For many decades, we have known that genetics play a key role in the development of celiac disease. Last month, a new study expanded this research by studying several different factors that may be associated with a child’s risk of developing celiac disease. Along with genetics, these researchers found that the child’s sex and country of residence were all associated with celiac disease prevalence.
Within this study, 6,403 children who carried at least one copy of a celiac disease risk gene were screened for celiac disease using tTG IgA antibody blood testing. By age 5, a total of 786 children became positive for tTG antibodies after testing started at age 2.
Of children born with 2 copies of the highest-risk gene (HLA-DQ2) inherited from both parents, 26% developed persistent tTG antibodies by age 5. Of those with a single copy of DQ2, 11% developed persistent tTG antibodies by age 5.
In this study, it was noted that Swedish children had a 2-fold higher risk for developing celiac disease over their U.S. counterparts, suggesting that environmental factors may be triggering the onset of celiac disease in a genetically at-risk child.
Differences in infant feeding practices and childhood infections were noted by the researchers as potential interactions, and areas for possible future research. Published in the highly prestigious New England Journal of Medicine, this study helps to better define who is at risk for celiac disease, and is a step in the right direction for better screening recommendations and earlier diagnoses of celiac disease in children.
Dr. Edwin Liu was the lead researcher in this study. He is a pediatric gastroenterologist, and is also the director of the Colorado Center for Celiac Disease at Children's Hospital Colorado. He is the co-chair of the celiac disease committee in The Environmental Determinants of Diabetes in the Young (TEDDY) study – the multicenter NIH study that published these findings. NFCA was interested to learn what Dr. Liu had to say about these findings, and we thought you would be too. Read on for our Q&A with this celiac disease expert.
What are the implications of this study for celiac disease screening guidelines? Are there any specific implications on HLA typing for the pediatric population, at-risk family members, and the general population?
Dr. Liu: All of these children in the study had a genetic predisposition for celiac disease based on their HLA. When they were screened for tTG antibodies, many developed celiac disease even before the recommended age of screening, at age 3 years. Therefore, screening even earlier for celiac disease in children at risk could lead an earlier diagnosis, thereby possibly reducing morbidity.
When extending this to the general population, 40% of the general population has genes that already place them at risk for celiac disease (HLA-DQ2 or DQ8). However, in those screened for celiac disease due to a genetic predisposition, many diagnosed with celiac disease will not have recognizable symptoms at the time of diagnosis. Therefore, the utility of early childhood screening might be debated, and the costs vs benefits of such screening will have to be analyzed.
Can you expand upon the difference between celiac disease autoimmunity versus celiac disease and define each? How soon should those with celiac disease autoimmunity receive follow-up testing?
Dr. Liu: According to the Oslo definitions for celiac disease published in January 2013, celiac disease autoimmunity is defined as increased tTG or EMA on at least two occasions when the status of the biopsy is not known. For our study, celiac disease autoimmunity was simply defined as having positive tTG on two consecutive measurements at least 3 months apart, regardless of biopsy findings. Although not everyone who develops tTG antibodies will actually go on to develop celiac disease (defined as having an abnormal intestinal biopsy showing villous atrophy), we believe that the actual development of such autoimmunity is a significant immunologic process that signifies an early stage in the development of celiac disease.
In someone with celiac disease autoimmunity, the decision is often related to if/when that individual should get a biopsy to confirm celiac disease. I believe that since the appearance tTG antibodies is one of the early stages of celiac disease, performing a biopsy too early may lead to a “false positive” tTG test, meaning that the actual intestinal lesion may lag behind the appearance of the antibodies. Typically, higher and more persistent antibodies will be more predictive of finding intestinal lesions on biopsy, particularly in someone without symptoms.
After blood tests came back positive for tTG antibodies, children who underwent biopsy had to have a Marsh score of 2 or higher to be diagnosed with celiac disease. Can you explain what it means to have this score, and why a Marsh score of 2 was chosen as the minimum for diagnosis?
Dr. Liu: A Marsh score of 0 is considered normal. The earliest histologic findings of celiac disease are the appearance of immune cells (lymphocytes) that start to invade the surface of the intestinal villi. This is considered Marsh 1. However, this finding tends to be less specific for celiac disease, as opposed to actually seeing architectural changes on the biopsy, indicating Marsh 2 or Marsh 3 lesions.
Why did you choose to begin testing for celiac disease autoimmunity at 24 months? Is there a reason this wasn’t tested for earlier in the child’s life?
Dr. Liu: There were logistical reasons for not starting testing at 24 months, namely the availability of valuable serum in young infants. Serum in these children are required to also measure islet autoantibodies for type 1 diabetes, in addition to future testing for other related conditions and/or factors involved in triggering autoimmunity. However, in children who were found to be already tTG positive at the first measurement at 24 months, we used the stored serum that was collected every 3 months from birth to determine the earliest time point at which celiac disease autoimmunity started. This type of precision may be necessary when trying to determine triggers for autoimmunity, such as viral infections or other significant early childhood events.
Due to the fact that only 27% of children with celiac disease autoimmunity experienced celiac disease-related symptoms, what might prompt doctors to pay more attention to the other risk factors outlined in this study?
Dr. Liu: Well, the main risk factor for developing celiac disease is basically having HLA-DQ2 or DQ8, so if we knew that someone had one of these genes, then that in itself should prompt periodic screening. As per NASPGHAN guidelines from 2005, screening should take place in children with a genetic risk – which includes those with family members having celiac disease, those with type 1 diabetes, and those with autoimmune thyroid disease, to name a few.
Otherwise, it is now understood that symptoms in itself cannot be used as a criteria to screen for celiac disease. Therefore, knowing who has a genetic risk, and also having a high index of suspicion is still the best way to avoid missing a child with celiac disease.
You screened newborns who were at risk for both type 1 diabetes and celiac disease because they carried the risk haplotype DQ2 or DQ8. Can you describe the current state of screening those with type 1 diabetes for celiac disease?
Dr. Liu: This is a great question that I have been thinking about for a while. We know a lot about the incidence of celiac disease in those who have developed type 1 diabetes (about 10%). However, the development of type 1 diabetes in those with celiac disease (the reverse) is much less common. I believe that the reason for this is related to the specific HLAs that predispose to celiac disease versus type 1 diabetes. Even though DQ2 and DQ8 are both high-risk genes for these conditions, in actuality, DQ2 is the major risk gene for celiac disease, whereas having both DQ2 and DQ8 is the major risk gene for early onset type 1 diabetes. Therefore, those with type 1 diabetes in childhood tend to have also the DQ2 which may lead to the subsequent discovery/diagnosis of celiac disease. In other words, the highest-risk gene combinations for type 1 diabetes are very permissive for celiac disease, while the highest risk gene combinations for celiac disease are just not as permissive for diabetes. At present, there are no recommendations to screen for type 1 diabetes in those with celiac disease. However, as we start to diagnose celiac disease earlier, there may be a select group of children (i.e. those with both DQ2 and DQ8) who will be at higher risk for diabetes and may at least need counselling for the potential development of diabetes.
Your study examines HLA gene combinations of participants, focusing on differences in risk of developing celiac disease between homozygosity and heterozygosity. Can you explain the difference between homozygosity and heterozygosity?
Dr. Liu: Homozygosity indicates that a child has inherited 2 copies of the same gene, one from each parent. For example, a child that is DQ2 homozygous has 2 copies of DQ2. A child that is heterozygous has only inherited one copy of DQ2.
Children who had two copies of the DR3-DQ2 gene were at the highest risk of developing both celiac disease autoimmunity (26%) and celiac disease (11%), while children with DR4-DQ8/DR8-DQ4, DR3-DQ2/DR4-DQ8, or homozygous DR4-DQ8 gene combinations, had a much lower risk of developing celiac disease autoimmunity. Can you explain why there seems to be a greatly increased risk for celiac disease autoimmunity and celiac disease in children with two copies of DR3-DQ2 as opposed to the other HLA combinations?
Dr. Liu: DQ2 molecules play an important role in interacting with specific gluten proteins, and then stimulating the immune system. Basically, the more DQ2 you have, the more you will be able to stimulate the immune system and potentially activate celiac disease.
Living in Sweden nearly doubled the risk of a child developing celiac disease as compared to those living in the United States. Can you expand upon the celiac disease prevalence differences between countries and the reasons this may have occurred?
Dr. Liu: There was a well-characterized epidemic of celiac disease in young children in the mid 80’s that was believed to be related to the way Swedish infants were introduced gluten in relation to breast feeding. The incidence decreased after national changes were made in feeding practices in the mid-90’s. We speculate that the incidence in Sweden is still higher possibly due still to the way infants are being fed in Sweden. However, we are looking at other differences between countries, such as antibiotic use, frequency of infections, and many other factors. Finally, there may be a gene that is of higher frequency in Swedes that may also influence risk.
You also found that girls had a higher risk of developing celiac disease than boys. Can you explain why this might have occurred?
Dr. Liu: This has been a consistent trend observed in Europe, but is starting to be recognized in the US. We don’t understand why females have a higher risk of celiac disease, other than the fact that autoimmunity tends to be more common in females over males.
Are there any other study findings or implications you want to highlight?
Dr. Liu: It should be once again cautioned that not everyone that develops tTG antibodies will go on to develop celiac disease, particularly when we use a highly sensitive antibody assay (such as the one used in our study). The development of celiac disease autoimmunity is just the first step towards celiac disease – in some, the antibodies may resolve, some may come and go, and many especially with higher levels will proceed to develop biopsy-proven celiac disease. This is the nature of such long-term prospective birth cohort studies, and allows us to best understand the natural history of the development of childhood celiac disease.
Liu, E., Lee, H. S., Aronsson, C. A., Hagopian, W. A., Koletzko, S., Rewers, M. J., ... & Agardh, D. (2014). Risk of Pediatric Celiac Disease According to HLA Haplotype and Country. New England Journal of Medicine, 371(1), 42-49.