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 , 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 ЖЖFibromyalgia to a gluten-free diet as expected. Evidence is taken from symptoms of —, chronic (BMJ 2014;348:g1224) meta-analyses, systematic reviews, and randomised con- diarrhoea, or . This is best described as ЖЖTrigeminal 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 ЖЖManagement 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 -type symptoms, (BMJ 2014;348:g255) clear that coeliac disease is a global problem. Clinicians , altered bowel habit, and anaemia (most ЖЖManaging wheeze in in China and the Indian subcontinent are now recognis- commonly ). 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 into not include abdominal symptoms or signs of mal- (BMJ 2014;348:g15) these ethnic groups as their diet becomes more western- absorption. ЖЖErectile 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- , , 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 . 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 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 for a recent 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

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What tests should we use? positive p­redictive value of tTG was only 28.6%, despite The three most widely available serological tests— sensitivity­ and specificity of greater than 90%. Sec- endomysial (EMA), tissue ondly, the clinical response to a gluten-free diet is not (tTG) antibody, and deamidated (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 . However, it is sub- as expected, any uncertainty in the initial diagnosis jective, labour intensive, and the substrates of monkey can make subsequent ev­aluation 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 ; 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 not to start a gluten-free diet until investigations are and positive serological testing alone. In these patients c­ompleted. 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 ) 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 are usually taken from the distal pa­ediatric guidelines suggest an algorithm for avoid- . 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. This is understand- only site of villous atrophy in 1.8-12.5% of newly diag- able because endoscopic evaluation often requires a nosed patients. HLA genotyping may also be useful in general anaesthetic in children. Duodenal biopsy to this situation because the absence of the HLA DQ2 and confirm diagnosis­ is still needed in adults for several DQ8 has a near 100% negative predictive reasons. Firstly, although serology seems to be an excel- value. However, 25-40% of the healthy population also lent marker, studies­ into these tests are performed in carry these , so genotyping should not be used for high prevalence populations. This ascertainment bias routine diagnosis. This same strategy can be used for overestimates the performance of a diagnostic test. As patients with positive serological but normal histological the threshold for serological testing is lowered, the results and a high index of suspicion of coeliac disease. disease prevalence within the tested population will Coeliac serology testing is not 100% specific and false fall. As a result the positive predictive value of the test positives do occur, particularly in patients with other will also fall. For example, in a recent cohort of 2000 autoimmune conditions or conditions that lead to a patients with a 3.9% prevalence of coeliac disease, the raised total IgA level.

Table 1 | Modified Marsh criteria for the histological diagnosis of coeliac disease Marsh-Oberhuber stage Description Stage 0 Normal duodenal mucosa Stage 1 Increased intraepithelial lymphocytes (IELs) >25 IELs/100 (non-specific finding) Stage 2 Stage 1 plus crypt hyperplasia (non-specific finding) Stage 3a Increased IELs, crypt hyperplasia, and partial villous atrophy Stage 3b Increased IELs, crypt hyperplasia, and subtotal villous atrophy Stage 3c Increased IELs, crypt hyperplasia, and total villous atrophy

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adherence but this is important, particularly in patients Causes of persistent symptoms in coeliac disease who continue to have symptoms. Adherence is assessed Continued exposure to gluten in five ways: patient reported adherence, dietetic assess- Bacterial overgrowth of the small bowel ment, a validated adherence questionnaire, coeliac Exocrine pancreatic insufficiency serological testing, or a repeat duodenal biopsy. A recent Microscopic systematic review that used qualitative methods esti- Irritable bowel syndrome mated that adherence to a strict gluten-free diet ranged from 42% to 91%, although complete non-adherence Refractory coeliac disease was rare. Factors that were most associated with good —small bowel lymphoma or adherence were follow-up with an expert dietitian and membership of a coeliac disease advocacy group, both What if serological testing is negative but the clinical of which should be strongly encouraged. suspicion of coeliac disease is high? Many clinicians think that a repeat duodenal biopsy Although modern serological testing is highly sensitive, is the most objective measure of adherence. A recent UK cases of antibody negative coeliac disease do exist, par- cohort study has shown that follow-up biopsy before ticularly when a single test is used in the diagnostic algo- discharge to primary care services is a useful way to risk rithm. Selective IgA deficiency, present in 2% of patients stratify patients who are likely to have more severe dis- with coeliac disease, is a common cause of false negative ease and complications. However, mucosal healing can coeliac serological results because standard tests are take several years, and the ideal timing of a follow-up based on the IgA subclass of antibody. Immunoglobulin biopsy is not known. Repeat duodenal biopsy is invasive, levels should be checked alongside standard serological so quantitative serological measurements are often used tests, and duodenal biopsy is recommended in IgA defi- as a surrogate marker of intestinal healing. However, sero- cient patients.21‑23 Patients must be on a gluten contain- logical and histological findings do not seem to correlate ing diet at the time of serological testing because results in a linear manner. may normalise on a gluten-free diet. Adherence is complicated to assess and is probably IgA deficiency is not the only cause of antibody nega- best measured using a combination of factors. Patients tive coeliac disease. In the 11 studies reported in a recent should have access to a dietitian to assess adherence in meta-analysis of IgA tTG the mean rate of tTG negative conjunction with repeat serological testing and gastro- coeliac disease was 7%. A prospective study of a clini- enterology input to assess for resolution of symptoms. cal decision tool for diagnosing coeliac disease found Repeat duodenal biopsy is probably best reserved for that patients without high risk symptoms of anaemia, patients with raised serological markers, persistent symp- weight loss, or diarrhoea could safely have coeliac dis- toms, or deficiencies. Patients who are stable and ease excluded on the basis of negative serological testing. seem to be adhering to a gluten-free diet should be seen However, this algorithm has yet to be validated by other in primary or secondary care on an annual basis to assess groups. The diagnosis of antibody negative coeliac disease symptoms and discuss adherence. can also be problematic because other causes of villous atrophy need to be considered. Again, HLA genotyping What should we do if the patient doesn’t respond to a can be useful in this situation if it proves negative. Patients gluten-free diet? on immunosuppressants or steroids may also have nega- Although most patients with coeliac disease will respond tive serological results in the presence of villous atrophy. to a gluten-free diet, 7-30% of patients have persistent Finally, wheat or gluten can induce symptoms in patients symptoms. Some patients may have been initially misdi- without coeliac disease and self reported sensitivity is agnosed with coeliac disease and the diagnosis must be not always caused by coeliac disease. Refer all patients in confirmed by reviewing the histological and serological whom coeliac disease is suspected but the histological or results and history. The most common reason for persis- serological (or both) results are not diagnostic to a gastro- tent symptoms in patients with confirmed coeliac disease enterologist with an interest in coeliac disease. is persistent exposure to gluten. Several well documented associations with other gastrointestinal conditions, such How is coeliac disease managed? as bacterial overgrowth of the small bowel, pancreatic Currently, the only effective treatment for coeliac disease insufficiency, and , may also contribute is a gluten-free diet. However, many patients find avail- to ongoing gastrointestinal symptoms. able gluten-free foods unpalatable and report social dif- Patients who do not respond to a gluten-free diet are ficulties related to eating out. It can be difficult to assess described as non-responsive, and in a small number of

Table 2 | Treatments under development New treatment Mechanism Genetically modified wheat Strains of wheat in which gluten is absent or doesn’t trigger an immune response Therapeutic vaccine Desensitisation to gluten inhibitors Reduce Transglutaminase inhibitors Block transamidation of gluten Probiotics Reduce intestinal and accelerate mucosal healing on a gluten-free diet Peptidases Enzymatically degrade gluten in the gut

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at the same time or soon after the diagnosis of coeliac QUESTIONS FOR FUTURE RESEARCH disease, before the patient can start an effective gluten- What is an effective follow-up strategy for patients with free diet. A recent large population based study showed coeliac disease? that persistent villous atrophy, which is more common Is there a role for point of care tests in diagnosis or monitoring of adherence? in patients with poor adherence to a gluten-free diet, Will new treatments become a useful adjunct to a gluten- was associated with increased risk of lymphoma, with a free diet? hazard ratio of 2.26 compared with those with mucosal Will genetically modified “non-toxic” wheat allow healing on follow-up biopsy. However, direct evidence of consumption of a normal diet in the future? benefit is sparse. EATL is rare, so studies are small and data are conflicting. TIPS FOR NON-SPECIALISTS Osteoporosis A duodenal biopsy is still needed to diagnose coeliac disease. Patients should remain on a gluten containing Osteoporosis is prevalent in patients with coeliac disease, diet until biopsy is performed with 32-80% having abnormal bone mineral density, and Be aware of the complications of coeliac disease— a strict gluten-free diet has been shown to improve bone including anaemia and micronutrient deficiency ( mineral density. In a recent study of 95 patients with

D, calcium, vitamin B12, , and iron), osteoporosis, and newly diagnosed coeliac disease, adherence to a strict lymphoma—and monitor stable patients annually to make gluten-free diet significantly improved mean bone min- sure they remain well eral density, independent of other risk factors and the Refer patients with persistent symptoms to an expert effect of exercise. This validates results from a previous gastroenterologist, especially if they are losing weight, have systematic review. However, patients with silent or sub- severe micronutrient deficiency, or have other symptoms clinical disease may not have to suggestive of malabsorption despite a gluten-free diet the same extent as those with classical coeliac disease. A gluten-free diet is the only treatment that can prevent complications from coeliac disease. Although coeliac Current national guidelines recommend that patients serological testing can be helpful in assessing the are given lifestyle advice and that a baseline DEXA (dual response to a gluten-free diet, an interview with an expert energy X ray absorptiometry) scan should be requested dietitian is the best method of assessing dietary adherence to assess bone mineral density at diagnosis. The scan should be repeated at or 55 years of age for these persistent symptoms will be the result of refractory men, or if there is a suspected fragility fracture. Loss coeliac disease. This is a rare condition, which is defined of bone density at a greater than expected rate should as a persistence of villous atrophy despite strict adherence prompt measurement of levels, dietary review for 12 months to a gluten-free diet. It can be a precursor to of adherence, consideration of repeat intestinal mucosal associated lymphoma (EATL). Patients biopsy, and review of additional risk factors. with refractory coeliac disease will have persistent symp- toms including persistent nutritional deficiencies, weight Other management points loss, and malabsorption. These patients require urgent Patients with coeliac disease can have hyposplenism, evaluation by a gastroenterologist. The box provides a which results in a higher risk of infection from encapsu- comprehensive list of the causes of non-responsive coeliac lated bacteria. National guidelines recommend vacci­ disease. Table 2 summarises several new treatments that nations against Streptococcus pneumoniae, meningitis C, are under development for coeliac disease.

What long term risks are associated with coeliac disease ADDITIONAL EDUCATIONAL RESOURCES and how are they managed? Resources for healthcare professionals The potentially serious sequelae of coeliac disease can National Institute for Health and Clinical Excellence. be prevented by adherence to a strict lifelong gluten-free Coeliac disease: recognition and assessment of coeliac diet. These associated risks include the development of disease. 2009. www.nice.org.uk/nicemedia/pdf/ CG86FullGuideline.pdf. Useful guideline that explains the lymphoma and osteoporosis as well as hyposplenism, diagnosis of coeliac disease and which patient groups anaemia, and other micronutrient deficiencies. should be tested Ciclitira P, Dewar DH, McLaughlin SD, Sanders DS. The Lymphoma management of adults with coeliac disease. British Society Older estimates suggested that the relative risk of lym- of , 2010. www.bsg.org.uk/images/ phoma was 40-100 times that seen in the general popu- stories/clinical/bsg_coeliac_10.pdf. Useful for the long lation.50‑55 However, as the detection of coeliac disease term management of coeliac disease as well as initial has improved, newer studies have shown only a mod- diagnosis est risk.56‑58 A recent meta-analysis found a fourfold Resources for patients increased risk of non-Hodgkin’s lymphoma (including Coeliac UK (www.coeliac.co.uk)—National charity and EATL) compared with the general population, with an advocacy group for people with coeliac disease and estimated one in 2000 patients with coeliac disease herpetiformis developing lymphoma each year. Evidence for the pro- Celiac Disease Foundation. (www.celiac.org)—Provides support and information to people affected by coeliac tective effect of a gluten-free diet against the development disease of lymphoma is circumstantial. EATL is often diagnosed

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and Haemophilus influenzae B, as well as an annual influ- • The risk of lymphoma is greater than in the general enza vaccination, in this population. population but remains small, and a gluten-free diet Anaemia and other micronutrient deficiencies are may reduce this risk common in newly diagnosed coeliac disease. Clinicians • On average, patients with coeliac disease have

should measure iron, vitamin B12, folic acid, vitamin D, reduced bone mineral density. Patients should and calcium levels at diagnosis. Appropriate replace- maintain adequate calcium and vitamin D intake. A ment is required on diagnosis, with annual monitor- gluten-free diet should prevent further bone loss and

ing of haemoglobin, vitamin B12, folate, serology, and may improve bone density immunoglobulins. Adherence to a gluten-free diet may • If patients do not respond to a gluten-free diet as prevent recurrence of nutrient deficiencies if oral intake expected they should seek medical advice because is sufficient. this may indicate gluten exposure or another Finally, quality of life studies of patients with coeliac condition that needs investigating disease on a gluten-free diet show that they have a lower • Close family members have a one in 10 chance quality of life in both the short and long term compared of having coeliac disease and current guidelines with the general population and patients with other recommend offering serological testing for first chronic gastrointestinal conditions, such as ulcerative degree relatives colitis. Appropriate investigation and management of Contributors: PDM designed and drafted the article and is guarantor. MH symptoms as well as support with a gluten-free diet may revised the article and approved the final manuscript. DSS designed and 70‑72 improve quality of life. revised the article and approved the final manuscript. Competing interests: We have read and understood the BMJ Group policy What should you tell the patient diagnosed with coeliac on declaration of interests and declare the following interests: DSS has disease? received educational research grants from Dr Schaer (a gluten-free food manufacturer) and Tillotts (producer of a point of care test for coeliac The prognosis for coeliac disease is good, with a • disease) for investigator led studies. There are no contractual agreements normal life expectancy to disseminate product information and the funding sources have no • A gluten-free diet is currently the only known control over educational content. PDM and MH have none. treatment for coeliac disease. Adherence to the diet Provenance and peer review: Commissioned; externally peer reviewed. should lead to healing of the small bowel References are in the version on bmj.com.

Let’s stop “thinning the blood”

Coumarin anticoagulant drugs have been used in medicine since the 1940s,1 although the first recorded human administration of warfarin seems to have been a suicide attempt in 1952.2 Similarly, the role of aspirin as an antiplatelet agent has been long established, and several newer anticoagulant drugs have entered the MARAZZI/SPL P DR patients. There is a balance to strike between clarity market over the years. and being absolutely correct.) Although I was surprised to learn that in ponies with I propose that the correct approach is to inform navicular disease warfarin has been shown to reduce 3 patients that a particular drug is recommended because plasma viscosity, there are few data on the influence it will stop their blood clotting quite so easily, which of these drugs on blood rheology, and certainly they will reduce their risk of or heart attack, etc, and are not prescribed to alter blood viscosity. Despite this, explain why. This can then include a discussion of the generations of doctors and other staff have described balance of likely benefit to harm and give patients some them as “blood thinners.” There seems to be no logical possibility of understanding why they should take these explanation for why this term has been adopted with often inconvenient and sometimes dangerous agents. such enthusiasm, nor have I been able to discover So from now on let us all stop “thinning the blood” when or why it was first used. Patients often seem and instead allow patients to be fully informed about happy to accept that their blood has been thinned by their proposed anticoagulant or antiplatelet therapy. their new tablets and occasionally report that they have felt the cold more keenly since taking them. Paul Woodmansey consultant cardiologist, Mid Staffordshire NHS Foundation Trust, Stafford, UK Surely in these days of universal access to knowledge [email protected] and the laudable principle of “no decision about me 1 Hilton JHB, Cameron WM, Townsend SR, Mills ES. Problems involved without me” it is time to put away this particular vestige in the use of dicoumarol in acute coronary thrombosis. CMAJ of medical patronage. I believe that people are quite 1949;60:386-8. capable of grasping the concept that a drug can affect 2 O’Reilly RA, Aggeler PM, Leong LS. Studies on the coumarin anticoagulant drugs: pharmacodynamics of warfarin in man. J Clin Invest the ability of the blood to clot and separate this from 1963;42:1542-51. how concentrated blood is or how easily it flows. (I am 3 Amin TM, Sirs JA, Allen BV, Colles CM. Effects of warfarin on blood however happy to skate over the distinction between rheology in navicular disease. Res Vet Sci 1986;40:308-12. clotting and thrombosis when discussing this topic with Cite this as: BMJ 2012;344:e4114

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