Revising paediatric diagnostic criteria
Alex Gazzola reports on a conference in February 2012 to discuss the new European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) criteria.

Doctor Huw Jenkins, Consultant Paediatric Gastroenterologist at the University Hospital of Wales, Cardiff, and a member of the British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) Coeliac Disease Working Group, opened the discussion with an explanation of ESPGHAN’s newly revised criteria for the diagnosis of coeliac disease in children.

First, he provided background. The first set of ESPGHAN guidelines were published in 1970, and recommended three small intestinal biopsies: the first to look for signs of villous atrophy in the small intestine; the second, conducted after a period on the gluten-free diet (GFD) to confirm improvement; the third, conducted after reintroduction of gluten into the diet, to confirm the return of villous atrophy following the gluten challenge period. Needless to say, this was an extremely distressing process for both gastroenterologists, child patients and parents.

Revised guidelines were established in 1990, during a time when anti-gliadin antibody testing became available and amendments were felt necessary. With these, the 1970 guideline of three biopsies was in effect retained for children under the age of two, but for older children, only a single intestinal biopsy showing villous atrophy was deemed necessary for diagnosis.

Since then, in the last six or seven years, various guidelines from bodies such as BSPGHAN, NASPGHAN (its North American counterpart) and NICE have kept the biopsy at the core of diagnosis of coeliac disease in children. But due to the more recent strides which have been made in our knowledge of coeliac disease, new guidelines reflecting advances in blood antibody testing were felt necessary. This was additionally prompted by surveys of specialists which revealed that many were no longer adhering to 1990 guidelines. “Gastroenterologists were voting with their feet,” noted Jenkins.

Underpinning some of the changes is a new definition of coeliac disease as “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 key change, and the source of most controversy, explained Jenkins, is in the contention that not all children with symptoms and high antibody levels require a biopsy for diagnosis.

Rather than divide children into two groups dependent on age – ie above two, and under – the new recommendation is to divide them according to the presence or not of symptoms. Central to both are levels of IgA antibodies to tissue transglutaminase type 2 (tTG2), or IgG antibodies if the patient has IgA deficiency.

As far as symptomatic children go, any with symptoms of diarrhoea, constipation, failure to thrive and iron deficiency, for instance, should be tested, and according to these guidelines:

* If anti-tTG2 levels are normal, coeliac disease is unlikely, but should there be a strong clinical suspicion, the patient should be biopsied.
* If anti-tTG2 levels are under ten times the upper limit of normal (ULN), then a biopsy should be performed.
* If anti-tTG2 levels are over ten times the ULN, and the patient tests positive for both EMA (endomysial antibodies) and for the genes associated with coeliac disease (HLA-DQ2 or 8) – then there is no need to biopsy and coeliac disease can be diagnosed.

With regards to asymptomatic children, those who have a higher risk of coeliac disease – because they have type 1 diabetes, Down’s Syndrome, Turner’s Syndrome, or first-degree relatives with coeliac disease, for instance – should also be tested.

* All asymptomatic children should be first offered a HLA-DQ2/8 test – a negative result almost certainly excludes the possibility of coeliac disease.
* If positive, anti-tTG2 levels should be measured, and if these are over three times the ULN, then a biopsy should be performed.
* If anti-tTG2 levels are under three times the ULN, then EMA levels should be measured. If positive – a biopsy should be performed. If negative – the test should be repeated within 3-6 months.

Other recommendations include that blood tests performed using OTC testing kit should always be repeated clinically, that gluten challenges should be abandoned, and that referral to a paediatric gastroenterologist should be mandatory in positive cases.

Jenkins revealed that the new ESPGHAN guidelines had been discussed among members of the BSPGHAN Coeliac Disease Working Group, and despite some initial scepticism, there is now broad agreement. BSPGHAN’s own diagnostic guidelines have been revised, and are currently in draft form.

He did, however, admit to several potential problems. These guidelines are at “loggerheads” with current NICE guidelines for coeliac diagnosis – although the latter are being reviewed this year. There may be scenarios where a biopsy may have to be performed on an asymptomatic sibling of a symptomatic child previously diagnosed without biopsy, and this may be perceived as an ‘injustice’ – “why me but not him?” – which some parents or children may object to. Further, might the differing criteria for children versus adults prove confusing? And might there be implications for paediatric gastroenterology training if fewer biopsies are performed – meaning trainee gastroenterologists are granted fewer opportunities to practise them?

Dr William Egner, Director of the Protein Reference Unit, Northern General Hospital, Sheffield, then took to the stage, and cautioned against the proposed guidelines, which he said were “doomed to failure”. He pointed out that there are 24 different tests for tTG and these vary hugely in performance, and therefore that different tests would not be consistent in placing any one positive patient at the same level above the ULN.

Egner also questioned the logic of having an HLA typing test at the top of the asymptomatic diagnostic algorithm. Given the tests costs around £100, and 30-40% of the population will test positive (only 1 in 30 of which will have or go on to develop coeliac disease), this would not be a cost-effective strategy. EMA testing would be logical for this purpose – as there are very few false positives with this (cheap) serological test.

Following Dr Egner was Professor Julian Walters of Imperial College London, who explained why he felt the new diagnostic criteria should not be considered for adult diagnoses. Biopsies in adults remain vital, he said, because they tell gastroenterologists the extent of the enteropathy: mild enteropathy (Marsh 1) could be attributable to other causes, while extensive (Marsh 3) is more clear cut. While hardly pleasant, the biopsy is certainly not traumatic for an adult as it is for a child – “worse than a visit to the hairdresser, but better than a visit to the dentist” – and maintaining it would avoid future long-term problems related to mistaken diagnoses.

Speaking in defence of the ESPGHAN criteria was Dr Louisa Mearin, of Leiden University Medical Centre, Netherlands. She pointed out that the criteria offered “possibilities” and were not meant to be interpreted as compulsory: they are merely intended to signify that in serologically clear-cut cases, it is possible to diagnose without a biopsy. If gastroenterologists are not comfortable with this, or don’t have all serological / gene tests at their disposal, they can still take biopsies. “Thinking is not forbidden,” she asserted.

There was some dissent from the floor. One delegate warned that potential coeliac patients will be reluctant and perhaps resistant to undergo a biopsy if they become aware that some diagnoses can be made without them. Referrals, according to the criteria, are mandatory, but will GPs adhere to these or will they make coeliac diagnoses themselves? Doctors now have a further point of care antibody test in the anti-deamidated gliadin peptide (anti-dGp) test, which may further exacerbate this problem and increase the numbers of diagnoses at primary level. Community dietetics may not be ready to deal with sudden steep increases, and many patients will not receive the benefit of tertiary care at specialist gastroenterology clinics.

In response, Dr Mearin admitted there were risks involved, but that coeliac disease remains hugely under-recognised and under-diagnosed, and that the new criteria may go some way towards rectifying both.

The revised guidance has not yet been adopted. Coeliac UK have said it will require careful consideration by professional and NHS bodies to ensure coeliac diagnosis remains a rigorous process.

First published in March 2012

Coeliac Disease: What you need to know by Alex Gazzola, is now out.


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