Searching for the missing link in coeliac diseaseBMJ 2019; 364 doi: https://doi.org/10.1136/bmj.l696 (Published 13 February 2019) Cite this as: BMJ 2019;364:l696
- 1Department of Paediatrics, Poole Hospital NHS Foundation Trust, Poole, UK
- 2Child Health, Southampton Children’s Hospital, University Hospital Southampton NHS Foundation Trust, Southampton S016 6YD, UK
- Correspondence to: R M Beattie
Since the identification of gluten as the dietary trigger for coeliac disease in the Netherlands after the second world war, people have speculated about a “missing link” that could trigger active disease in genetically predisposed individuals who are exposed to gluten. Genetic predisposition to coeliac disease is conferred by two commonly occurring HLA variants: DQ2 and DQ8.1
Coeliac disease can present at any age. Although a historical peak in incidence occurred among children aged under 2 years, more recent data suggest that the median age of diagnosis is now 5 years (incidence 0.8-1.6/10 000), with another peak in incidence in adults in their 50s (2.3/1000).23
Coeliac disease is diagnosed using a combination of serology and duodenal biopsy.4 Importantly, negative testing for coeliac disease does not rule out the possibility of the disease developing later. Regular screening has a role in groups at high risk, including children with Down’s syndrome or type 1 diabetes, who have a lifetime risk of 5-10%. Serological screening for coeliac disease (IgA and IgA anti-TTG) every two to three years is particularly valuable for children with Down’s syndrome, who may have an erratic bowel habit and communication difficulties. Coeliac disease can adversely affect glycaemic control in children with type 1 diabetes, so early diagnosis reduces the risk of complications of diabetes.
We need to know more about why and when coeliac disease presents, to help to optimise the targeting and timing of screening. In the linked study (doi:10.1136/bmj.231), Kahrs and colleagues report an association between enterovirus infection and later coeliac disease in children positive for the risk variants HLA DQ2 or DQ8.5 Stool samples were tested for enterovirus and adenovirus up to the age of 3 years (and identified in 370/2135 (17%) samples). Children who developed coeliac disease up to the age of 10 were significantly more likely than controls to have had positive stool samples for enterovirus (adjusted odds ratio 1.49, 95% confidence interval 1.07 to 2.06). Greater viral loads in stool samples and longer lasting infections (more than two months) were associated with a higher risk. The authors found no association between adenovirus infection and coeliac disease.
Enterovirus infections are common among children aged under 3 years, causing hand-foot-mouth disease and respiratory and diarrhoeal symptoms. This study shows a weak association between enterovirus infection and later coeliac disease, but we cannot infer causation. The authors postulate that enterovirus infection may disrupt gut mucosa, allowing increased translocation of gluten peptides, and that this might be a triggering event in the development of coeliac disease. Alternative explanations include that a “malabsorbing gut,” with an evolving inflammatory process and reduced local humoral immunity, could be more vulnerable to enterovirus infection compared with controls or that certain HLA phenotypes produce a stronger immune response to enterovirus. This effect has been noted in closely linked risk alleles (HLA DR3 and DR4) for type 1 diabetes.6
Some of these authors have previously identified earlier, more latent signs of coeliac disease, such as impaired growth. In a cohort study of 440 children diagnosed as having coeliac disease at a mean age of 4.4 years, retrospective analysis of their heights from 12 months showed significantly lower z scores compared with controls.7 They have also reported that intercurrent infections are very common in this age group, but only 0.8% go on to develop coeliac disease, and that those with more than 10 infections before 18 months have a higher risk of disease than those with fewer than four.8 These associations could suggest firstly that a substantial latent period exists between the environmental trigger and clinical disease and secondly that a stronger stimulation of the immune system could be more likely to provoke an autoimmune condition. Further work is needed to understand whether these findings are clinically meaningful.
HLA DQ2 or DQ8 variants occur in 30-40% of northern Europeans, but only 3% of people with this genotype will go onto develop coeliac disease.9 The identification of infective or other triggers in genetically susceptible people would be of interest but requires prospective screening of multiple clinical and laboratory variables in a large cohort on a normal diet, along with serial testing for coeliac disease. This could potentially enable better stratification of high risk groups and help to inform the optimal timing and frequency of screening. Furthermore, early diagnosis of this chronic condition is important to reduce the risk of long term sequelae.
Until then, we should continue to have a low threshold for testing for coeliac disease, particularly in high risk groups. Repeat testing should be considered in patients with persistent symptoms.
Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: RMB declares expenses (for attending meetings) from Nutricia and Abbvie that are unrelated to the topic of this editorial. Further details of The BMJ policy on financial interests is here https://www.bmj.com/sites/default/files/attachments/resources/2016/03/16-current-bmj-education-coi-form.pdf
Provenance: Commissioned; not peer reviewed.