Daniel C. Sadowski

Clinical Practice Guidelines for the Use of Video Capsule Endoscopy

BACKGROUND & AIMS Video capsule endoscopy (CE) provides a noninvasive option to assess the small intestine, but its use with respect to endoscopic procedures and cross-sectional imaging varies widely. The aim of this consensus was to provide guidance on the appropriate use of CE in clinical practice. METHODS A systematic literature search identified studies on the use of CE in patients with Crohns disease, celiac disease, gastrointestinal bleeding, and anemia. The quality of evidence and strength of recommendations were rated using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. RESULTS The consensus includes 21 statements focused on the use of small-bowel CE and colon capsule endoscopy. CE was recommended for patients with suspected, known, or relapsed Crohns disease when ileocolonoscopy and imaging studies were negative if it was imperative to know whether active Crohns disease was present in the small bowel. It was not recommended in patients with chronic abdominal pain or diarrhea, in whom there was no evidence of abnormal biomarkers typically associated with Crohns disease. CE was recommended to assess patients with celiac disease who have unexplained symptoms despite appropriate treatment, but not to make the diagnosis. In patients with overt gastrointestinal bleeding, and negative findings on esophagogastroduodenoscopy and colonoscopy, CE should be performed as soon as possible. CE was recommended only in selected patients with unexplained, mild, chronic iron-deficiency anemia. CE was suggested for surveillance in patients with polyposis syndromes or other small-bowel cancers, who required small-bowel studies. Colon capsule endoscopy should not be substituted routinely for colonoscopy. Patients should be made aware of the potential risks of CE including a failed procedure, capsule retention, or a missed lesion. Finally, standardized criteria for training and reporting in CE should be defined. CONCLUSIONS CE generally should be considered a complementary test in patients with gastrointestinal bleeding, Crohns disease, or celiac disease, who have had negative or inconclusive endoscopic or imaging studies.

Canadian Association of Gastroenterology Clinical Practice Guidelines: the use of infliximab in Crohn's disease.

These guidelines are presented as a follow-up to the original Canadian Association of Gastroenterology Clinical Practice Guidelines: The use of infliximab in Crohns disease, published in the Canadian Journal of Gastroenterology (1). The original guidelines represented publications between 1998 and 2000. The current guidelines have been updated to reflect knowledge gained from two pivotal randomized clinical trails, with the use of infliximab in the maintenance of inflammatory Crohns disease in remission (2) and in the maintenance of fistulous Crohns disease in remission (3).

Biochemical models as early predictors of the etiology of acute pancreatitis

In this study we observed the discriminative ability of five commonly measured laboratory tests to distinguish between gallstone-and non-gallstone-associated pancreatitis. We also assessed the ability of the lipase-amylase ratio to discriminate between alcohol-and non-alcohol-induced pancreatitis. One hundred sixty-two patients with acute pancreatitis were included in the study. Group A consisted of patients presenting to our hospital in 1988 and 1989. Group B consisted of patients presenting in 1992. Models developed using group A patients were validated using group B patients. For gallstone pancreatitis, AST (threshold value 80 IU/liter) alone and a three-factor model, ST, ALP and bilirubin (threshold values of 80 IU/liter, 115 IU/liter, and 15 μmol/liter, respectively) were the best predictors, correctly classifying at least 80% of cases in group A and B. A lipase-amylase ratio of two correctly classified only 48% of cases in group A and 54% in group B. We conclude that biochemical models are useful in predicting the presence of gallstone pancreatitis but not alcoholic pancreatitis.

Crohn's disease genotypes of patients in remission vs relapses after infliximab discontinuation.

AIM To investigate genetic differences between Crohns disease (CD) patients with a sustained remission vs relapsers after discontinuing infliximab while in corticosteroid-free remission. METHODS Forty-eight CD patients received infliximab and were in full corticosteroid-free clinical remission but then discontinued infliximab for reasons other than a loss of response, were identified by review of an electronic database and charts. Infliximab-associated remission was defined as corticosteroid-free plus normalization of clinical disease activity [CD activity index (CDAI) < 150] during follow-up visits based on physician global assessments. A CD relapse (loss of infliximab-induced remission) was clinically defined as a physician visit for symptoms of disease activity (CDAI > 220) and a therapeutic intervention with CD medication(s), or a hospitalization with complications related to active CD. Genetic analyses were performed on samples from 14 patients (n = 6 who had a sustained long term remission after stopping infliximab, n = 8 who rapidly relapsed after stopping infliximab). Nucleotide-binding oligomerization domain 2 (NOD2)/caspase activation recruitment domain 15 (CARD15) polymorphisms (R702W, G908R and L1007fs) and the inflammatory bowel disease 5 (IBD5) polymorphisms (IGR2060a1 and IGR3081a1) were analyzed in each group. RESULTS Five single nucleotide polymorphisms of IBD5 and NOD2/CARD15 genes were successfully analyzed for all 14 subjects. There was no significant increase in frequency of the NOD2/CARD15 polymorphisms (R702W, G908R and L1007fs) and the IBD5 polymorphisms (IGR2060a1 and IGR3081a1) in either group of patients; those whose disease relapsed rapidly or those who remained in sustained long term remission following the discontinuation of infliximab. Nearly a third of patients in full clinical remission who stopped infliximab for reasons other than loss of response remained in sustained clinical remission, while two-thirds relapsed rapidly. There was a marked difference in the duration of clinical remission following discontinuance of infliximab between the two groups. The patients who lost remission did so after 1.0 years ± 0.6 years, while those still in remission were at the time of this study, 8.1 years ± 2.6 years post-discontinuation of infliximab, P < 0.001. The 8 patients who had lost remission after discontinuing infliximab had a mean number of 5 infusions (range 3-7), with a mean treatment time of 7.2 mo (range 1.5 mo-15 mo). The mean duration of time from the last infusion of infliximab to the time of loss of remission was 382 d (range 20 d-701 d). The 6 patients who remained in remission after discontinuing infliximab had a mean number of 6 infusions (range 3-12), with a mean treatment duration of 12 mo (range 3.6 mo-32 mo) (P = 0.45 relative to those who lost remission). CONCLUSION There are no IBD5 or NOD2/CARD15 mutations that predict which patients might have sustained remission and which will relapse rapidly after stopping infliximab.

Proton pump inhibitors and clopidogrel - hazardous drug interaction or hazardous interpretation of data?

Gastroenterologists frequently prescribe proton pump inhibitors (PPIs) for the prevention of nonsteroidal anti-inflammatory drug-induced upper gastrointestinal (GI) bleeding. There is good scientific evidence to support this treatment strategy (1). It is increasingly recognized that antiplatelet agents such as clopidogrel are also associated with increased rates of GI bleeding, similar to those reported with cardioprotective doses of acetylsalicylic acid (ASA) (2). Indeed, a randomized controlled trial (3) has demonstrated that the risk of GI bleeding is higher in patients taking clopidogrel compared with those taking ASA plus a PPI. When administered in combination with ASA, clopidogrel is particularly potent in increasing the risk for upper GI bleeding (RR of bleeding 15.2; 95% CI 4.1 to 56.5) (4). Because of this, PPIs are prescribed with clopidogrel in this situation in the belief that their administration will reduce bleeding. Until recently, the safety of this therapeutic manoeuvre has not been questioned. It is well known in the cardiovascular community that the antiplatelet effect of clopidogrel varies from patient to patient, and that reduced platelet inhibition by clopidogrel is associated with an increased risk for cardiac events (5). The mechanisms underlying clopidogrel resistance are controversial and may relate to heterogeneity in clopidogrel metabolism. Clopidogrel is a prodrug that requires metabolism by cytochrome P450 to an active form. One isoenzyme potentially critical in this step is cytochrome P450 2C19 (CYP2C19). It has been demonstrated that this critical enzyme can be inhibited by PPIs and that reduced patient responsiveness to clopidogrel may be associated with PPI use. An example of this drug-drug interaction is seen in the Omeprazole CLopidogrel Aspirin (OCLA) study (6). One hundred twenty-four consecutive patients undergoing coronary artery stent implantation were randomly assigned to clopidogrel plus omeprazole (20 mg/day) or clopidogrel plus placebo. The effect of clopidogrel on platelet function was assessed by using the platelet phosphorylated vasodilator-stimulated phosphoprotein assay at day 7. The study found that the omeprazole group had a significantly decreased clopidogrel inhibitory effect on platelet function. This report has prompted the United States Food and Drug Administration to request additional studies from the manufacturers of clopidogrel (sanofi-aventis, Bristol-Myers Squibb) to further characterize this potential interaction. In addition to the OCLA trial, two large observational studies (7,8) presented in abstract form have suggested that PPIs may attenuate the beneficial effects of clopidogrel. However, these studies have several shortcomings and a joint comment by the American College of Cardiology (ACC), the American Heart Association (AHA) and the American College of Gastroenterology (ACG) stated that “In the interest of patient safety, the AHA/ACC and the ACG advise that patients who are currently taking these medications should not change their medication regimen unless advised by their health care provider” (9,10). A new Canadian study by Juurlink et al (10) examined hospital discharge data after treatment for myocardial infarction. The investigators found that readmission rates for cardiovascular events within 90 days were statistically higher in patients taking PPIs and clopidogrel. This interaction was not demonstrated with pantoprazole. Similar observations were made in a recently published American study (11) that was previously available only in abstract form. Should these new data change the recommendation by ACC/AHA and ACG? Should we avoid using PPI therapy in patients taking clopidogrel or at least switch them to pantoprazole? The Canadian (10) and American (11) studies are difficult to interpret because the increase in the RR of cardiovascular events for patients taking PPIs was very modest. Because these studies relied on provincial or Veterans Affairs’ retrospective databases, the authors were unable to control for important confounding factors. Studies (12) have shown that patients at high risk for upper GI bleeding (and therefore more likely to be prescribed PPI therapy) are also at higher risk of mortality from cardiovascular events. The results seen in these observational studies may simply be due to a greater tendency to prescribe prophylactic PPIs to patients at higher risk of cardiovascular events. Therefore, it would be important to control for predictors of recurrent myocardial infarction such as left ventricular function, smoking status, ASA use and blood pressure. In both studies, the control and case groups had marked differences in important comorbid health factors, with those taking PPIs having a higher prevalence of renal disease, cancer, chronic obstructive pulmonary disease, congestive heart failure, low left ventricular ejection fraction, previous myocardial infarction, previous coronary artery bypass surgery and diabetes mellitus. The authors performed the appropriate analyses to control for these imbalances but statistics cannot control for unknown or unmeasured confounders that may also exist between the two groups. Given the differences both studies found between cases and controls, it is likely that further imbalances exist and the results could simply be due to residual confounding. To demonstrate the effect of these confounders, a randomized controlled trial (13) of clopidogrel versus placebo stratified for PPI use found that patients given PPIs were more likely to have a cardiovascular event at one year compared with subjects not taking PPIs. Clopidogrel, however, reduced the incidence of cardiovascular events at one year compared with placebo, regardless of whether patients were taking a PPI. Are there other factors at play that may provide an alternative explanation to the PPI-clopidogrel interaction theory? Recently, the existence of reduced-function CYP2C19 alleles has been characterized (14). It was shown that carriers of a CYP2C19 reduced-function allele have significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition and a higher rate of major adverse cardiovascular events, including stent thrombosis, than do noncarriers. To date, there are no published reports of the interaction between these alleles and PPIs. The distribution of these reduced-function alleles in the general population is unknown but preliminary evidence suggests that they may be present in 30% of Caucasians and in up to 55% of East Asians (15). Is there a difference between PPIs in their ability to inhibit CYP2C19? Juurlink et al (10) suggest that pantoprazole does not significantly inhibit CYP2C19. However, a systematic review (16) evaluating the impact of PPIs on cytochrome P450 suggests that the data are heterogeneous and the picture is far from clear. As well, a recent Austrian study (17) of 300 patients undergoing coronary stent insertion found no effect of either pantoprazole or esomeprazole on platelet inhibition by clopidogrel. Esomeprazole was not evaluated by Juurlink et al (10) because this drug was not captured by the Ontario Health Insurance Plan database. Furthermore, from an epidemiological perspective, the data regarding pantoprazole are not as statistically signficant as Juurlink et al (10) claim. When conducting subgroup analyses, it is important not to find just one subgroup that is (or is not) statistically significant for the outcome of interest. The conservative statistical approach is to determine whether one subgroup is significantly different from the other (ie, if there is significant heterogeneity between groups). When this analysis was conducted, there was no significant difference between pantoprazole and the other PPIs (χ2=2.99, degrees of freedom = 1; P=0.08). In light of the above, should PPI prophylaxis of GI bleeding for patients taking ASA and clopidogrel be curtailed? Given the ambiguity in the current level of evidence, we believe that the conclusion reached by the ACC/AHA and ACG remains valid. The United States Food and Drug Administration have also maintained that there is insufficient evidence regarding the interaction between clopidogrel and PPIs, and have highlighted the need for further studies (18). The data are far from clear and multiple confounders require a careful reappraisal of the literature. In particular, some of the previous investigations, such as the OCLA study, will need to be repeated with a subgroup analysis based on reduced-function CYP2C19 allele status. GI bleeding in the setting of ASA and clopidogrel is often severe and is frequently associated with adverse outcomes in groups with pre-existing cardiovascular disease. Discontinuation of PPI prophylaxis for these patients, given the current shaky level of evidence, is premature at best and hazardous at worst.

Proline transport across the intestinal microvillus membrane may be regulated by membrane physical properties

There is now abundant evidence that integral membrane protein function may be modulated by the physical properties of membrane lipids. The intestinal brush border membrane represents a membrane system highly specialized for nutrient absorption and, thus, provides an opportunity to study the interaction between integral membrane transport proteins and their lipid environment. We have previously demonstrated that alterations in this environment may modulate the function of the sodium-dependent glucose transporter in terms of its affinity for glucose. In this communication we report that membrane lipid-protein interactions are distinctly different for the proline transport proteins. Maximal transport rates for L-proline by either the neutral brush border or imino transport systems are reduced 10-fold when the surrounding membrane environment is made more fluid over the physiological range that exists along the crypt-villus axis. Furthermore, in microvillus membrane vesicles prepared from enterocytes isolated from along the crypt-villus axis a similar gradient exists in the functional activity of these transport systems. This would imply that either the functional activity of these transporters are regulated by membrane physical properties or that the synthesis and insertion of these proteins is coordinated in concert with membrane physical properties as the enterocyte migrates up the crypt-villus axis.

Canadian Association of Gastroenterology: Strategic Plan 2016–2020

The CAG is a professional organization that seeks to promote the discipline of gastroenterology in Canada and internationally through a series of activities aligned with a Strategic Plan (renewed and updated every five years) in order to advance our mandate of (i) supporting and engaging in the study of the organs of the digestive tract in health and disease, (ii) promoting the advancement of the science and art of gastroenterology by providing leadership in patient care, research, education, and continuing professional development (CPD), and (iii) promoting and maintaining the highest ethical standards (https://www.cag-acg.org/about/what-is-the-cag/).

Mo1129 Distributed Acoustic Catheter for Real-Time Ambulatory Monitoring of the Opening and Closing of the Lower Esophageal Sphincter

during esophageal impedance-manometry have been associated to the diagnosis of GERD in patients with typical reflux symptoms. In patients with limited compliance this may represent an alternative method in order to investigate GERD. However, due to the complexity of this disorder, the miscellaneous manifestations and inconstant benefit of treatment, MIIpH study remains crucial in the management of patients referred to tertiary centers.

Mo1930 Post Colonoscopy Colorectal Cancer: How Should We Calculate a Rate? Implications for Quality Programs

Background and aim: The fecal immunochemical test (FIT) outperforms guaiac fecal occult blood test in detecting early neoplasms and nowadays many programs have adopted it for population colorectal cancer (CRC) screening but interval cancers still exist. This study aims to elucidate whether adding another fecal sample can further improve the detection rate for advanced adenoma or cancer by FIT. Method: A community-based randomized controlled trial was conducted in four counties (Chang-Hwa, Tainan, Keelung, and Kaohsiung) of Taiwan. Average-risk subjects aged 50 to 69 years were invited and randomized (1:1) to either oneor two-sample arm. The OC-Sensor system (Eiken Chemical, Japan) was used with the cutoff concentration of 100 ng hemoglobin/mL of buffer (equivalent to 20 μg hemoglobin/g of feces). In the two-sample arm, FIT was considered as positive if any one of the samples yielded a positive result. Those subjects with positive tests were verified with colonoscopy. An advanced neoplasm was defined as neoplastic lesions larger than 10 mm, with villous component or high-grade dysplasia, or invasive cancer. Our outcome measures were the intention-to-treat analysis and per-protocol analysis, including the indicators of detection rate for advanced adenoma, advanced neoplasm, and CRC. This trial is registered with ClinicalTrials.gov: NCT01741363. Results: A total of 40,164 subjects participated in the trial and were randomized to either one-day (n=20,132) or two-day (n=20,032) sampling arms. Demographic characteristics, including male gender (42.4% vs. 43.8%) and mean age (58.8 years vs. 58.6 years) were similar between two groups. The positivity rates were 5.6% in one-day and 8.0% in two-day arm (p<0.001). Compliance rate were 96.8% vs. 94.7% (p<0.001) and the referral rates for confirmatory colonoscopy were 62.1% vs. 61.3% (p= 0.68) between two groups. A total of 354 advanced neoplasms (one-day: 166; two-day: 188), including 71 cancers (one-day: 29; two-day: 42) were detected. In the intention-totreat analysis, the detection rate was 0.9% vs. 1.1% for advanced adenoma (p=0.07), 1.0% vs. 1.1% for advanced neoplasm (p=0.09), and 0.2% vs. 0.3% for cancer (p=0.07) in the comparison between one-day and two-day groups. In the per-protocol analysis, the detection rates were 0.9% vs. 1.2% advanced adenoma (p=0.01), 1.0% vs. 1.2% for advanced neoplasm (p=0.02), and 0.2% vs. 0.3% for CRC (p=0.04) in the comparison between two groups. Conclusion:Our community-based randomized trial showed that FIT with two-day sampling may improve the detection of advanced neoplasm or CRC in the per-protocol analysis.

The Perfect Way to Predict the Severity of Acute Pancreatitis: The Search Continues

This study was designed to determine the clinical utility of three rating scales (Ransons, Acute Physiology And Chronic Health Evaluation [APACHE] II and Glasgow) in predicting the severity of acute pancreatitis experienced by patients known to have human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS). A retrospective analysis identified 73 patients with both acute pancreatitis and HIV who had been admitted to two Canadian hospitals between 1989 and 1999. Of those 73, 11 (15%) went on to have a clinical course consistent with a diagnosis of severe pancreatitis. For the purposes of the study, severe pancreatitis was defined by the occurrence of death, intensive care unit admission, surgical intervention or significant symptomatic local complications (necrosis, abscess or pseudocyst). The authors found that the APACHE II and Ransons scores had a sensitivity of 100% and specificities of 70% and 33% for severe pancreatitis, respectively. The Glasgow score had a statistically poorer diagnostic performance.