An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis.

BACKGROUND & AIMS: Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH. METHODS: In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment. Secondary endpoints included safety and tolerability. RESULTS: Seventy patients (mean 57.9 years [SD 14.0]; 72.9% female) were randomly assigned to the MMF plus prednisolone (n = 39) or azathioprine plus prednisolone (n = 31) group. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (difference, 27.4 percentage points; 95% CI 4.0 to 46.7; p = 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%; p = 0.004). No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034). Two patients in the MMF group (5.1%) and eight patients in the azathioprine group (25.8%) discontinued treatment owing to adverse events or serious adverse events (p = 0.018). CONCLUSIONS: In patients with treatment-naive AIH, MMF with prednisolone led to a significantly higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more (serious) adverse events leading to cessation of treatment, suggesting superior tolerability of MMF. IMPACT AND IMPLICATIONS: This randomised-controlled trial directly compares azathioprine and mycophenolate mofetil, both in combination with prednisolone, for the induction of biochemical remission in treatment-naive patients with autoimmune hepatitis. Achieving complete remission is desirable to prevent disease progression. Patients assigned to the mycophenolate mofetil group reached biochemical remission more often and experienced fewer adverse events. The findings in this trial may contribute to the re-evaluation of international guidelines for the standard of care in treatment-naive patients with autoimmune hepatitis. TRIAL REGISTRATION NUMBER: #NCT02900443.

Evaluation of Prevent ID and Quantum Blue rapid tests for fecal calprotectin.

BACKGROUND: Tests for fecal calprotectin are usually either enzyme-linked immunosorbent assays (ELISA) or a time-resolved fluorimetric immunoassay (TRFIA). These time-consuming tests are performed only once every 1 or 2 weeks. Before the results of the tests are known most patients have already undergone colonoscopy. A rapid test, performed on outpatients, could minimize the number of necessary colonoscopies. To establish optimal cut-off values minimizing the necessity for colonoscopies, we compared two commercially available rapid tests with a quantitative TRFIA. METHODS: Fecal samples were collected from 85 patients with lower gastrointestinal complaints. Calprotectin was measured using quantitative TRFIA as well as using two rapid tests: Prevent ID CalDetect and Quantum Blue calprotectin. We used the TRFIA method as the golden standard with a cut-off value of 50 µg/g. The percentage correct classification, sensitivity, specificity and positive and negative predictive value were calculated for both rapid tests at various cut-off levels. RESULTS: Correlation between both of the rapid tests with TRFIA was significant. Quantum Blue calprotectin (κ 0.77) correlated better than Prevent ID CalDetect (κ 0.46). Optimal cut-off levels for Prevent ID CalDetect and Quantum Blue calprotectin rapid tests were 15 µg/g and 40 µg/g with a reduction in the number of necessary colonoscopies of 39% and 62%, respectively. CONCLUSIONS: The Quantum Blue calprotectin rapid test demonstrated better analytical performance than the Prevent ID CalDetect in reducing the number of colonoscopies. Furthermore, the former test has the advantage of using a point of care reader for quantitative measurement and for establishing an optimal cut-off level.

In gastroesophageal reflux disease, differential gene expression in the duodenum points towards enhanced chylomicron production and secretion.

BACKGROUND: Duodenal signaling affects esophageal motility and perception, both pathophysiological factors in gastroesophageal reflux disease (GERD). Duodenal gene expression abnormalities, contributing to altered esophageal sensorimotor function, have not been reported to date. AIM: To identify differentially expressed genes in GERD patients' duodenum. METHODS: Twenty GERD patients (total 24-h acid exposure 6-12%, SAP ≥95%) and ten healthy controls (HC) were included. Two weeks prior to duodenal biopsy collection, ten patients discontinued proton pump inhibitor (PPI) treatment and ten took maximum dose PPI. RNA was profiled on an Affymetrix Human Genome U133 Plus 2.0 array (Affymetrix, Santa Clara, CA, USA). Genes exhibiting a fold change ≥ 1.4 (t test p value <1E-4) were considered differentially expressed. A subset of 21 differentially expressed genes was selected for confirmatory TaqMan low-density array RT-PCR. Mucosal apolipoprotein A-IV (apoA-IV) and cholecystokinin (CCK) concentrations were determined by ELISA and RIA, respectively. RESULTS: In GERD patients off PPI, 23 up- and 23 down-regulated genes relative to HC were found. In GERD patients on PPI, 33 and five genes were higher, respectively, lower expressed. The majority of up-regulated genes were associated with lipid absorption, particularly triglyceride resynthesis and intracellular vesicular transport, rate-limiting processes for chylomicron production and secretion. Differential expression of 11 genes was confirmed by RT-PCR. Mucosal apoA-IV and CCK concentrations (signaling proteins released upon chylomicron secretion) were similar in GERD patients and HC. CONCLUSIONS: The identified mRNA expression differences suggest that in GERD patients' duodenum, the chylomicron production and secretion potential is elevated, and may underlie a mechanism by which postprandial duodenal signaling contributes to GERD symptom generation.

Hyoscine N-butylbromide does not improve polyp detection during colonoscopy: a double-blind, randomized, placebo-controlled, clinical trial.

BACKGROUND: Colonoscopy is used for the detection of neoplastic polyps, although a significant miss rate has been reported. Limited data suggest that the administration of the antispasmodic hyoscine N-butylbromide during colonoscopy improves polyp detection. OBJECTIVE: To investigate whether the use of 20 mg hyoscine N-butylbromide intravenously during colonoscopy improves polyp detection or removal. DESIGN: A prospective, double-blind, placebo-controlled, randomized, clinical trial. SETTING: Nonacademic teaching hospital. PATIENTS: This study involved 674 patients who were routinely referred and accepted for either diagnostic or screening colonoscopy. INTERVENTION: Intravenous injection of either 1 mL hyoscine N-butylbromide (n = 340) or 0.9% NaCl solution (n = 334) when withdrawal was started. MAIN OUTCOME MEASUREMENTS: Polyp detection rate (PDR), adenoma detection rate (ADR), and the advanced lesion detection rate (ALDR), 5% trimmed mean number of polyps, mean withdrawal time. RESULTS: The cecal intubation rate was 96%. The PDR, ADR, and ALDR were 56% versus 60%, 30% versus 31%, and 14% versus 14% in the hyoscine N-butylbromide and placebo groups, respectively (all P values > .25). The means of the total number of detected, removed, and harvested polyps per patient were 1.13 versus 1.21, 1.03 versus 1.06, and 0.89 versus 0.89 in the hyoscine N-butylbromide and placebo groups, respectively (all P values > .37). Mean withdrawal time was 561 versus 584 seconds in the hyoscine N-butylbromide and placebo groups, respectively (P = .34). Multivariate analysis demonstrated no effect of hyoscine N-butylbromide on the investigated parameters. LIMITATIONS: Only experienced colonoscopists participated in the study. CONCLUSION: We found no evidence to support the use of hyoscine N-butylbromide during withdrawal of the colonoscope to improve polyp detection or removal. ( CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN25405865.).

Functional dyspepsia and irritable bowel syndrome in patients with achalasia and its association with non-cardiac chest pain and a decreased health-related quality of life.

OBJECTIVE: In patients with achalasia, little is known about symptoms of the gastrointestinal tract other than the esophagus. The purpose of this study was to determine the prevalence of two functional disorders, functional dyspepsia (FD) and irritable bowel syndrome (IBS), in a group of treated achalasia patients and to assess the additional impact of these disorders on health-related quality of life (HRQoL). MATERIAL AND METHODS: Questionnaires assessing the Rome II criteria for FD and IBS together with the Eckardt clinical symptom score and RAND-36 were sent to 171 treated achalasia patients. RESULTS: Of these patients, 76.6% returned their questionnaires. In the group of achalasia patients, 23% fulfilled the criteria for FD (Dutch general population 13-14%), and 21% fulfilled the criteria for IBS (Dutch general population 1-6%). The prevalence of frequent chest pain (at least weekly) was higher in patients with FD and/or IBS than in those without these symptoms (54.2% versus 28.2%; p=0.004). Female patients with achalasia and with frequent chest pain showed a higher probability of fulfilling the FD and/or IBS criteria (adjusted OR 2.90 (1.18-7.14) and 3.35 (1.4-8.1), respectively; both with p <0.05). Patients fulfilling the FD and/or IBS criteria scored a lower HRQoL on the RAND-36 subscales--pain, social functioning, and vitality--as compared with patients not fulfilling these criteria (p <0.006). CONCLUSIONS; Symptoms of FD and IBS in patients with treated achalasia are common and have a negative impact on HRQoL. Therefore, this has to be included in the standard evaluation of achalasia patients. The association with chest pain suggests a mutual underlying mechanism.

Increased intragastric pressure gradients are involved in the occurrence of acid reflux in gastroesophageal reflux disease.

OBJECTIVE: Increased pressure gradients across the esophagogastric junction (DeltaEGJp) play a role in gastroesophageal flow during TLESR. The aim of this study was to further explore DeltaEGJp in patients with gastroesophageal reflux disease (GERD) and controls. MATERIAL AND METHODS: Twenty GERD patients were studied along with 20 control subjects. High resolution manometry and pH recording were performed 1 h before and 2 h after a liquid meal (500 ml/300 kcal). DeltaEGJp was calculated at the start of a TLESR and at 180, 60, and 10 s before TLESR. RESULTS: DeltaEGJp at the start of a TLESR and at 180, 60, and 10 s before TLESR was markedly increased in GERD patients compared with that in control subjects (9.9 mmHg and 7.5 mmHg, respectively; p<0.05). Whilst intragastric pressure gradients in GERD patients were increased compared with those in controls (4.6 mmHg and 2.5 mmHg, respectively; p<0.01), intraesophageal pressure gradients were similar in both groups. Furthermore, in controls, first- and second-hour postprandial intragastric pressures were decreased compared with in fasting periods (1.9 +/- 0.4 mmHg and 2.1 +/- 0.4 mmHg versus 3.5 +/- 0.4 mmHg; p<0.05), while this was not observed in GERD patients. CONCLUSIONS: In GERD patients, DeltaEGJp is greater than that in controls both before and during TLESR. This phenomenon is caused by increased intragastric pressure and might contribute to increased rates of acid reflux during TLESR in GERD patients.

Gastroesophageal pressure gradients in gastroesophageal reflux disease: relations with hiatal hernia, body mass index, and esophageal acid exposure.

OBJECTIVES: The roles of intragastric pressure (IGP), intraesophageal pressure (IEP), gastroesophageal pressure gradient (GEPG), and body mass index (BMI) in the pathophysiology of gastroesophageal reflux disease (GERD) and hiatal hernia (HH) are only partly understood. METHODS: In total, 149 GERD patients underwent stationary esophageal manometry, 24-h pH-metry, and endoscopy. RESULTS: One hundred three patients had HH. Linear regression analysis showed that each kilogram per square meter of BMI caused a 0.047-kPa increase in inspiratory IGP (95% confidence interval [CI] 0.026-0.067) and a 0.031-kPa increase in inspiratory GEPG (95% CI 0.007-0.055). Each kilogram per square meter of BMI caused expiratory IGP to increase with 0.043 kPa (95% CI 0.025-0.060) and expiratory IEP with 0.052 kPa (95% CI 0.027-0.077). Each added year of age caused inspiratory IEP to decrease by 0.008 kPa (95% CI -0.015-0.001) and inspiratory GEPG to increase by 0.008 kPa (95% CI 0.000-0.015). In binary logistic regression analysis, HH was predicted by inspiratory and expiratory IGP (odds ratio [OR] 2.93 and 2.62, respectively), inspiratory and expiratory GEPG (OR 3.19 and 2.68, respectively), and BMI (OR 1.72/5 kg/m(2)). In linear regression analysis, HH caused an average 5.09% increase in supine acid exposure (95% CI 0.96-9.22) and an average 3.46% increase in total acid exposure (95% CI 0.82-6.09). Each added year of age caused an average 0.10% increase in upright acid exposure and a 0.09% increase in total acid exposure (95% CI 0.00-0.20 and 0.00-0.18). CONCLUSIONS: BMI predicts IGP, inspiratory GEPG, and expiratory IEP. Age predicts inspiratory IEP and GEPG. Presence of HH is predicted by IGP, GEPG, and BMI. GEPG is not associated with acid exposure.

Concomitant functional dyspepsia and irritable bowel syndrome decrease health-related quality of life in gastroesophageal reflux disease.

OBJECTIVE: Previous studies have reported an overlap between gastroesophageal reflux symptoms, functional dyspepsia (FD) and irritable bowel syndrome (IBS). The aim of this study was to investigate the prevalence of FD and IBS in gastroesophageal reflux disease (GERD) and the effect on health-related quality of life (HRQoL). MATERIAL AND METHODS: FD and IBS prevalence and HRQoL were assessed by means of questionnaires in 215 referred and 48 non-referred (non-care-seeking) GERD patients, proven with 24-h pH-metry. HRQoL in 131 matched controls was used for comparison. RESULTS: In this group of GERD patients 25% had FD (Dutch general population 13-14%), 35% had IBS (Dutch general population 0.6-6%) and 5% had both FD and IBS. Only 35% had neither FD nor IBS. Among referred GERD patients, the prevalence of FD and IBS was higher (p=0.002 versus non-referred). Compared with controls, GERD patients without FD/IBS had lower HRQoL scores on only one of the nine SF-36 subscales (p

The role of hiatus hernia in gastro-oesophageal reflux disease.

This article gives an overview of the role of sliding hiatus hernia in gastro-oesophageal reflux disease (GORD). The crural diaphragm acts as an external sphincter of the anti-reflux barrier. Contractions of the crural diaphragm increase lower-oesophageal-sphincter (LOS) pressure during each inspiration and in situations of increased abdominal pressure, whereas these contractions are inhibited when gas and/or a bolus has to pass the gastro-oesophageal junction. A hiatus hernia is associated with GORD symptoms, increased oesophageal acid exposure, and oesophagitis and its severity. In patients with hiatus hernia, the incidence of reflux episodes is increased during periods with low LOS pressure, straining and swallowing. These findings underline the importance of the crural diaphragm, which, when surrounding the LOS, protects against gastro-oesophageal reflux.

Are manometric parameters of the upper esophageal sphincter and pharynx affected by age and gender?

The effects of age and gender on the upper esophageal sphincter's (UES) and pharyngeal manometric parameters were investigated in 84 healthy subjects (45 men, 39 women, mean age = 44 years, range = 18-91). Manometric recordings were performed with solid-state circumferential transducers. Subjects older than 60 years (n = 23) showed a significant lower UES resting pressure. In addition, during water swallows they had a higher UES residual pressure, shorter UES relaxation interval and UES relaxation duration, and a decreased UES relaxation rate. Furthermore, pharyngeal contraction had significant higher amplitude and longer duration in subjects older than 60 years during water swallows. Some of these findings were also observed during cookie and pudding swallows. Women had a higher UES resting pressure and a longer UES relaxation interval than men. The observed changes with increasing age indicate loss of basal tone and decreased compliance of the UES. Increased pharyngeal contraction amplitude and its prolonged duration in the elderly might be compensatory to this. These physiologic effects of age and gender on UES and pharyngeal parameters should be taken into account during analysis of manometric studies.

Small bowel motility affects glucose absorption in a healthy man.

OBJECTIVE: To investigate the relationship between duodenojejunal motor activity and glucose absorption and to evaluate the effect of modification of duodenojejunal motility on glucose absorption by using the prokinetic drug cisapride. RESEARCH DESIGN AND METHODS: We examined seven healthy males, mean age 22 years, who were treated with cisapride 10 mg t.i.d. and placebo during 3 days in a randomized order, with a 2-week time interval. Duodenojejunal manometry was performed after each treatment on the morning of day 3, using an 18-lumen catheter. A liquid nutrient (3 kcal/min) was administered intraduodenally for 30 min, followed by a bolus of the glucose analog 3-O-methylglucose (3-OMG). Plasma 3-OMG concentrations were measured to assess absorption kinetics. RESULTS: The area under the 3-OMG concentration curve in the first 30 min after infusion was related to the number of antegrade propagated pressure waves (r = 0.49, P < 0.05), but not to the peak concentration, time to peak, and absorption fraction. The mean amplitude of pressure waves was higher during cisapride than placebo (P < 0.05), but the reoccurrence of interdigestive motility, numbers of pressure waves, and propagated pressure waves, as well as 3-OMG absorption characteristics, were not significantly different between the two treatments. During both treatments >60% of antegrade propagated pressure waves were propagated over a very short distance (1.5 cm). CONCLUSIONS: Glucose absorption in the human small intestine is related to short-traveling propagated intestinal contractile activity. Cisapride increases the amplitude of pressure waves, but does not affect the organization of pressure waves or the absorption of 3-OMG.