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Interpreting Tests for Coeliac Disease

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Interpreting Tests for Coeliac Disease CLINICAL Interpreting tests for coeliac disease Tips, pitfalls and updates Jason A Tye-Din COELIAC DISEASE is an immune illness, coeliac disease serology, but this is triggered by dietary gluten, that causes a uncommon and excluding other causes of broad range of gastrointestinal and extra- villous atrophy (see below) is important. This article is the second in a series intestinal manifestations.1 Untreated Testing at-risk individuals is strongly on pathology testing. Articles in this disease reduces quality of life, increases recommended to detect cases before series aim to provide information about healthcare use and is associated with substantial morbidity develops.3,6 An emerging laboratory tests that general 2–4 practitioners (GPs) may encounter. substantial morbidity. Mortality is active case-finding approach can improve increased because of lymphoproliferative detection of coeliac disease by more than Background malignancy, sepsis and refractory 40-fold,7 but this only works when doctors Coeliac disease is one of most prevalent disease.3 As 1.5% of Australians have are mindful of the disease. Approximately autoimmune illnesses encountered coeliac disease, it is one of the most 30 at-risk individuals need to be tested in general practice, and GPs have a common autoimmune illnesses that to find a positive case of coeliac disease.7 central role in its diagnosis and follow- up. Key challenges are improving its general practitioners (GPs) will encounter. There is insufficient evidence to support poor rate of detection, distinguishing it However, its broad and often subtle population screening.8 Figure 2 provides from ‘gluten sensitivity’, and monitoring presentation makes detection challenging, an outline of a recommended diagnostic and optimising treatment to enhance and means 80% of Australians with pathway. long-term outcomes. coeliac disease remain undetected.5 As Objective expeditious diagnosis and treatment with When to test for coeliac disease The objective of this article is to review a strict, lifelong gluten-free diet (GFD) the evidence-based use of serology, minimises long-term complications,3 Symptoms and clinical features that histology and genetic testing in the application of the appropriate tests to identify patients who might benefit diagnosis and follow-up care of adults ensure accurate diagnosis and follow-up from testing are shown in Table 1.9 and children with coeliac disease. is crucial. ‘Classical’ symptoms caused by intestinal Discussion inflammation, such as diarrhoea and Recognition and testing of at-risk Making the diagnosis weight loss, are frequent, but the ‘non- patients are keys to expediting classical’, extra-intestinal manifestations the diagnosis of coeliac disease. In clinical practice, suspected patients are even more common. These non- Knowing when and how to use are generally screened with coeliac classical features include lethargy, serology, histology, human leukocyte disease serology. In patients with headaches, osteoporosis, iron deficiency, antigen typing and gluten challenge positive coeliac disease serology, the transaminase elevation, infertility, other will increase the accuracy of both diagnosis and disease monitoring. diagnosis is confirmed by the presence autoimmune disease and dermatitis of characteristic small intestinal mucosal herpetiformis. A positive family history changes. The key diagnostic features are: of coeliac disease carries the strongest • intestinal histology showing raised predictive value for the disease. intraepithelial lymphocytes (>25 per 100 enterocytes), crypt hyperplasia and Tips and pitfalls villous atrophy (Figure 1) • Coeliac disease can develop at any age. • disease remission confirmed by The median age of diagnosis is 40 years, symptom resolution, normalised coeliac but do not discount coeliac disease in disease serology and, most reliably and the young and elderly. importantly, mucosal healing following • Coeliac disease affects both sexes, treatment with a GFD.3,6 with a modest female predominance. Correlation of histology and serology Men with coeliac disease are often with clinical history is important. Coeliac overlooked.5 disease can be present despite negative • Coeliac disease is a global disorder that 28 | REPRINTED FROM AJGP VOL. 47, NO. 1–2, JAN–FEB 2018 © The Royal Australian College of General Practitioners 2018 INTERPRETING TESTS FOR COELIAC DISEASE CLINICAL is common in Western populations, Coeliac serology is typically performed with intravenous North Africa, the Middle East, India sedation, is simple and safe, and takes and Pakistan.10 Reports from Asian Currently, serologic testing for coeliac as little as 10 minutes. As coeliac disease countries, such as China, are on the rise. disease consists of the transglutaminase causes patchy involvement of the proximal Coeliac disease should not be excluded (tTG) and deamidated gliadin peptide small intestine, multiple biopsies are on the basis of a patient’s ethnicity or (DGP) antibody tests. In practice, both recommended (eg two from the first appearance. tests have >85% sensitivity and >90% and four from the second part of the • Clinical heterogeneity is substantial. specificity.12 The DGP assay has replaced duodenum).3,6 Endoscopic changes of Some patients have minimal or the whole-protein anti-gliadin antibody coeliac disease, such as mucosal scalloping, no obvious symptoms, or only (AGA) assay because of improved are occasionally seen, but diagnosis rests extra-intestinal issues. One-third specificity; however, many labs will on the microscopic appearance. of patients with coeliac disease are report the DGP result as the ‘anti-gliadin overweight or obese at diagnosis.11 antibody’. The anti-endomysial antibody Tips and pitfalls (EMA) test measures tTG antibodies, but is • Villous atrophy is suggestive but labour-intensive, user-dependent and less not pathognomonic of coeliac widely performed. Testing approaches are disease. Other causes to consider, shown in Table 2. especially if coeliac disease serology is negative, include Giardia, common Tips and pitfalls variable immunodeficiency, Crohn’s • Positive coeliac disease serology in disease, tropical sprue, autoimmune isolation is insufficient for the diagnosis enteropathy, cow’s milk protein of coeliac disease. intolerance and some medications • The higher the titre of serology, the (eg olmesartan). greater the positive predictive value for • A GFD or immunosuppression can coeliac disease.13 obscure changes of villous atrophy. • Coeliac disease serology has a false • Correct biopsy processing and negative rate of 10–15%.14 Check if interpretation by a skilled pathologist your patient is on a GFD or taking is vital. When there is diagnostic immunosuppressants. uncertainty, review of the pathology • The tTG normal range varies can be informative. by manufacturer as there is no international standard. Comparing A Human leukocyte antigen titres is not possible if different labs or DQ2/8 genotyping tTG assays are used. • In patients with risk factors for coeliac The strong association between coeliac disease, negative coeliac disease disease and specific human leukocyte serology has lower negative predictive antigen (HLA) genes makes HLA value, so further work-up should be genotyping a useful tool in specific considered.15 situations (Table 3).16 The main • Point-of-care tests to detect coeliac susceptibility genes are HLA-DQ2 disease antibodies have not been (specifically HLA-DQ2.5 and HLA-DQ2.2) validated in primary practice, so cannot and HLA-DQ8, which are collectively currently be recommended.11 seen in almost all (99%) patients with • Patients with persistently positive coeliac disease, compared with 40–50% B coeliac disease serology but normal of the Australian community.5 Although small intestinal histology may have these genes, especially HLA-DQ2.5, Figure 1. Healthy small intestine, compared ‘potential’ (or ‘latent’) coeliac disease, impart substantial relative risk for coeliac with villous atrophy in coeliac disease. and follow-up is recommended.3,6 disease, the absolute risk is low, and most A. Normal small intestinal mucosa in adequately treated coeliac disease patients with one or more of these genes B. Untreated coeliac disease showing the Gastroscopy and small bowel will not develop coeliac disease. HLA-DQ7 classic triad of infiltration of the epithelium biopsies (composed of half the DQ2.5 allele, with lymphocytes, crypt hyperplasia and DQA1*05) may impart a very low risk for villous atrophy 16 Magnification ×100, haematoxylin and Histological evaluation of biopsies from coeliac disease but this remains unclear. eosin stain. the small intestine is the cornerstone of The main benefit of HLA typing is its coeliac disease diagnosis.3,6 Gastroscopy ability to exclude coeliac disease diagnosis © The Royal Australian College of General Practitioners 2018 REPRINTED FROM AJGP VOL. 47, NO. 1–2, JAN–FEB 2018 | 29 CLINICAL INTERPRETING TESTS FOR COELIAC DISEASE Option 1: HLA-DQ2/8 genotyping 9 Table 1. When to test for coeliac disease The absence of HLA susceptibility Offer serological testing for coeliac disease to people with any of the following: means that coeliac disease is unlikely and further investigations can focus on • Persistent unexplained abdominal or gastrointestinal symptoms other diagnoses. The presence of HLA • Faltering growth susceptibility genes is not diagnostic of • Prolonged fatigue coeliac disease, so option 2 is required. • Unexpected weight loss • Severe or persistent mouth ulcers Option 2: Gluten
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