Do gastroenterologists have medical inertia towards coeliac disease? A UK multicentre secondary care study.

OBJECTIVE: This study aimed to assess if there is secondary care medical inertia towards coeliac disease (CD). DESIGN: Group (1): Time from primary care presentation to diagnostic endoscopy was quantified in 151 adult patients with a positive endomysial antibody test and compared with 92 adult patients with histologically proven inflammatory bowel disease (IBD). Group (2): Across four hospitals, duodenal biopsy reports for suspected CD were reviewed (n=1423). Group (3): Clinical complexity was compared between known CD (n=102) and IBD (n=99) patients at their respective follow-up clinic appointments. Group (4): 50 gastroenterologists were questioned about their perspective on CD and IBD. RESULTS: Group (1): Suspected coeliac patients waited significantly longer for diagnostic endoscopy following referral (48.5 (28-89) days) than suspected patients with IBD (34.5 (18-70) days; p=0.003). Group (2): 1423 patients underwent diagnostic endoscopy for possible CD, with only 40.0% meeting guidelines to take four biopsies. Increased diagnosis of CD occurred if guidelines were followed (10.1% vs 4.6% p<0.0001). 12.4% of newly diagnosed CD patients had at least one non-diagnostic gastroscopy in the 5 years prior to diagnosis. Group (4): 32.0% of gastroenterologists failed to identify that CD has greater prevalence in adults than IBD. Moreover, 36.0% of gastroenterologists felt that doctors were not required for the management of CD. CONCLUSION: Prolonged waiting times for endoscopy and inadequacies in biopsy technique were demonstrated suggesting medical inertia towards CD. However, this has to be balanced against rationalising care accordingly. A Coeliac UK National Patient Charter may standardise care across the UK.

Office-Based Point of Care Testing (IgA/IgG-Deamidated Gliadin Peptide) for Celiac Disease.

OBJECTIVES: Celiac disease (CD) is common yet under-detected. A point of care test (POCT) may improve CD detection. We aimed to assess the diagnostic performance of an IgA/IgG-deamidated gliadin peptide (DGP)-based POCT for CD detection, patient acceptability, and inter-observer variability of the POCT results. METHODS: From 2013-2017, we prospectively recruited patients referred to secondary care with gastrointestinal symptoms, anemia and/or weight loss (group 1); and patients with self-reported gluten sensitivity with unknown CD status (group 2). All patients had concurrent POCT, IgA-tissue transglutaminase (IgA-TTG), IgA-endomysial antibodies (IgA-EMA), total IgA levels, and duodenal biopsies. Five hundred patients completed acceptability questionnaires, and inter-observer variability of the POCT results was compared among five clinical staff for 400 cases. RESULTS: Group 1: 1000 patients, 58.5% female, age 16-91, median age 57. Forty-one patients (4.1%) were diagnosed with CD. The sensitivities of the POCT, IgA-TTG, and IgA-EMA were 82.9, 78.1, and 70.7%; the specificities were 85.4, 96.3, and 99.8%. Group 2: 61 patients, 83% female; age 17-73, median age 35. The POCT had 100% sensitivity and negative predictive value in detecting CD in group 2. Most patients preferred the POCT to venepuncture (90.4% vs. 2.8%). There was good inter-observer agreement on the POCT results with a Fleiss Kappa coefficient of 0.895. CONCLUSIONS: The POCT had comparable sensitivities to serology, and correctly identified all CD cases in a gluten sensitive cohort. However, its low specificity may increase unnecessary investigations. Despite its advantage of convenience and rapid results, it may not add significant value to case finding in an office-based setting.

A comparison study between Magniview and high definition white light endoscopy in detecting villous atrophy and coeliac disease: A single centre pilot study.

BACKGROUND AND AIMS: Coeliac disease may be missed at gastroscopy. We aimed to assess the sensitivity of Pentax optical zoom technology endoscopes in detecting duodenal villous atrophy and the ease of image interpretation by non-coeliac specialists. METHOD: All patients attending for a gastroscopy were assessed for endoscopic villous atrophy in part one and two of the duodenum with high definition white light endoscopy and magnification endoscopy. Endoscopic findings of the duodenum were compared to histology as the reference standard. A short training video of varying degrees of villous atrophy seen by magnification endoscopy was used to train individuals. They were then assessed for the ability to differentiate between normal duodenum and villous atrophy. RESULTS: Two hundred and fifty patients were prospectively recruited (145 females, 58%; age range 16-84, median age 50.5). Ninety-six patients had villous atrophy on histology (38.4%) 154 were controls. Magnification endoscopy had a higher sensitivity in detecting villous atrophy compared to high definition white light endoscopy (86.4% versus 78.4%, p = .0005). 9/10 individuals undertaking magnification endoscopy training correctly identified all cases of villous atrophy. CONCLUSION: Magnification endoscopy has superior diagnostic sensitivity in detecting villous atrophy compared to high definition white light endoscopy and the potential to be easily adopted by all endoscopists.

The Role of an IgA/IgG-Deamidated Gliadin Peptide Point-of-Care Test in Predicting Persistent Villous Atrophy in Patients With Celiac Disease on a Gluten-Free Diet.

OBJECTIVES: Mucosal healing is important in celiac disease (CD) for the prevention of complications. However, obtaining duodenal biopsies is invasive, and there is currently no reliable surrogate marker for histological remission in clinical practice. We aimed to assess the role of a point-of-care test (POCT) based on IgA/IgG-deamidated gliadin peptide, in detecting persistent villous atrophy (VA) in CD. METHODS: We prospectively recruited patients with CD attending endoscopy for the assessment of histological remission. All patients had IgA-endomysial (EMA) antibodies, IgA-tissue transglutaminase (TTG) antibodies, and the POCT performed, and completed a validated dietary adherence questionnaire. A gastroscopy was performed in all patients, with four biopsies taken from the second part of the duodenum and one from the duodenal bulb. We compared the diagnostic performance of the surrogate markers against duodenal histology as the reference standard. RESULTS: A total of 217 patients with CD (70% female, age range 16-83 years, median age 53 years) on a gluten-free diet (median duration 6 years) were recruited from 2013 to 2017. Eighty-five (39.2%) patients had persistent VA. The sensitivities of the POCT, TTG, EMA, and the adherence score in detecting VA were 67.1%, 44.7%, 37.7%, and 24.7% respectively (P=0.0005). The combination of the POCT and adherence score only marginally increased the sensitivity to 70.6% (59.7-80.0%). CONCLUSIONS: The sensitivity of the POCT was higher than the other surrogate markers in predicting VA. A POCT may provide the additional advantage of an immediate objective assessment of mucosal healing at the time of an office-based follow-up consultation.

High definition endoscopy with or without I-Scan increases the detection of celiac disease during routine endoscopy.

BACKGROUND AND AIMS: Celiac disease remains underdiagnosed at endoscopy. We aimed to assess the utility of I-Scan (virtual chromo-endoscopy) to improve sensitivity of endoscopy to detect markers of villous atrophy in this condition. METHODS: Patients from 2 UK hospitals were studied in 3 groups. Group 1: standard high definition, white light endoscopy (WLE); Group 2: WLE plus I-Scan; Group 3: non-high definition control group. The presence of endoscopic markers was recorded. At least 4 duodenal biopsies were taken from all patients. Serology was performed concurrently and observations were compared with histology. RESULTS: 758 patients (62% female, mean age 52) were recruited (Group 1: 230; Group 2: 228; Group 3: 300). 135 (17.8%) new diagnoses of coeliac disease were made (21 Group 1; 24 Group 2; 89 Group 3). The sensitivity for detection of endoscopic markers of villous atrophy was significantly higher in both Group 1 (85.7%, p=0.0004) and Group 2 (75%, p=0.005) compared to non-high definition controls (41.6%). There was no significant difference between high definition only and I-Scan groups (p=0.47). In non-high definition endoscopy a missed diagnosis was associated with lesser degrees of villous atrophy (p=0.019) and low tTG titre (p=0.007). CONCLUSIONS: High definition endoscopy with or without I-Scan increases the detection of celiac disease during routine endoscopy.

Clinical and Immunologic Features of Ultra-Short Celiac Disease.

BACKGROUND & AIMS: The clinical effects of gluten-sensitive enteropathy with villous atrophy limited to the duodenal bulb (D1) have not been delineated in adults with celiac disease. We investigated the sensitivity of D1 biopsy analysis in the detection of celiac disease, the number and sites of biopsies required to detect ultra-short celiac disease (USCD, villous atrophy limited to D1), and the clinical phenotype of USCD. METHODS: We performed a prospective study of 1378 patients (mean age, 50.3 y; 62% female) who underwent endoscopy at a tertiary medical center in the United Kingdom from 2008 through 2014; routine duodenal biopsy specimens were collected from D1 and the second part of the duodenum (D2). Quadrantic D1 biopsy specimens were collected from 171 consecutive patients with a high suspicion of celiac disease (mean age, 46.5 y; 64% female). Clinical data from patients diagnosed with USCD, based on biopsy analysis, were compared with those from patients with conventional celiac disease (CCD) (villous atrophy beyond D1) and individuals without celiac disease (controls). The number of intraepithelial lymphocytes (IELs) and immune phenotypes were compared between D1 vs D2 in patients with celiac disease. RESULTS: Of the 1378 patients assessed, 268 (19.4%) were diagnosed with celiac disease; 9.7% of these patients had villous atrophy confined to D1 (USCD; P < .0001). Collection of a single additional biopsy specimen from any D1 site increased the sensitivity of celiac disease detection by 9.3%-10.8% (P < .0001). Patients with USCD were younger (P = .03), had lower titers of tissue transglutaminase antibody (P = .001), and less frequently presented with diarrhea (P = .001) than patients with CCD. Higher proportions of patients with CCD had ferritin deficiency (P = .007) or folate deficiency (P = .003) than patients with USCD or controls. Patients with celiac disease had a median of 50 IELs/100 enterocytes in D1 and a median of 48 IELs/100 enterocytes (P = .7) in D2. The phenotype of IELs from patients with D1 celiac disease was indistinguishable from those of patients with D2 celiac disease. CONCLUSIONS: Collection of a single additional biopsy specimen from any site in the D1 intestine increases the sensitivity of detection for celiac disease. Patients with USCD may have early stage or limited celiac disease, with a mild clinical phenotype and infrequent nutritional deficiencies.

Neurological Dysfunction in Coeliac Disease and Non-Coeliac Gluten Sensitivity.

OBJECTIVES: Non-coeliac gluten sensitivity (NCGS) refers to patients with primarily gastrointestinal symptoms without enteropathy that symptomatically benefit from gluten-free diet (GFD). Little is known about its pathophysiology, propensity to neurological manifestations, and if these differ from patients with coeliac disease (CD). We investigated the clinical and immunological characteristics of patients presenting with neurological manifestations with CD and those with NCGS. METHODS: We compared clinical, neurophysiological, and imaging data of patients with CD and NCGS presenting with neurological dysfunction assessed and followed up regularly over a period of 20 years. RESULTS: Out of 700 patients, 562 were included. Exclusion criteria included no bowel biopsy to confirm CD, no HLA type available, and failure to adhere to GFD. All patients presented with neurological dysfunction and had circulating anti-gliadin antibodies. Out of 562 patients, 228 (41%) had evidence of enteropathy (Group 1, CD) and 334 (59%) did not (Group 2, NCGS). The most common neurological manifestations were cerebellar ataxia, peripheral neuropathy, and encephalopathy. There was a greater proportion of patients with encephalopathy in Group 1 and with a greater proportion of neuropathy in Group 2. The severity of ataxia did not differ between the two groups. Patients in Group 1 had more severe neuropathy. All patients from both groups responded to gluten-free diet. Anti-tissue transglutaminase (TG2) antibodies were found in 91% of patients in Group 1 and in 29% of patients in Group 2. Comparison between those patients in Group 2 with HLA-DQ2/DQ8 and those without as well as those with positive TG2 compared with those with negative TG2 antibodies identified no differences within these subgroups. Serological positivity for TG6 antibodies was similar in the two groups (67 and 60%). CONCLUSIONS: The neurological manifestations of CD and NCGS are similar and equally responsive to a GFD suggestive of common pathophysiological mechanisms.

Celiac Disease and Double-Balloon Enteroscopy: What Can We Achieve?: The Experience of 2 European Tertiary Referral Centers.

BACKGROUND: Indications to double-balloon enteroscopy (DBE) are not standardized in celiac disease (CD). GOALS: To evaluate the clinical usefulness of DBE in complicated CD. STUDY: DBE findings in celiac patients with suspected small bowel (SB) complications were retrospectively evaluated in 2 tertiary referral centers (Milan and Sheffield). Demographic data of the studied cohort were compared with a database of 1000 noncomplicated CD patients. RESULTS: Twenty-four CD cases (12 males, P=0.01 vs. controls) were reviewed. Mean age at CD diagnosis (y±SD) was 37±20 versus 27±18 and at SB evaluation 47±15 versus 38±13 (P<0.01 compared with controls). Indications for DBE were refractory CD (#9), gastrointestinal symptoms (#6), severe iron-deficiency anemia (#6), and long standing poor dietary adherence (#3). Two jejunal adenocarcinomas and an ileal neuroendocrine tumor were detected in presence of iron-deficiency anemia. Three type I and 3 type II refractory CD patients showed jejunal ulcerations; 2 of type II presented small white raised patches. Patchy atrophy was observed in nonadherent patients and in 2 on a gluten-free diet for a short time. Therapy was planned in 33% of patients after DBE. No adverse events were detected at follow-up [21 mo (range, 0 to 60 mo)]. CONCLUSIONS: This is the largest international study on the outcomes of DBE in CD demonstrating its usefulness to exclude/confirm malignant or premalignant conditions, associated with even minor lesions. Studies are needed to understand the clinical relevance of the SB endoscopic features and to optimize DBE indications.

Cost and availability of gluten-free food in the UK: in store and online.

OBJECTIVE: Coeliac disease (CD) is a lifelong condition requiring strict adherence to a gluten-free (GF) diet and good availability of GF foods is critical to this. Patients with CD from lower socioeconomic groups are recognised to have higher treatment burden and higher food costs may impact this. Therefore, we aimed to assess the availability and cost of GF food in supermarkets and via the internet. DESIGN: Supermarkets and internet shops delivering to homes in a single city (UK) were analysed between February and March 2014. Stores were identified with comprehensive internet searches. Ten commonly purchased items were analysed for cost and compared with standard non-GF alternatives. Direct measurement of the number of GF foods available was compared between stores which were categorised according to previously published work. SETTING: Supermarkets covering the whole of Sheffield, UK. RESULTS: None of the budget supermarkets surveyed stocked any GF foods. Quality and regular supermarkets stocked the greatest range, each stocking a median of 22 (IQR 39) items (p<0.0001). All GF foods were at least four times more expensive than non-GF alternatives (p<0.0001). GF products are prevalent online, but 5/10 of the surveyed products were significantly more expensive than equivalents in supermarkets. CONCLUSIONS: There is good availability of GF food in regular and quality supermarkets as well as online, but it remains significantly more expensive. Budget supermarkets which tend to be frequented by patients from lower socioeconomic classes stocked no GF foods. This poor availability and added cost is likely to impact on adherence in deprived groups.

Gastro-oesophageal reflux symptoms and coeliac disease: no role for routine duodenal biopsy.

BACKGROUND: Coeliac disease (CD) has been linked to gastro-oesophageal reflux disease (GORD). Previous studies have demonstrated an increased prevalence of reflux in patients with CD. However data on the risk for CD in patients presenting with reflux are conflicting. AIMS: The aim of this study was to establish the prevalence of CD in patients with GORD and to elucidate the mechanisms for reflux symptoms in newly diagnosed CD patients. METHODS: Group A: patients who had undergone routine duodenal biopsy were prospectively recruited between 2004 and 2014. Diagnostic yield was compared with that of a screening cohort. Group B: 32 patients with newly diagnosed CD who had undergone oesophageal manometry and 24-h pH studies were prospectively recruited. RESULTS: Group A: 3368 patients (58.7% female, mean age 53.4 years) underwent routine duodenal biopsy. Of these patients, 850 (25.2%) presented with GORD. The prevalence of CD among GORD patients was 1.3% (0.7-2.4%), which was not significantly higher than that in the general population (P=0.53). Within the context of routine duodenal biopsy at endoscopy (when corrected for concurrent symptoms, age and sex), reflux was found to be negatively associated with CD [adjusted odds ratio 0.12 (0.07-0.23), P<0.0001]. In group B, 34% of patients complained of reflux. On manometry, 9% had a hypotensive lower oesophageal sphincter and 40.6% had oesophageal motor abnormalities, with 25% significantly hypocontractile. On pH studies, 33% demonstrated reflux episodes. CONCLUSION: The prevalence of undiagnosed CD among GORD patients is similar to that in the general population, and routine duodenal biopsy cannot be recommended. A significant number of patients with newly diagnosed CD were found to have reflux and/or oesophageal dysmotility on pH/manometry studies; this may explain the high prevalence of reflux symptoms in CD.

Increased Detection of Celiac Disease With Measurement of Deamidated Gliadin Peptide Antibody Before Endoscopy.

BACKGROUND & AIMS: Celiac disease is underdiagnosed. Many patients are examined by endoscopy, but celiac disease is missed or not detected. We evaluated the accuracy of finger prick-based point-of-care tests in the detection of celiac disease and developed an algorithm for diagnosis. METHODS: We performed a prospective study of 2 groups of patients with celiac disease evaluated at the Royal Hallamshire Hospital in Sheffield (United Kingdom) from March 2013 through February 2014. In group 1, patients at high risk of celiac disease who tested positive for endomysial antibody (n = 55) were evaluated using the Biocard test (BHR Pharmaceuticals, Nuneaton, UK) and the Celiac Quick Test (Biohit Healthcare UK, Ellesmere Port, UK), which measure antibodies to tissue transglutaminase (anti-tTG), and the Simtomax test (Tillotts Pharma, Rheinfelden, Switzerland), which measures deamidated gliadin peptide antibodies (DGP). Patients in group 2 (508 consecutive patients who underwent an endoscopy examination for any indication) received the DGP test, and also were evaluated using a diagnostic algorithm that incorporated results from the DGP test and data on symptoms. In both groups, point-of-care tests were taken at the time of endoscopy and results were compared with results from histologic analyses of duodenal biopsy specimens from all patients. RESULTS: In group 1, the DGP test identified patients with celiac disease with 94.4% sensitivity, the Celiac Quick Test identified patients with 77.8% sensitivity (P = .03 vs the DGP test), and the Biocard test identified patients with 72.2% sensitivity (P = .008 vs the DGP test). In group 2, the DGP test identified patients with celiac disease with 92.7% sensitivity (95% confidence interval, 83.0-97.3), 85.2% specificity (95% confidence interval, 81.5-88.3), a positive predictive value of 49.2% (95% confidence interval, 40.3-58.2), and a negative predictive value of 98.7% (95% confidence interval, 96.8-99.5). Measurement of serum anti-tTG identified patients with celiac disease with 91.2% sensitivity (95% confidence interval, 81.1-96.4), 87.5% specificity (95% confidence interval, 84.0-90.4), a positive predictive value of 53.0% (95% confidence interval, 43.6-62.2), and a negative predictive value of 98.5% (95% confidence interval, 96.5-99.4). The algorithm identified patients with celiac disease with 98.5% sensitivity; its use could reduce duodenal biopsies by 35%. CONCLUSIONS: In a prospective study, a test for DGP identified patients with celiac disease with similar levels of sensitivity and specificity as standard serologic analysis of anti-tTG. Use of the DGP test before endoscopy could increase the accuracy of the diagnosis of celiac disease. Further studies, in lower-prevalence populations, are required to assess the impact of the test in clinical practice.

Emerging drugs for coeliac disease.

INTRODUCTION: Coeliac disease is an autoimmune gluten sensitive enteropathy and is now known to affect 1% of the adult population. A gluten-free diet (GFD) should be curative; however, up to 30% of patients have persistent symptoms and many patients find the diet difficult to fully adhere to. Currently, there are no licensed therapeutic options for patients with coeliac disease outside of a GFD. AREAS COVERED: This review will outline the case for alternative treatments and discuss the potential therapeutic targets. The products in the most advanced stage of development will be discussed in detail. EXPERT OPINION: There is clearly an unmet need for alternatives to a GFD for the treatment of coeliac disease. Oral glutenase supplements to improve the degradation of gluten into non-toxic peptides appear to be the most likely to provide a breakthrough in the treatment of coeliac disease; however, other modalities such as a therapeutic vaccine or zonulin inhibitors to reduce intestinal permeability have shown promising results.

Prevalence, investigational pathways and diagnostic outcomes in differing irritable bowel syndrome subtypes.

BACKGROUND: There has been increasing interest in subclassifying irritable bowel syndrome (IBS) to make a positive diagnosis. AIM: The aim of this study was to assess the population prevalence of differing subtypes, investigational pathways and diagnostic outcomes. MATERIALS AND METHODS: Data were prospectively collected from three groups between 2005 and 2012. Group 1 [n=1002, 55% female, mean age 39 years (range 16-93 years)] comprised healthy volunteers who were interviewed using the Rome III diagnostic questionnaire. In secondary care, group 2 [n=64, 80% female, mean age 44 years (range 23-79 years)] comprised patients with constipation-predominant IBS (IBS-C) and group 3 [n=333, 66% female, mean age 51 years (range 23-92 years)] comprised patients with diarrhoea-predominant IBS (IBS-D). In groups 2 and 3, demographic data and diagnostic yield of investigations were evaluated as per normal clinical practice. RESULTS: IBS prevalence in group 1 was 6% (60/1002). IBS-C patients were significantly older than those with IBS-D (mean age 45 vs. 30 years, P=0.027). In groups 2 and 3, patients with IBS-C underwent a total of 56 additional investigations (mean 0.88 per patient), which was significantly lower than the number of investigations undertaken in the IBS-D group of 734 (mean 2.2 per patient, P<0.001). Further investigations in group 3 (IBS-D) identified an alternative diagnosis in 22%, whereas in group 2 (IBS-C) this was 0% (P<0.0001). CONCLUSION: This is the first study to evaluate the population prevalence of different IBS subtypes within a UK population. Although further investigations in IBS-D patients have led to alternative diagnoses, none were identified in the IBS-C population. The merits of investigating IBS-C patients should be questioned.