CLINICAL REVIEW Coeliac disease Follow the link from the online version of this article to obtain certi ed continuing 1 2 1 medical education credits Peter D Mooney, Marios Hadjivassiliou, David S Sanders 1 Regional Gastrointestinal and Liver Coeliac disease is a common autoimmune condition SOURCES AND SELECTION CRITERIA Unit, Royal Hallamshire Hospital, characterised by a heightened immunological response Sheffield S10 2JF, UK We searched Medline and the Cochrane Database of to ingested gluten, with estimated prevalence rates in 2Department of Neurology, Royal Systematic Reviews with the search terms “coeliac Hallamshire Hospital, Sheffield, UK adults of 0.2-1% in the United States and Europe. Con- disease” or “celiac disease”. Studies included those Correspondence to: P D Mooney temporary studies suggest that the prevalence of this dis- in adult and paediatric populations but preference [email protected] ease is increasing.3-5 Meta-analyses have shown that for was given to adult studies in the past five years. We Cite this as: BMJ 2014;348:g1561 every patient identified as having coeliac disease seven focused on meta-analyses and systematic reviews where doi: 10.1136/bmj.g1561 to eight remain undiagnosed. Here, we will summarise possible. recent evidence on how the investigation and diagnosis of bmj.com coeliac disease can be improved and also provide an evi- How does coeliac disease present? Previous articles in this dence based approach to managing patients with newly Until the 1980s, coeliac disease was considered a rare series diagnosed coeliac disease and those who do not respond condition that usually presented in childhood with Ж Fibromyalgia to a gluten-free diet as expected. Evidence is taken from symptoms of malabsorption—weight loss, chronic (BMJ 2014;348:g1224) meta-analyses, systematic reviews, and randomised con- diarrhoea, or failure to thrive. This is best described as Ж Trigeminal neuralgia trolled trials where possible. “classical” coeliac disease and remains relatively rare. (BMJ 2014;348:g474) Coeliac disease is now known to be common, presenting Ж Management of Who gets coeliac disease? in adulthood usually in the fourth or fifth decade of life traumatic amputations of In the past coeliac disease was considered to be a dis- with “non-classical” symptoms. Non-classical presenta- the upper limb ease that affects white populations only, but it is now tions include irritable bowel syndrome-type symptoms, (BMJ 2014;348:g255) clear that coeliac disease is a global problem. Clinicians abdominal pain, altered bowel habit, and anaemia (most Ж Managing wheeze in in China and the Indian subcontinent are now recognis- commonly iron deficiency). Clinicians need to be aware ing patients with this disease. Possible reasons for this of the variable manifestations of coeliac disease, which preschool children increased prevalence are the introduction of wheat into may not include abdominal symptoms or signs of mal- (BMJ 2014;348:g15) these ethnic groups as their diet becomes more western- absorption. Ж Erectile dysfunction ised and an increasing trend in all autoimmune diseases. (BMJ 2014;348:g129) Patients at increased risk include those with another Who should we test for coeliac disease? autoimmune condition or a family history of coeliac dis- Current national and international guidelines recom- ease. Patients with a first degree relative with coeliac dis- mend case finding in at risk groups as the best method of ease have a 5-11% chance of being affected.10-12 Second case detection.21-23 The aim of case finding is to identify degree relatives also seem to be at increased risk (~2.5%), patients at an early stage and potentially reduce the risks although the exact prevalence in this population is uncer- of developing complications of coeliac disease such as tain. There is a strong genetic component to coeliac dis- lymphoma, osteoporosis, and anaemia. ease—90% of patients carry genes encoding HLA DQ2. Recent US guidelines recommend testing for coeliac dis- Most of the remainder carry the HLA DQ8 haplotype. In ease in patient populations with a prevalence of coeliac common with other autoimmune conditions it is more disease more than twice that of the general population. common in females than males (1.5-2:1).14-17 This approach has been shown to be useful in prospective case finding studies in patients with classical symptoms or SUMMARY POINTS sequelae of malabsorption, such as anaemia or osteoporo- 14-17 Adult coeliac disease is a common autoimmune sis. These same studies also show that the prevalence condition with an estimated prevalence of 1% of coeliac disease is higher in patients with more non-spe- Test for coeliac disease in patients with unexplained cific symptoms, although there was heterogeneity in the anaemia, weight loss, diarrhoea, or gastrointestinal patient populations studied. The best evidence for testing symptoms, particularly irritable bowel syndrome, and in for abdominal symptoms comes from two meta-analyses first degree relatives of index cases in patients fulfilling the Rome III diagnostic criteria for Confirm the diagnosis with duodenal biopsy in all adult irritable bowel syndrome. Symptoms of this syndrome are patients seen in 38% of patients with coeliac disease, and the prev- Treatment with a lifelong strict gluten-free diet is alence of coeliac disease is 4.1% in patients with irritable currently the only treatment of known effectiveness bowel syndrome. Evidence for testing in patients with other abdominal symptoms is less compelling, although Patients should have access to an expert dietitian for a recent systematic review of diagnostic testing for coeliac advice on a gluten-free diet and for assessment of adherence if symptoms persist on institution of the diet disease in secondary care showed a prevalence of 2-13% in patients presenting with all abdominal symptoms. The Regular follow-up is necessary to assess adherence and web table (on bmj.com) summarises the patient groups micronutrient deficiency where testing is recommended.26-29 30 BMJ | 8 MARCH 2014 | VOLUME 348 CLINICAL REVIEW What tests should we use? positive p redictive value of tTG was only 28.6%, despite The three most widely available serological tests— se nsitivity and specificity of greater than 90%. Sec- endomysial antibody (EMA), tissue transglutaminase ondly, the clinical response to a gluten-free diet is not (tTG) antibody, and deamidated gliadin peptide (DGP) diagnostic of coeliac disease, particularly in patients antibody—have excellent sensitivity and specificity in with irritable bowel syndrome, whose symptoms may appropriate patient groups. EMA testing is highly accu- be gluten sensitive in the absence of coeliac disease. rate, with a sensitivity and specificity of 95% or more in Finally, if patients do not respond to a gluten-free diet patients with overt villous atrophy. However, it is sub- as expected, any uncertainty in the initial diagnosis jective, labour intensive, and the substrates of monkey can make subsequent ev aluation problematic. Patients oesophagus or human umbilicus have limited availability. should remain on a gluten containing diet until endos- tTG assays are generally cheaper than EMA testing and copy because histological features may normalise on a may be more reliable. One weakness of tTG assays, how- gluten-free diet. ever, is that their accuracy varies between manufacturers. The best assays have a higher sensitivity than EMA test- What if serological tests are positive but duodenal biopsy ing and a comparable specificity, both around 98%. More is non-diagnostic? recently DGP assays have become available. However, a As previously discussed, a diagnosis of adult coeliac recent meta-analysis has shown that they are inferior to disease requires a duodenal biopsy that shows villous tTG assays, and they are not currently recommended by atrophy. However, in some cases a biopsy may be normal the National Institute for Health and Care Excellence. or show evidence of increased intraepithelial lympho- tTG is currently the preferred first line test owing to its cytes without villous atrophy (Marsh 1; table 1). These high sensitivity and negative predictive value. Point of changes are non-specific and are seen in many other care tests are now commercially available in high street conditions, including Helicobacter pylori infection or as pharmacies and on the internet for patients to purchase. a result of non-steroidal anti-inflammatory use. Coeliac Further research is needed to ascertain their utility. Clini- disease is subsequently confirmed on repeat gastros- cians should treat the results of such tests with caution copy and biopsy in 16-43.3% of patients. As a result, a and confirm them with standard serology; gastroenterol- diagnosis of coeliac disease cannot be made on the basis ogy referral should also be considered. Counsel patients of an increased number of intraepithelial lymphocytes not to start a gluten-free diet until investigations are and positive serological testing alone. In these patients c ompleted. a repeat gastroscopy and duodenal biopsy should be considered after a six week gluten challenge of 10 g Is a duodenal biopsy still needed for diagnosis? of gluten (equivalent to four slices of bread) a day.21-23 Currently, most patients are diagnosed on the basis Some patients may not tolerate this amount of gluten of positive coeliac serology followed by a confirma- and evidence is emerging that shorter challenges with tory duodenal biopsy showing the presence of villous less gluten might be sufficient, although clinical data atrophy and increased intraepithelial lymphocytes are lacking. (Marsh 3a-c; table 1). However, recent European Duodenal biopsies are usually taken from the distal pa ediatric guidelines suggest an algorithm for avoid- duodenum. However, recent evidence suggests that an ing biopsy in children with clinical symptoms, very high additional biopsy from the first part of the duodenum antibody titres (tTG >10× normal and positive EMA), may increase the diagnostic yield because this is the and an appropriate genotype.