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Diagnosing coeliac disease
  1. H R Jenkins1,
  2. S H Murch2,
  3. R M Beattie3,
  4. Coeliac Disease Working Group of British Society of Paediatric Gastroenterology, Hepatology and Nutrition
  1. 1Department of Child Health, University Hospital of Wales, Cardiff, UK
  2. 2Department of Child Health, Warwick Medical School, Warwick, UK
  3. 3Department of Child Health, Southampton General Hospital, Southampton, UK
  1. Correspondence to Dr Huw R Jenkins, Department of Child Health, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK; huw.jenkins2{at}

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Guidelines from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) for diagnosis and treatment of coeliac disease (CD) have not been revisited for 20 years. During this time, the perception of CD has changed from a rather uncommon enteropathy presenting in childhood, with obvious gastrointestinal symptoms, to a much more common multiorgan disease with a strong genetic predisposition (mainly associated with human leucocyte antigen (HLA)-DQ2 and HLA-DQ8). Previous ESPGHAN diagnostic criteria1 stated that histological confirmation of the typical changes of CD in the small intestine were mandatory for diagnosis and that a gluten challenge, and rebiopsy would need to be performed in those children under the age of 2 years diagnosed as having CD.

Since that time, largely because of the increasing availability of specific serological testing, it has become clear that CD may present with a large variety of non-specific signs and symptoms, rather than a specific gastrointestinal presentation.

In addition, certain individuals are at an increased risk and presymptomatic screening is advised, although individuals who screen negatively may subsequently screen positively. Diagnosis can be made at any age but it is clear that it is important to diagnose CD in children with obvious gastrointestinal symptoms and in children with a less clear clinical picture, as the disease may have negative health consequences in the longer term. Since the previous ESPGHAN criteria, serological tests with high accuracy have become available, as well as other diagnostic tests that, in conjunction with biopsy and response to gluten exclusion, allow a firm diagnosis to be made in the majority of patients.

A working group was established within ESPGHAN in 2007 to formulate new guidelines for the diagnosis of CD, and these have recently been published. They suggest a new definition: ‘an immune-mediated systemic disorder elicited by gluten and related prolamines in genetically susceptible individuals which is characterised by the presence of a variable combination of gluten-dependent clinical manifestations, CD specific antibodies, HLA-DQ2 and HLA-DQ8 haplotypes and enteropathy’.

The guidance puts increased emphasis on serological testing using tissue transglutaminase as the major autoantigen in CD, which led to the wider recognition of the autoimmune nature of the disease.2 This increased knowledge of CD pathogenesis has led to the further development of reliable diagnostic serological tests based on determination of autoantibodies against transglutaminase type 2 (TG2) and endomysial antibodies (EMA). Small bowel biopsies have been considered as the reference standard for the diagnosis of CD but over the last decade, evidence has accumulated on the diagnostic value of specific CD antibodies, as well as the use of HLA typing. The primacy of histology for the diagnosis of CD has been questioned as it is now clear that histological findings are not specific for CD, lesions may be patchy and may occur only in the duodenal bulb, and interpretation of the biopsies depends on the preparation of the tissue and is prone to high interobserver variability.3 Thus, the current diagnosis of CD may depend on the result of small bowel biopsy and on information from clinical and family data and on results from specific CD antibody testing and HLA typing.

The current ESPGHAN working group has produced evidence-based guidelines, statements and recommendations based on careful, critical review of the evidence and a modified Delphi voting procedure.4 These suggest that:

  • Testing for CD should be offered to children and young people with otherwise unexplained gastrointestinal symptoms and signs and, in addition, those children with unexplained poor growth, delayed puberty, iron deficiency anaemia, chronic abdominal pain, constipation, recurrent aphthous stomatitis and abnormal liver biochemistry.

  • There should be testing of asymptomatic individuals known to have an increased risk of CD: that is, patients with type I diabetes mellitus, Down's syndrome, autoimmune thyroid disease, Turner's syndrome, Williams' syndrome, selective IgA deficiency, autoimmune liver disease and first degree relatives with CD.

  • Typing for HLA-DQ2 and HLA-DQ8 can be a useful tool to exclude CD and it is a negative result that is most useful, as this virtually excludes CD.

  • HLA testing should be performed in cases where there is an uncertain diagnosis of CD (eg, cases with negative CD specific antibodies and mild changes on proximal small intestinal biopsy specimens).

  • If CD is considered in children where there is a strong clinical suspicion of CD, highly specific CD antibodies are present and small bowel biopsies are not going to be performed, the recommendation is that HLA-DQ2/HLA-DQ8 typing is required to add strength to the diagnosis.

  • Anti-gliadin antibody testing is no longer recommended, although a further antibody test against anti-deamidated gliadin peptide antibody may provide further specificity in cases of doubt, particularly in children under 2 years of age.

Overall, it is now evident that CD specific antibody measurement is the first tool used to identify individuals for further investigation to diagnose or rule out CD. It is of course vital that CD specific antibody testing is only undertaken in those individuals on an adequate gluten-containing diet. It is also important to test total serum IgA to be able to interpret the IgA anti-TG2 result (as IgA deficiency is more frequent in patients with CD) and, in those individuals with IgA deficiency, IgG TG2 antibodies may be used (although these are less specific). Again, it is the negative test that may be very helpful. It essential that children found positive for CD specific antibodies should be evaluated by a paediatric gastroenterologist or paediatrician with experience in CD, to confirm or exclude CD. The clinical relevance of positive antibodies should be confirmed by histology unless certain conditions are fulfilled which allow the option to omit confirmatory biopsies.

Thus, the recommendation is that in children and young people with signs of symptoms suggestive of CD and very high anti- TTG2 levels exceeding 10 times the upper limit of normal, the likelihood of villous atrophy on a small intestinal biopsy is very high. In this situation, the paediatric gastroenterologist may discuss with the family the option of performing further laboratory testing (EMA, HLA) in order to make the diagnosis of CD without biopsy.

If EMA testing is also positive on a second sample (to exclude possible mislabelling or laboratory error), then the diagnosis of CD can be made and the child started on a gluten-free diet without a biopsy.

The guidelines state it is also necessary to check for HLA typing in patients diagnosed as having CD without biopsy, to reinforce the diagnosis of CD. In the UK, HLA testing is not always widely available and/or cheap (although it is considerably less expensive than endoscopic biopsy under general anaesthetic), and this may have implications for management of such patients in the future.

The guidelines state that for an asymptomatic child in high-risk groups, HLA testing should be offered as a preferred test. The absence of HLA-DQ2 and HLA-DQ8 makes the diagnosis of CD highly unlikely and no further follow-up serological test is needed. This may be of benefit in patients with type 1 diabetes mellitus and other autoimmune disease in whom initial antibody testing is negative; at the current time it is unclear how frequently these individuals' CD antibody status should be retested and it may be that no further testing will be necessary if HLA-DQ2/HLA-DQ8 is absent on initial testing.

We now know that patients with an increased genetic risk for CD may have fluctuating levels of CD specific antibodies and thus, in this group of individuals without classical clinical signs and symptoms, the duodenal biopsy with the demonstration of enteropathy should always be part of the diagnosis of CD. There is increasing use of rapid CD antibody detection kits (available ‘over the counter’) and the recommendation is that a positive test result should always be confirmed by a laboratory-based quantitative test (anti-TG2 levels) and a full diagnostic testing sequence and referral to a paediatric specialist as outlined above prior to starting a gluten-free diet.

The guidelines state that once the diagnosis of CD is made by the above criteria, the child should receive professional dietary counselling for a gluten-free diet and then followed up on a regular basis, looking for symptomatic improvement, as well as normalisation of CD specific antibody tests (generally within 12 months after starting a gluten-free diet). In patients fulfilling the diagnostic criteria for CD, it is unnecessary to perform a small bowel biopsy on a gluten-free diet. Likewise, gluten challenge is not considered necessary except under unusual circumstances (eg, where there is doubt about the initial diagnosis) and this should be discouraged before the age of 5 years and during the pubertal growth spurt.

It is clear that these new guidelines may have considerable implications for the diagnosis of CD in children and young people in the UK. The British Society of Paediatric Gastroenterology, Hepatology and Nutrition recommends that all children with a possible diagnosis of CD should be referred to a paediatric gastroenterologist or a paediatrician with a special interest in CD. In those who have symptoms and signs suggestive of CD, if the anti-TTG antibodies are >10 times normal then the diagnosis of CD may be made without the need for intestinal biopsy (preferably with a confirmatory positive EMA and HLA-DQ2, HLA-DQ8 positivity). For those asymptomatic individuals, the position is less clear and small intestinal biopsy is still necessary as part of the diagnostic investigation. What remains paramount is that starting a gluten-free diet without a firm diagnostic ‘investigation’ is to be discouraged.

These guidelines challenge current UK practice. In particular the proposed ESPGHAN guidelines for children differ from the National Institute of Clinical Excellence (NICE) guidance produced in 20095 but these proposed changes are to be considered by NICE in the planned review of their CD guidelines in 2012. It is clear that their adoption requires careful consideration by paediatricians, adult gastroenterologists, NICE and Government so that there are adequate safeguards to ensure that the diagnosis of CD, for which treatment is lifelong, remains sufficiently robust to best serve our children and young people.


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  • Competing interests None.

  • Provenance and peer review Commissioned; internally peer reviewed.

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