BMJ  2004;328:322-323 (7 February), doi:10.1136/bmj.328.7435.322

Paper

Undiagnosed coeliac disease at age seven: population based prospective birth cohort study

¹ Division of Medicine, University of Bristol, Southmead Hospital, Bristol BS10 5NB, ² Department of Immunology, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, ³ Unit of Paediatric and Perinatal Epidemiology, Division of Child Health, University of Bristol, Bristol BS8 1TQ

Introduction

Coeliac disease is uncommon in childhood and diagnosed in fewer than 1 in 2500 children in the United Kingdom.¹ Subclinical disease is, however, common in adults, and can be detected by testing for serum IgA antiendomysial antibodies (IgA-EMA).² We aimed to establish the prevalence of undiagnosed coeliac disease in the general population at age seven, and to look for associated clinical features.

Participants, methods, and results

We studied children aged 7.5 years participating in the Avon Longitudinal Study of Parents and Children (ALSPAC), a population based birth cohort study established in 1990.³ Two stage screening included a sensitive initial radioimmunoassay for antibodies to tissue transglutaminase (endomysial antigen) with further testing of positive samples for IgA-EMA by indirect immunofluorescence.⁴ Children with tTG antibodies below the 97.5th centile were defined as antibody negative. Height, weight, and haemoglobin levels were measured at dedicated study clinics. Details of gastrointestinal symptoms and special diets were collected by routine questionnaire at age 6.75 years.

Of 5470 children tested, 54 tested positive for IgA-EMA (1.0%; 95% confidence interval 0.8 to 1.4). IgA-EMA were more common in girls (odds ratio 2.12; 1.20 to 3.75). IgA-EMA positive children were shorter and weighed less than those who tested negative for tTG antibody (P < 0.0001 for all comparisons). 4324 (79%) returned questionnaires, and 50% of IgA-EMA positive children reported diarrhoea compared with 34% of tTG antibody negative (odds ratio 1.96; 1.06 to 3.59). Only one IgA-EMA positive child had consulted a doctor about diarrhoea. There was no overall difference in the number of episodes of diarrhoea. Vomiting, abdominal pain, and constipation were not associated with EMA, but more IgA-EMA positive children reported multiple symptoms. Only four children (0.09%; 0.1 to 0.32) were on a gluten-free diet. Of these, three were tTG antibody negative, consistent with effective treatment, and one was IgA-EMA positive (table).

View this table: [in this window] [in a new window]   Coeliac antibody status and height, weight, haemoglobin concentration, and gastrointestinal symptoms. An additional 137 children were tTG antibody positive but IgA-EMA negative

 

Comment

At age 7, 1% of children were IgA-EMA positive and likely therefore to have subclinical coeliac disease, though less than 0.1% were reported to be on a gluten-free diet. The prevalence of coeliac disease in these children is therefore comparable to that in UK adults.⁵ The benefit of early diagnosis of subclinical coeliac disease remains unproven, but long term follow up of this cohort may help to resolve this. If screening is worth while, it should be started in childhood.

Since ALSPAC is an observational study based on analysis of anonymous samples,³ confirmatory biopsy was not possible. IgA-EMA have however repeatedly been shown to have high sensitivity and specificity for coeliac disease, and in a recent general population study the combination of IgA-EMA and tTG antibodies that we used was associated with diagnostic histological changes in 83% of those subsequently biopsied, with abnormal intestinal / T-lymphocyte density in a further 12%.² Our strategy may even miss some affected children, as individuals with high levels of tTG antibodies without IgA-EMA may have coeliac disease.²

Reported clinical features were similar to those in adults with coeliac disease identified by screening. Gastrointestinal symptoms were not prominent, and the excess in girls mirrors that seen in affected adults. The most striking observation was that children with IgA-EMA were shorter by more than 0.76 standard deviation scores and lighter by 0.54 standard deviation scores than antibody negative children matched for date and place of birth. This equates to about 9 months' growth and weight gain in an average child around this age. These features were independent of gastrointestinal symptoms and anaemia and presumably unrelated to malabsorption.

Occult coeliac disease seems to start in childhood, even in those who are subsequently diagnosed as adults. The search for the trigger resulting in the breakdown of immune tolerance to gluten therefore needs to focus on infancy and intrauterine life.

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We thank the children and their families taking part in the study for their continuing support and the midwives for their cooperation and help in recruitment. The ALSPAC study team comprised interviewers, computer technicians, clerical workers, research scientists, volunteers, and managers who continue to make the study possible.

Contributors: PJB, DJU, and AJKW designed the study with members of the ALSPAC study team. AJKW, RJL, and AJN developed and completed all antibody assays. RWJ coordinated the collection of biological samples and supervised handling of the samples. PJB analysed and interpreted the data with help from ARN. PJB wrote the report with help from the other authors. PJB is guarantor.

Funding: Coeliac UK, Medical Research Council, Wellcome Trust, UK government departments, and various charitable organisations and commercial companies. ALSPAC is part of the WHO initiated European Longitudinal Study of Pregnancy and Childhood.

Competing interests: None declared.

Ethical approval: ALSPAC ethics and law committee and local ethical research committees.

References

1. Hawkes ND, Swift GL, Smith PM, Jenkins HR. Incidence and presentation of coeliac disease in South Glamorgan. Eur J Gastroenterol Hepatol 2000;12: 345-9.[Medline]
2. Maki M, Mustalahti K, Kokkonen J, Kulmala P, Haapalahti M, Karttunen T, et al. Prevalence of celiac disease among children in Finland. N Engl J Med 2003;348: 2517-24.[Abstract/Free Full Text]
3. Golding J, Pembrey M, Jones R, ALSPAC study team. ALSPAC: the Avon longitudinal study of parents and children. I. Study methodology. Paediatr Perinat Epidemiol 2001;15: 74-87.[CrossRef][ISI][Medline]
4. Bazzigaluppi E, Lampasona V, Barera G, Venerando A, Bianchi C, Chiumello G, et al. Comparison of tissue transglutaminase-specific antibody assays with established antibody measurements for coeliac disease. J Autoimmun 1999;12: 51-6.[CrossRef][ISI][Medline]
5. West J, Logan RF, Hill PG, Lloyd A, Lewis S, Hubbard R, et al. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut 2003;52: 960-5.[Abstract/Free Full Text]

(Accepted 11 September 2003)

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