undiagnosed, these people may face a lifetime of health complications as a result.

The diagnosis of CD relies on clinical features, as well as serologic and histologic findings.3,4,5 Clinical presentations describing CD include “Typical,” “Atypical,” “Silent,” and “Potential” forms. 3,4 Typical CD presents with malabsorption-related manifestations consisting of gastrointestinal symptoms; atypical CD is predominantly characterized by extra intestinal symptoms.3,4 Silent CD describes the disease in asymptomatic patients with positive blood serology and characteristic intestinal inflammation on biopsy; potential CD refers to a disease subtype in which individuals with positive blood serology may or may not have symptoms, but show no apparent intestinal inflammation on biopsy. 3,4

Although the typical presentation was most prevalent in the early and mid-20th century, there appears to have been a dramatic shift in subtype diagnosis from the 1980s onward, accompanied by a shift from classical gastrointestinal symptoms to higher rates of atypical and asymptomatic presentations.5 This phenomenon of under-diagnosis is likely due to a combination of lack of awareness and a high prevalence of asymptomatic patients.


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CD and gluten sensitivity have no cure. Like most multifactorial disorders, CD is the result of a complex interaction between genes, the immune status of the host, and environmental triggers and can cause more than 200 symptoms. 2,3 The most common symptoms include abdominal pain and bloating, diarrhea and vomiting, constipation, pale stool, fatigue, and weight loss. Presentation also seems to vary between sexes and ages, with females typically diagnosed at a younger age and presenting more frequently with constipation, bloating, and iron deficiency anemia.3 Furthermore, because no biomarkers for gluten sensitivity have yet been identified, the disease can only be diagnosed through a process of elimination under the supervision of a physician or registered dietitian. The only treatment for CD is strict adherence to a gluten-free diet (GFD), in which patients must consume only foods and drinks with a gluten content of less than 20 parts per million. 3,4

CD commonly presents during early childhood, which highlights the importance of studying early life events to identify triggers of the disease.2,4,5 Children who have CD and are undiagnosed could develop a condition called failure to thrive. Whether the amount of dietary gluten consumed in early life contributes to the risk of developing CD is unclear. The notion that gluten consumed in adolescence may increase CD risk is supported by an unusual epidemic in Sweden that took place from 1984 to 1996.6 This phenomenon occurred partly due to changes in national dietary recommendations and to the content of commercial baby food. 7

In a new prospective, international study, researchers examined this possible association in 6605 children carrying human leukocyte antigens (HLA) genotypes associated with CD, followed from birth until the age of 5, in Sweden, Finland, Germany, and the United States.1 Using food records, Aronsson and colleagues recorded each child’s gluten intake over a 3-day span at 6, 9, and 12 months and bi-annually until age 5 years and screened for CD (via serum sampling for tissue transglutaminase autoantibodies) at age 2 years and annually until age 5 years ( 49% were female; median follow-up, 9 years). 1

Of the 6605 genetically predisposed children with food records, 1216 (18%) had developed CD autoimmunity and 447 (7%) developed CD. 1 What’s more, for every gram of gluten ingested per day (1g/d), the risk for developing the condition increased. The researchers found that a higher gluten intake was associated with a 6.1% increased risk for CD autoimmunity and a 7.2% increased risk for CD for each additional gram above the average gluten intake per day. 1 Generally, the peak age for each outcome was between 2 and 3 years. 1

In another analysis, gluten intake per 10 kg of body weight was also tied to autoimmunity, with every 1g/d/10 kg increase in consumption carrying a hazard ratio  (HR) of 1.87 (95% CI, 1.66-2.11; P <.001).1 Absolute risk by age 3 if the reference amount was consumed was 51.9%, rising to 70.2% if 1g/d/10 kg more was consumed (absolute risk difference 18.3%; 95% CI, 16.7-19.9). 1

For CD, gluten intake per 10 kg of body weight was similarly associated with an elevated risk. For every 1g/d/10 kg increase, the HR was 2.18 (95% CI, 1.75-2.71; P <.001).1 Absolute risk by age 3 was 35% at the reference amount, rising to 55% at 1g/d/10 kg higher, for an absolute risk difference of 20% (95% CI, 19.0-21.0).1 The increase in risk was noticeable even with small amounts of gluten — a daily intake of 2 g — or the equivalent of 1 slice of white bread. The association was evident in all participating countries except Germany, where there was insufficient data to draw any definitive conclusions. 1

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Study limitations include the fact that information on analyzed gluten content in foods in national food composition databases is lacking. Also, calculations of gluten content were approximate because they were based on self-reported dietary data. In addition, dietary assessment methods and differences in methods of estimating gluten content posed challenges when comparing results from previous studies.6 Furthermore, the results of the study do not apply to children at large, only children with an HLA genotype.

While the results of the TEDDY study are impressive, the new study is observational and therefore does not prove causation. Moreover, the results cannot be used to create guidelines for how all children are fed because the majority of the group who have increased risk of CD do not develop the disease. Therefore, additional factors must contribute to the prevalence of CD.

However, it is the most comprehensive study of its kind to date and should inspire larger studies. More information is required to understand the potential advantage of reducing the intake of gluten-rich grains in at-risk children and the potential risk for chronic health problems by the reduction of whole grains and fiber in the Western diet before any dietary changes to gluten introduction can be made. Future studies should also include randomized clinical trials to assess the effects of different intakes during early childhood in genetically at-risk children, whether removing gluten from the diet reduces the risk of developing CD, as well as how strictly gluten needs to be removed from the diet and for how long.

Disclosures: Dr. Koletzko reported being a member of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition guideline for celiac disease and a member of the PreventCD consortium. Please see original references for a full list of authors’ disclosures.

References

  1. Aronsson CA, Hye-Seung L, Hard af Segerstad EM, et al. Association of gluten intake during the first 5 years of life with incidence of celiac disease autoimmunity and celiac disease among children at increased risk. JAMA. 2019; 322(6):514-523.
  2. Popp A, Maki M. Changing pattern of childhood celiac disease epidemiology: contributing factors. Front. Pediatr. 2019;7:357.
  3. Hujoel IA, Reilly NR, Rubio-Tapia A. Celiac disease clinical features and diagnosis. Gastroenterol Clin N Am. 2019;48(1):19-37.
  4. Myleus A, Reilly NR, Green PHR. Rate, risk factors, and outcomes of nonadherence in pediatric patients with celiac disease: a systematic review [published online June 4, 2019]. Clinc Gastroenterol Hepatol. doi:10.1016/j.cgh.2019.05.046
  5. Guandalini S. The approach to celiac disease in children. Int J Pediatr Adol Med. 2017;4(3):124-127.
  6. Ivarsson A, Hernell O, Stenlund H, Persson LA. Breast-feeding protects against celiac disease. Am J of Clinc Nut. 2002;75(5):914-921.
  7. Ivarsson A. The Swedish epidemic of coeliac disease explored using an epidemiological approach-some lessons to be learnt.Best Pract Res Clin Gastroenterol. 2005;19(3):425-440.