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Background & aims: It is currently unclear whether reported changes in the gut microbiome are cause or consequence of inflammatory bowel disease (IBD). Therefore, we studied the gut microbiome of IBD-discordant and -concordant twin pairs, which offers the unique opportunity to assess individuals at increased risk of developing IBD, namely healthy cotwins from IBD-discordant twin pairs. Methods: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex-, and body mass index–matched controls, and 99 unrelated patients with IBD. Whole-genome metagenomic shotgun sequencing was performed. Taxonomic and functional (pathways) composition was compared among healthy cotwins, IBD-twins, unrelated patients with IBD, and healthy controls with multivariable (ie, adjusted for potential confounding) generalized linear models. Results: No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins (false discovery rate

Contains fulltext : 220040.pdf (Publisher’s version ) (Closed access) BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.

Purpose: Previous studies have shown that > 50% of colorectal cancer (CRC) patients treated with adjuvant chemotherapy gain weight after diagnosis. This may affect long-term health. Therefore, prevention of weight gain has been incorporated in oncological guidelines for CRC with a focus on patients that undergo adjuvant chemotherapy treatment. It is, however, unknown how changes in weight after diagnosis relate to weight before diagnosis and whether weight changes from pre-to-post diagnosis are restricted to chemotherapy treatment. We therefore examined pre-to-post diagnosis weight trajectories and compared them between those treated with and without adjuvant chemotherapy. Methods: We included 1184 patients diagnosed with stages I–III CRC between 2010 and 2015 from an ongoing observational prospective study. At diagnosis, patients reported current weight and usual weight 2 years before diagnosis. In the 2 years following diagnosis, weight was self-reported repeatedly. We used linear mixed models to analyse weight trajectories. Results: Mean pre-to-post diagnosis weight change was −0.8 (95% CI −1.1, −0.4) kg. Post-diagnosis weight gain was + 3.5 (95% CI 2.7, 4.3) kg in patients who had lost ≥ 5% weight before diagnosis, while on average clinically relevant weight gain after diagnosis was absent in the groups without pre-diagnosis weight loss. Pre-to-post diagnosis weight change was similar in patients treated with (−0.1 kg (95%CI −0.8, 0.6)) and without adjuvant chemotherapy (−0.9 kg (95%CI −1.4, −0.5)). Conclusions: Overall, hardly any pre-to-post diagnosis weight change was observed among CRC patients, because post-diagnosis weight gain was mainly observed in patients who lost weight before diagnosis. This was observed independent of treatment with adjuvant chemotherapy.

Background: The understanding of gender differences in inflammatory bowel disease (IBD) patients is an important step towards tailored treatment for the individual patient. The aim of this study was to compare disease phenotype, clinical manifestations, disease activity, and healthcare utilization between men and women with Crohn's disease (CD) and ulcerative colitis (UC).Methods: Two multicenter observational cohort studies with a prospective design were used to explore the differences between men and women regarding demographic and phenotypic characteristics and healthcare utilization. Detailed data on IBD-phenotype was mainly available from the Dutch IBD Biobank, while the COIN cohort provided healthcare utilization data.Results: In the Dutch IBD Biobank study, 2118 CD patients and 1269 UC patients were analyzed. Female CD patients were more often current smokers, and male UC patients were more often previous smokers. Early onset CD (Conclusions: Sex differences in patients with IBD include age of onset, disease location, and EIM prevalence. No large differences in therapeutic management of IBD were observed between men and women with IBD.

Contains fulltext : 172797.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) is considered to be an effective procedure for patients with morbid obesity. Belching is frequently reported after this procedure, but it has not been well studied in the bariatric population. This study aims to assess the changes in belching before and after sleeve gastrectomy, as measured with impedance monitoring. METHODS: In a prospective study, patients underwent 24-h pH-impedance monitoring before and 3 months after LSG. Using this technique, belches can be identified. Preoperative and postoperative upper gastrointestinal symptoms were assessed using the Reflux Disease Questionnaire (RDQ). RESULTS: Fifteen patients (1 M/14 F, mean age 42.2 +/- 11.0 years, mean weight 134.5 +/- 21.1 kg, mean BMI 46.4 +/- 6.0 kg/m(2)) participated in this study. Belching occurred significantly more often after LSG, with an increase in symptom score from 2.9 +/- 2.6 before to 5.3 +/- 3.5 3 months after LSG (p = 0.04). The total number of gastric belches increased from 29.7 +/- 11.7 before to 59.5 +/- 38.3/24 h 3 months after LSG (p = 0.03). The total number of supragastric belches did not change after LSG. The number of swallows decreased from 746.9 +/- 302.4 before to 555.7 +/- 172.5 3 months after the procedure (p = 0.03). The number of air swallows tended to decrease (p = 0.08). Esophageal acid exposure increased significantly, from 3.7 +/- 2.9 % before to 12.6 +/- 10.5 % after LSG (p = 0.01). CONCLUSION: Subjectively (as reported by patients) and objectively (as measured by impedance monitoring), an increase in gastric belches is seen after LSG, while the number of (air) swallows tends to decrease after the procedure and the incidence of supragastric belches remains constant. The altered anatomy as well as increased gastroesophageal reflux after LSG may play a role in the increase of belching.

Background Inflammatory bowel disease (IBD) is associated with high costs to society. Few data on the impact of IBD on work disability and potential predictive factors are available. Aim To assess the prevalence of and predictive factors for work disability in Crohn's disease (CD) and ulcerative colitis (UC). Methods A web-based questionnaire was sent out in seven university hospitals and seven general hospitals in the Netherlands. Initially, 3050 adult IBD patients were included in this prospective, nationwide cohort study, whereof 2629 patients were within the working-age (18–64 years). We used the baseline questionnaire to assess the prevalence rates of work disability in CD and UC patients within working-age. Prevalence rates were compared with the Dutch background population using age- and sex-matched data obtained from Statistics Netherlands. Multivariable logistic regression analyses were performed to identify independent demographic- and disease-specific risk factors for work disability. Results In CD, 18.3% of patients was fully disabled and 8.8% partially disabled, compared to 9.5% and 5.4% in UC patients (p Conclusion We report high work disability rates in a large sample of IBD patients in the Netherlands. CD patients suffer more frequently from work disability than UC patients. A combination of demographic and disease-related factors is predictive of work disability.

Contains fulltext : 109239.pdf (Publisher’s version ) (Open Access) BACKGROUND: Lynch syndrome is a disorder caused by mismatch repair gene mutations. Mutation carriers have a high risk of developing colorectal cancer. In patients with Lynch syndrome in whom colon cancer has been diagnosed, in general, subtotal colectomy instead of partial colectomy is recommended because of the substantial risk of metachronous colorectal cancer. However, the effect of more extensive surgery on quality of life and functional outcome is unknown. OBJECTIVE: The aim of this study was to investigate quality of life and functional outcome in patients with Lynch syndrome after partial colectomy and subtotal colectomy. DESIGN: This is a nationwide cross-sectional study in the Netherlands. SETTINGS: Two quality-of-life questionnaires (Short Form-36 and The European Organization for Research and Treatment of Cancer Colorectal Cancer-specific Quality of Life Questionnaire Module) and a functional outcome questionnaire (Colorectal Functional Outcome) were used. PATIENTS: Patients with Lynch syndrome who underwent surgery for colon cancer were included. MAIN OUTCOME MEASURES: The primary outcomes measured were quality of life and functional outcome. RESULTS: Questionnaires were sent to 192 patients with Lynch syndrome who underwent surgery for colorectal cancer. A total of 136 patients returned the questionnaire (response rate, 71%). Eighteen patients with rectal cancer, 9 patients with a permanent ileostomy, and 5 patients with an IPAA were excluded. Fifty-one patients underwent partial colectomy, and 53 underwent subtotal colectomy. None of the scales of the Short Form-36 survey showed a significant difference. Analysis of the Colorectal Functional Outcome questionnaire revealed that, after subtotal colectomy, patients have a significantly higher stool frequency (p

Patients with Lynch syndrome (LS) are at an increased risk of developing gastric cancer. In 2010, a guideline that recommended to screen all patients for Helicobacter pylori was implemented in the Netherlands. H. pylori is an important risk factor in the development of gastric cancer in the general population, and eradication of the bacterium reduces this risk. We aimed to assess the proportion of LS patients being tested and the yield and also addressed the question whether H. pylori infection is more prevalent in LS families with known cases of gastric cancer. Proven mutation carriers from five different Dutch hospitals were included. The implementation of H. pylori screening and its outcome was examined. The observation period was 2008–2013. The presence of first-degree family members with gastric cancer was noted, and it was observed if H. pylori infection was more prevalent in Lynch families with known cases of gastric cancer. Obtainable endoscopy reports were reviewed. Four hundred forty-three (male, 184) proven mutation carriers were included. The proportion of patients screened increased after 2010, from 37 to 68 %. Twenty percent of the patients were infected. The 25 patients who had a first-degree family member with gastric cancer did not have a higher infection rate. In 30 % of cases, an endoscopy was performed; in four patients, intestinal metaplasia and in eight patients, gastric cancer was found. The recommendation to screen for H. pylori is increasingly followed. The prevalence of infection in this patient group does not differ from the general population. Patients who had a first-degree family member with gastric cancer did not have a higher infection rate.

Contains fulltext : 151954.pdf (Publisher’s version ) (Closed access) BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is an effective bariatric procedure. However, postprandial symptoms can compromise its beneficial effect. It is not known if a changed gastric emptying and these symptoms are related. This study aimed to assess the association between postprandial symptoms and the gastric emptying pattern after LSG. METHODS: A gastric emptying study with a solid and liquid meal component was performed in the second year after LSG. Before the test, symptoms were assessed using a standardized questionnaire, and during the test, symptoms were scored on a visual analog scale (VAS). Gastric emptying results were expressed as lag phase, half time of gastric emptying (T(1/2)), and caloric emptying rate/minute. RESULTS: Twenty patients (14 F/6 M; age 45.6 +/- 7.7 years, weight 93.4 +/- 28.2 kg, BMI 31.6 +/- 8.1 kg/m(2)) participated in this study; 13 had a low symptom score (/=18, group II). VAS scores for epigastric pain, nausea, and belching were significantly higher in group II. Lag phase (solid) was 6.4 +/- 4.5 min in group I, 7.3 +/- 6.3 in group II (p = 0.94); T(1/2) (solid) was 40.6 +/- 10.0 min in group I, 34.4 +/- 9.3 in group II (p = 0.27); caloric emptying rate was 3.9 +/- 0.6 kcal/min in group I, 3.9 +/- 1.0 kcal/min in group II (p = 0.32). CONCLUSIONS: Patients with postprandial symptoms after LSG reported more symptoms during the gastric emptying study than patients without symptoms. However, there was no difference between gastric emptying characteristics between both groups, suggesting that abnormal gastric emptying is not a major determinant of postprandial symptoms after LSG.

During treatment with ursodeoxycholic acid (UDCA), the fasting gallbladder volume increases by a yet unknown mechanism. The present study tests whether in vitro human gallbladder contractility in response to acetylcholine and cholecystokinin is affected by UDCA therapy. Gallbladder tissue was obtained from 15 patients treated with UDCA (10 mg/kg/day) during three weeks prior to surgery, and from 15 comparable patients not treated. Data were correlated with in vivo contractility, bile composition, and gallbladder wall inflammation. The inflammation score was lower in the treated patient group. UDCA treatment enhanced gallbladder contractility in vitro: Dose-response curves for acetylcholine and cholecystokinin were both shifted to the left, and the maximal contractile stress generated in response to cholecystokinin was higher in the treated group, whereas the maximal acetylcholine-induced stress was not increased. Maximal cholecystokinin-induced stress correlated positively with fasting gallbladder volume and negatively with the biliary cholesterol saturation index, but not with bile salt hydrophobicity or gallbladder wall inflammation score. In conclusion, UDCA treatment improves in vitro gallbladder contractility, possibly related to a reduced biliary cholesterol saturation. Increased fasting gallbladder volumes during UDCA treatment thus do not appear to result from decreased gallbladder muscle contractile strength.

Background/Aims: Ursodeoxycholic acid has been reported to be of potential benefit for primary sclerosing cholangitis but little is known about the long-term biochemical, histological and radiological efficacy or the optimum frequency of ursodeoxycholic acid administration. Methods: A 2-year multicentre randomised controlled trial was initiated to assess the effects of ursodeoxycholic acid (10 mg · kg −1 · d − ), given in either single or multiple daily doses, on symptoms, serum liver tests, cholangiographic and histological findings and the occurrence of treatment failure. Liver biopsies were taken and endoscopic retrograde cholangiography was performed at entry and after 2 years; follow-up examinations were at 3-month intervals. Treatment failure was defined as death, liver transplantation, 4-fold increase in serum bilirubin, variceal bleeding, de novo ascites or cholangitis. Actuarial survival was compared with predicted survival using the revised Mayo natural history model for primary sclerosing cholangitis. Results: Forty-eight patients were enrolled. In one case, ursodeoxycholic acid had to be discontinued because of gastro-intestinal complaints. No other side-effects were observed. Afte 2 years of follow-up, treatment was not associated with a beneficial effect on either symptoms or liver histology. Serum liver tests (alkaline phosphate, γ-glutamyl transferase, aspartate aminotransferase) improved significantly in both groups, while serum bilirubin (which was near normal at entry) and IgG remained stable. No major changes in radiographic bile duct appearance seemed to be present. After 2 years, actuarial survival was 91% (95 CI 83%–99%), which is comparable to the predicted 97% survival rate. Treatment failure occurred in 15% of cases. No significant differences in any of the study endpoints (symptoms, serum liver tests, cholangiographic findings, histology, disease progression) were found between the two groups. Conclusions: Ursodeoxycholic acid is well obtained in primary sclerosing cholangitis. Significant effects on biochemical parameters were found and symptoms, bilirubin and histology did not deteriorate. No advantage of a multiple daily dose over a single dose was observed.

OBJECTIVES This study aimed to investigate the association between BMI and esophageal acid exposure in a cohort of patients referred for esophageal pH monitoring. The contributing roles of hiatal hernia, lower esophageal sphincter (LES) pressure, and intragastric pressure (IGP) were investigated, with an emphasis on reflux in the supine position. METHODS Esophageal manometry and 24-h pH-metry results were extracted from a prospectively collected database, and supplemental data (body mass, endoscopy results) from patient files. RESULTS In total, 245 patients (mean age 52.2±14 years, 54% men) were included in this study. In the normal-weight subgroup (n=87), the median acid exposure time was 1.1% [0-8.1] in the supine position (with interquartile range 25-75%) and 7.7% [2.5-14.8] in the upright position; the total acid exposure time was 7.4% [2.7-11.7]/24 h. In the overweight subgroup (n=104), the median acid exposure time was 4.9% [0.3-13.3] in the supine position and 11.1% [5.4-16.9] in the upright position; the total acid exposure time was 8.9% [4.7-15.8]/24 h. In the obesity subgroup (n=54), the median acid exposure time was 4.1% [0.7-14.3] in the supine position and 10.5% [5-17.5] in the upright position; the total acid exposure time was 8.3% [5.3-14.7]/24 h. Supine acid exposure was significantly higher in overweight and obese patients than in normal-weight patients (both P=0.02). In overweight patients, a hiatal hernia was predictive of supine and total acid exposure, as was a decreasing LES pressure in both the supine and the upright position. In obese patients, increased IGP contributed toward an increased total acid exposure. Although an association between increasing BMI and acid exposure was observed, BMI was not independently predictive. CONCLUSION Overweight and obesity is associated with increased reflux, especially in the supine position. The most important factors that contribute toward reflux are the presence of a hiatal hernia and a lower LES pressure in overweight patients and an increased IGP in obese patients.

Contains fulltext : 87226.pdf (Publisher’s version ) (Closed access) BACKGROUND & AIMS: Two percent to 4% of all cases of colorectal cancer (CRC) are associated with Lynch syndrome. Dominant clustering of CRC (non-Lynch syndrome) accounts for 1%-3% of the cases. Because carcinogenesis is accelerated in Lynch syndrome, an intensive colonoscopic surveillance program has been recommended since 1995. The aim of the study was to evaluate the effectiveness of this program. METHODS: The study included 205 Lynch syndrome families with identified mutations in one of the mismatch repair genes (745 mutation carriers). We also analyzed data from non-Lynch syndrome families (46 families, 344 relatives). Patients were observed from January 1, 1995, until January 1, 2009. End points of the study were CRC or date of the last colonoscopy. RESULTS: After a mean follow-up of 7.2 years, 33 patients developed CRC under surveillance. The cumulative risk of CRC was 6% after the 10-year follow-up period. The risk of CRC was higher in carriers older than 40 years and in carriers of MLH1 and MSH2 mutations. After a mean follow-up of 7.0 years, 6 cases of CRC were detected among non-Lynch syndrome families. The risk of CRC was significantly higher among families with Lynch syndrome, compared with those without. CONCLUSIONS: With surveillance intervals of 1-2 years, members of families with Lynch syndrome have a lower risk of developing CRC than with surveillance intervals of 2-3 years. Because of the low risk of CRC in non-Lynch syndrome families, a less intensive surveillance protocol can be recommended. 01 juni 2010

Item does not contain fulltext Observational studies suggest that fish consumption is associated with a decreased colorectal cancer (CRC) risk. A possible mechanism by which fish could reduce CRC risk is by decreasing colonic genotoxicity. However, concerns have also been raised over the levels of toxic compounds found in mainly oil-rich fish, which could increase genotoxicity. Therefore, the objective was to investigate the effects of fish on genotoxicity markers in the colon in a randomized controlled parallel intervention study. For a period of 6 months, subjects were randomly allocated to receive two extra weekly portions of (i) oil-rich fish (salmon), (ii) lean fish (cod) or (iii) just dietary advice (DA). The Comet Assay was used to measure the DNA damage-inducing potential of fecal water (n = 89) and DNA damage in colonocytes (n = 70) collected pre- and post-intervention as markers of genotoxicity. Genotoxicity of fecal water was not markedly changed after fish consumption: 1.0% increase in tail intensity (TI) [95% confidence interval (CI) -5.1; 7.0] in the salmon group and 0.4% increase in TI (95% CI -5.3; 6.1) in the cod group compared with the DA group. DNA damage in colonocytes was also not significantly changed after fish consumption, in either the salmon group (-0.5% TI, 95% CI -6.9; 6.0) or cod group (-3.3% TI, 95% CI -10.8; 4.3) compared with the DA group. Measurements of genotoxicity of fecal water and DNA damage in colonocytes did not correlate (r = 0.06, n = 34). In conclusion, increasing consumption of either oil-rich or lean fish did not affect genotoxicity markers in the colon. 01 juni 2010

BACKGROUND:Diet is a major factor in the etiology of colorectal cancer, with high fish consumption possibly decreasing colorectal cancer risk, as was shown in several observational studies. To date, no intervention trials have examined the possible beneficial effects of fish intake on colorectal cancer risk.OBJECTIVE:The objective was to investigate the effects of a 6-mo intervention with oil-rich or lean fish on apoptosis and mitosis within the colonic crypt.DESIGN:In a multicenter, randomized, controlled intervention trial, patients with colorectal polyps, inactive ulcerative colitis, or no macroscopic signs of disease were recruited (n = 242) and randomly allocated to receive dietary advice plus either 300 g oil-rich fish (salmon) per week (n = 82), 300 g lean fish (cod) per week (n = 78), or only dietary advice (DA) (n = 82). Apoptosis and mitosis were measured in colonic biopsy samples collected before and after intervention (n = 213).RESULTS:The total number of apoptotic cells per crypt did not increase in the salmon or cod group: -0.10 (95% CI: -0.36, 0.16) and -0.06 (95% CI: -0.32, 0.20), respectively, compared with the DA group. The total number of mitotic cells per crypt decreased nonsignificantly in the salmon group (-0.87; 95% CI: -2.41, 0.68) and in the cod group (-1.04; 95% CI: -2.62, 0.53) compared with the DA group. Furthermore, the distribution of mitosis within the crypt did not significantly change in either group.CONCLUSION:An increase in the consumption of either oil-rich or lean fish to 2 portions weekly over 6 mo does not markedly change apoptotic and mitotic rates in the colonic mucosa. This trial was registered at www.clinicaltrials.gov as NCT00145015.

Background: Ursodeoxycholic acid (UDCA) improves liver biochemistry in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Since UDCA acts partly by reducing the intestinal absorption of hydrophobic endogenous bile salts and is poorly absorbed from the intestine, a multiple dose regimen has been advocated. Single dose treatment, on the other hand, may improve compliance. Aim: The effects of a single or multiple dose regimen on liver enzymes and serum and biliary bile salts composition were evaluated. Methods: Twenty-seven patients (19 PSC, 8 PBC), most with early stage disease, received UDCA (10 mg kg −1 day −1 ) in a single dose at bed time ( n =13) or in three divided gifts with meals ( n =14) over 3 months. Five patients had both treatment regimens in random order with a 1-month wash-out period in between. Results: Liver biochemistry equally improved in both groups. Biliary enrichment (% UDCA of total bile salts, mean±SEM) was 40.1±2.4 in the single dose group vs 40.8±2.8 in the multiple dose group ( p =NS) and was positively correlated with biochemical improvement (AP: r =0.47, p =0.02; GGT: r =0.58, p =0.002; ASAT: r =0.67, p =0.002; ALAT: r =0.52, p =0.01). Biochemical improvement was not correlated with the concentration or %UDCA in serum. Patients participating in the cross-over design had comparable biochemical response and biliary %UDCA during both regimens. Conclusion: Single and multiple dose UDCA have similar effects on liver biochemistry and biliary enrichment in cholestatic liver disease. Biochemical improvement appears to be related to biliary (but not serum) enrichment with UDCA.

P194 Is there a difference in quality of life or costs between ulcerative colitis patients with a pouch or an ileostomy? M. Van der Valk1 *, M.-J. Mangen2, G. Dijkstra3, A. van Bodegraven4, H. Fidder1, D. de Jong5, M. Pierik6, C.J. van der Woude7, M. Romberg-Camps8, C. Clemens9, J. Jansen10, P. van de Meeberg11, N. Mahmmod12, C. Ponsioen13, C. Rogge-Wolf14, R. Vermeijden15, P. Siersema1, M. Van Oijen1, B. Oldenburg16. 1University Medical Center Utrecht, Department of Gastroenterology and Hepatology, Utrecht, Netherlands, 2University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care, Utrecht, Netherlands, 3University Medical Center Groningen, Gastroenterology and Hepatology, Groningen, Netherlands, 4VU University Medical Center, Gastroenterology, Amsterdam, Netherlands, 5Universitair Medisch Centrum St Radboud, Afd Maag Darm Leverziekten, Nijmegen, Netherlands, 6Maastricht University Medical Center, Dept of Gastroenterology, Maastricht, Netherlands, 7Erasmus Medical Center, Department of Gastroenterology & Hepatology, Rotterdam, Netherlands, 8Orbis Medical Center, Gastroenterology and Hepatology, Sittard, Netherlands, 9Diaconessenhuis, Gastroenterology and Hepatology, Leiden, Netherlands, 10Onze Lieve Vrouwe Gasthuis, Gastroenterology and Hepatology, Amsterdam, Netherlands, 11Slingeland Hospital, Gastroenterology and Hepatology, Doetinchem, Netherlands, 12Antonius Hospital, Gastroenterology and Hepatology, Nieuwegein, Netherlands, 13Academic Medical Center, Gastroenterology and Hepatology, Amsterdam, Netherlands, 14Reinier de Graaf Gasthuis, Gastroenterology and Hepatology, Delft, Netherlands, 15Meander Medical Center, Gastroenterology and Hepatology, Amersfoort, Netherlands, 16University Medical Centre Utrecht, Department of Gastroenterology, Utrecht, Netherlands