Approach

Coeliac disease can present in many varied ways and requires a high degree of clinical suspicion.

Presenting features

Patients with unexplained gastrointestinal symptoms (including those diagnosed with irritable bowel syndrome and/or dyspepsia), chronic diarrhoea, unexplained iron deficiency anaemia, or a skin rash consistent with dermatitis herpetiformis should be tested for coeliac disease.[37][38][39]

Other situations that may prompt testing include failure to thrive, short stature, vitamin deficiency (B12, D, or folate), recurrent severe aphthous stomatitis, recurrent spontaneous abortion, and infertility.[40]

Investigations

Before testing, it is crucial to ensure that the patient is ingesting gluten, because all diagnostic tests will normalise on a gluten-free diet.

1. Serology

  • Immunoglobulin A-tissue transglutaminase (IgA-tTG) titre should be evaluated.[41][42] Although not supported by evidence, quantitative IgA is often routinely requested to assess for IgA deficiency.

  • Endomysial antibody (EMA) is a more expensive alternative to IgA-tTG, with greater specificity but lower sensitivity, which may be used if IgA-tTG is unavailable.[43] Unlike tTG, which is an enzyme-linked immunosorbent assay, EMA is based on immunofluorescence and thus is operator dependent.

  • In patients with IgA deficiency, request IgG-deamidated gliadin peptide (DGP) serology, although the diagnostic accuracy of this test is somewhat less than that of IgA-tTG.[42][44] Patients with an elevated IgA-tTG level should be advised to remain on a gluten-containing diet and referred for duodenal biopsy. It is also reasonable to proceed to duodenal biopsy in patients with IgA deficiency. IgG-tTG was previously one of the common serological tests for coeliac disease in individuals with known or suspected IgA deficiency. However, this test has been largely replaced by the newer and more accurate IgG DGP or IgA/IgG DGP.

  • A normal IgA-tTG and total IgA test result are adequate to exclude a diagnosis in patients with a low clinical index of suspicion for coeliac disease.

2. Histology

  • Patients with an elevated IgA-tTG level should be advised to remain on a gluten-containing diet and referred for duodenal biopsy.

  • Small intestinal biopsies should be obtained regardless of the IgA-tTG result in patients with a high clinical index of suspicion, since 2% of patients with coeliac disease may not have circulating tTG at the time of diagnosis (seronegative coeliac disease).[45]

  • Paediatric patients with symptoms consistent with coeliac disease and a high IgA-tTG titre (above 10 times normal range for laboratory) may go on to have confirmatory EMA testing. If EMA is positive, coeliac disease may be diagnosed without a small intestinal biopsy.[46]

  • Some experts advise that adult patients with very high IgA-tTG titres (above 10 times normal range for laboratory), and positive EMA in a second blood sample, may be diagnosed without duodenal biopsy.[47]

  • Duodenal biopsy changes in coeliac disease are typically graded by the Marsh classification, from 0 to 4.[48] To diagnose coeliac disease, intra-epithelial lymphocytes should be increased and the villous-to-crypt ratio decreased. The presence of only one of these changes raises the possibility of a different diagnosis.com.bmj.content.model.Caption@6e97972c[Figure caption and citation for the preceding image starts]: Histological image of small intestinal villous atrophy and crypt hyperplasiaFrom the personal collection of DA Leffler; used with permission [Citation ends].

  • The presence of typical coeliac changes on duodenal histology with clinical improvement on a gluten-free diet confirms the diagnosis. A repeat duodenal biopsy after gluten withdrawal is no longer routinely necessary for verification.com.bmj.content.model.Caption@348dabc8[Figure caption and citation for the preceding image starts]: Histological image of small intestinal villi showing resolution of intestinal injury on gluten-free dietFrom the personal collection of DA Leffler; used with permission [Citation ends].com.bmj.content.model.Caption@736ef692[Figure caption and citation for the preceding image starts]: Photograph of small intestinal villi affected by coeliac diseaseFrom the personal collection of DA Leffler; used with permission [Citation ends].com.bmj.content.model.Caption@1df24be1[Figure caption and citation for the preceding image starts]: Photograph of normal small intestinal villiFrom the personal collection of DA Leffler; used with permission [Citation ends].com.bmj.content.model.Caption@4f8e9184[Figure caption and citation for the preceding image starts]: Capsule endoscopy pictures of ulcerative jejunitis in a patient with coeliac diseaseFrom the personal collection of CP Kelly; used with permission [Citation ends].

3. Human leukocyte antigen (HLA) typing

  • May be used to rule out coeliac disease in patients already on a gluten-free diet or in patients with an idiopathic coeliac-like enteropathy, but is not helpful for diagnosis.

  • HLA typing may be used as a first-line screening test to rule out coeliac disease among first-degree relatives.[23] However, the availability and cost of this test may be prohibitive.

4. Endoscopy

  • Atrophy and scalloping of mucosal folds; nodularity and mosaic pattern of mucosa may be seen, but these findings are not sensitive for coeliac disease diagnosis.com.bmj.content.model.Caption@1604a056[Figure caption and citation for the preceding image starts]: Scalloping of the duodenal mucosa in a patient with coeliac diseaseFrom the personal collection of DA Leffler; used with permission [Citation ends].com.bmj.content.model.Caption@12da1e62[Figure caption and citation for the preceding image starts]: Scalloping of the duodenal mucosa in a patient with coeliac diseaseFrom the personal collection of DA Leffler; used with permission [Citation ends].

Gluten challenge

People with coeliac disease on a gluten-free diet prior to evaluation cannot be differentiated from healthy controls. In these patients, gluten challenge is necessary. In a gluten challenge, the person is placed back on a gluten-containing diet, containing 3 to 10 grams of gluten per day (2-5 slices of wheat bread), with serological tests and small bowel histology assessed after 2 to 8 weeks on the gluten-containing diet.[49]

Commercial kits

Patients who have used a home-testing kit, or are considering using one, should be counselled to discuss their symptoms with their healthcare professional, irrespective of the test outcome.

Commercially available tests for the assessment of individual risk for coeliac disease detect the presence of HLA-DQ2 and HLA-DQ8 genes in saliva.[50] However, UK guidelines recommend against HLA-DQ2 and HLA-DQ8 testing in the initial diagnosis of coeliac disease in non‑specialist settings.[51]

Healthcare professionals should be aware that patients who test positive for tTG antibodies using self-administered blood tests (finger-prick tests) may begin a gluten-free diet before being evaluated by their healthcare professional.[52]

Tests for detection of tTG antibodies in saliva are being investigated, but there is insufficient evidence to recommend their use.[23]

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