Acute pancreatitis precedes chronic pancreatitis in the majority of patients: Results from the NAPS2 consortium.

INTRODUCTION: The mechanistic definition of chronic pancreatitis (CP) identifies acute pancreatitis (AP) as a precursor stage. We hypothesized that clinical AP frequently precedes the diagnosis of CP and is associated with patient- and disease-related factors. We describe the prevalence, temporal relationship and associations of AP in a well-defined North American cohort. METHODS: We evaluated data from 883 patients with CP prospectively enrolled in the North American Pancreatitis Studies across 27 US centers between 2000 and 2014. We determined how often patients had one or more episodes of AP and its occurrence in relationship to the diagnosis of CP. We used multivariable logistic regression to determine associations for prior AP. RESULTS: There were 624/883 (70.7%) patients with prior AP, among whom 161 (25.8%) had AP within 2 years, 115 (18.4%) within 3-5 years, and 348 (55.8%) >5 years prior to CP diagnosis. Among 504 AP patients with available information, 436 (86.5%) had >1 episode. On multivariable analyses, factors associated with increased odds of having prior AP were a younger age at CP diagnosis, white race, abdominal pain, pseudocyst(s) and pancreatic duct dilatation/stricture, while factors associated with a lower odds of having prior AP were exocrine insufficiency and pancreatic atrophy. When compared with patients with 1 episode, those with >1 AP episode were diagnosed with CP an average of 5 years earlier. CONCLUSIONS: Nearly three-quarters of patients were diagnosed with AP prior to CP diagnosis. Identifying which AP patients are at-risk for future progression to CP may provide opportunities for primary and secondary prevention.

Differences in Age at Onset of Symptoms, and Effects of Genetic Variants, in Patients With Early vs Late-Onset Idiopathic Chronic Pancreatitis in a North American Cohort.

BACKGROUND & AIMS: Idiopathic chronic pancreatitis (ICP) is the second most common subtype of CP. In 1994, researchers reported the bimodal age at onset of ICP symptoms: early onset ICP (EO-ICP; median age, 19.2 y) and late-onset ICP (LO-ICP; median age, 56.2 y). Ages of onset and clinical features of ICP differed from those of alcohol-related CP (ACP). However, variants in PRSS1 had not yet been associated with ICP. We reexamined ages of onset of ICP in a large, North American cohort of patients, and investigated the effects of genetic factors and alcohol use in patients with EO-ICP, LO-ICP, and ACP. METHODS: We performed a cross-sectional analysis of patients with CP of European ancestry enrolled in the North American Pancreatitis Study 2, a prospective study of 1195 patients with CP from 26 centers in the United States from August 2000 through December 2014. We compared age at onset of symptoms for 130 patients with CP who were lifetime abstainers from alcohol (61 patients with early onset and 69 patients with late onset), 308 light to moderate alcohol drinkers with CP, and 225 patients with ACP and heavy to very heavy alcohol use. DNA from available patients was analyzed for variants associated with CP in SPINK1, CFTR, and CTRC. The Kruskal-Wallis test was used to compare continuous variables across groups and based on genetic variants. RESULTS: Median ages at onset of symptoms were 20 years for patients with EO-ICP and no alcohol use, 58 years for patients with LO-ICP and no alcohol use, 47 years for light to moderate alcohol drinkers with CP, and 44 years for patients with ACP. A higher proportion of patients with EO-ICP had constant pain (65%) than patients with LO-ICP (31%) (P = .04). A higher proportion of patients with ACP had pseudocysts (43%) than patients with EO-ICP (11%) (P = .001). A higher proportion of patients with EO-ICP had pathogenic variants in SPINK1, CFTR, or CTRC (49%) than patients with LO-ICP (23%), light to moderate alcohol drinking with CP (26%), or ACP (23%) (P = .001). Among patients with variants in SPINK1, those with EO-ICP had onset of symptoms at a median age of 12 years, and light to moderate alcohol drinkers with CP had an age at onset of 24 years. Among patients with variants in CFTR, light to moderate alcohol drinkers had an age at onset of symptoms of 41 years, but this variant did not affect age at onset of EO-ICP or ACP. CONCLUSIONS: We confirmed previously reported ages at onset of symptoms for EO-ICP and LO-ICP in a North American cohort. We found differences in clinical features among patients with EO-ICP, LO-ICP, and ACP. Almost half of patients with EO-ICP have genetic variants associated with CP, compared with approximately one quarter of patients with LO-CP or ACP. Genetic variants affect ages at onset of symptoms in some groups.

Pain Experience in Pancreatitis: Strong Association of Genetic Risk Loci for Anxiety and PTSD in Patients With Severe, Constant, and Constant-Severe Pain.

INTRODUCTION: Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are progressive inflammatory syndromes with variable features. Pain is the primary feature that contributes to low physical and mental quality of life with a third of patients reporting severe pain. Pain experience is worsened by depression. Here, we tested the hypothesis that genetic risk of the psychiatric conditions of anxiety and post-traumatic stress disorder (PTSD) is associated with pain in CP and RAP + CP subjects. METHODS: The study cohort included phenotyped and genotyped RAP and CP patients from the North American Pancreatitis Study II of European Ancestry. Candidate genetic association studies were based on the absence of pain vs pain that is constant, constant-severe, or severe. Twenty-eight candidate genetic loci for anxiety and PTSD risk were identified in the literature and were the focus of this study. RESULTS: We identified 24 significant pain-associated single nucleotide polymorphisms within 13 loci across the 3 pain patterns in CP and RAP + CP (P < 0.002). Thirteen anxiety or PTSD genes were within these pain loci indicating nonrandom associations (P < 4.885 × 10-23). CTNND2 was associated with all pain categories and all pancreatitis etiologies. Implicated systems include neuronal signaling (HTR2A, DRD3, NPY, and BDNF), hypothalamic-pituitary-adrenal axis (NR3C1 and FKBP5), and cell-cell interaction (CTNND2 and THBS2). DISCUSSION: A component of constant and severe pain in patients with RAP and CP is associated with genetic predisposition to anxiety and PTSD. Identification of patients at risk eligible for trials of targeted treatment as a component of a multidisciplinary pain management strategy should be formally evaluated.

Increased awareness enhances physician recognition of the role of smoking in chronic pancreatitis.

BACKGROUND: We have previously reported that physicians under-recognize smoking as a chronic pancreatitis (CP) risk factor. We hypothesized that availability of empiric data will influence physician recognition of this relationship. METHODS: We analyzed data from 508 CP patients prospectively enrolled in the North American Pancreatitis Study-2 Continuation and Validation (NAPS2-CV) or NAPS2-Ancillary (AS) studies (2008-2014) from 26 US centers who self-reported ever-smoking. Information on smoking status, physician-defined etiology and identification of smoking as a CP risk factor was obtained from structured patient and physician questionnaires. We compared how often physician identified smoking as a CP risk factor in NAPS2-CV/NAPS2-AS studies with NAPS2-original study (2000-2006). RESULTS: Enrolling physician identified smoking as a risk factor in significantly (all p < 0.001) greater proportion of patients in NAPS2-CV/AS studies when compared with NAPS2-original study among ever (80.7 vs. 45.3%), current (91.3 vs. 53%), past (60.3 vs. 30.2%) smokers, in those who smoked ≤1 pack/day (79.3 vs. 39.5%) or ≥1 packs/day (83 vs. 49.8%). In multivariable analyses, the enrolling physician was 3.32-8.49 times more likely to cite smoking as a CP risk factor in the NAPS2-CV/NAPS2-AS studies based on smoking status and amount after controlling for age, sex, race and alcohol etiology. The effect was independent of enrolling site in a sub-analysis limited to sites participating in both phases of enrollment. CONCLUSIONS: Availability of empiric data likely enhanced physician recognition of the association between smoking and CP. Wide-spread dissemination of this information could potentially curtail smoking rates in subjects with and those at risk of CP.

Chronic Pancreatitis: Pediatric and Adult Cohorts Show Similarities in Disease Progress Despite Different Risk Factors.

OBJECTIVES: The aim of the present study was to investigate the natural history of chronic pancreatitis (CP); patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared. METHODS: Demographics, risk factors, disease duration, management and outcomes of 224 children and 1063 adults were compared using appropriate statistical tests for categorical and continuous variables. RESULTS: Alcohol was a risk in 53% of adults and 1% of children (P < 0.0001); tobacco in 50% of adults and 7% of children (P < 0.0001). Obstructive factors were more common in children (29% vs 19% in adults, P = 0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, P = 0.107). Diabetes was more common in adults than children (36% vs 4% respectively, P < 0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2-CO) were compared with INSPPIRE subjects. These 2 cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2-CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2-CO vs 1% INSPPIRE cohorts, P = 0.011). CONCLUSIONS: Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP.

Validation of Demographics, Etiology, and Risk Factors for Chronic Pancreatitis in the USA: A Report of the North American Pancreas Study (NAPS) Group.

BACKGROUND/OBJECTIVES: Our aim was to validate recent epidemiologic trends and describe the distribution of TIGAR-O risk factors in chronic pancreatitis (CP) patients. METHODS: The NAPS-2 Continuation and Validation (NAPS2-CV) study prospectively enrolled 521 CP patients from 13 US centers from 2008 to 2012. CP was defined by definitive changes in imaging, endoscopy, or histology. Data were analyzed after stratification by demographic factors, physician-defined etiology, participating center, and TIGAR-O risk factors. RESULTS: Demographics and physician-defined etiology in the NAPS2-CV study were similar to the original NAPS2 study. Mean age was 53 years (IQR 43, 62) with 55% males and 87% white. Overall, alcohol was the single most common etiology (46%) followed by idiopathic etiology (24%). Alcohol etiology was significantly more common in males, middle-aged (35-65 years), and non-whites. Females and elderly (≥65 years) were more likely to have idiopathic etiology, while younger patients (<35 years) to have genetic etiology. Variability in etiology was noted by participating centers (e.g., alcohol etiology ranged from 27 to 67% among centers enrolling ≥25 patients). Smoking was the most commonly identified (59%) risk factor followed by alcohol (53%), idiopathic (30%), obstructive (19%), and hyperlipidemia (13%). The presence of multiple TIGAR-O risk factors was common, with 1, 2, ≥3 risk factors observed in 27.6, 47.6, and 23.6% of the cohort, respectively. CONCLUSION: Our data validate the current epidemiologic trends in CP. Alcohol remains the most common physician-defined etiology, while smoking was the most commonly identified TIGAR-O risk factor. Identification of multiple risk factors suggests CP to be a complex disease.

Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis.

CFTR is a dynamically regulated anion channel. Intracellular WNK1-SPAK activation causes CFTR to change permeability and conductance characteristics from a chloride-preferring to bicarbonate-preferring channel through unknown mechanisms. Two severe CFTR mutations (CFTRsev) cause complete loss of CFTR function and result in cystic fibrosis (CF), a severe genetic disorder affecting sweat glands, nasal sinuses, lungs, pancreas, liver, intestines, and male reproductive system. We hypothesize that those CFTR mutations that disrupt the WNK1-SPAK activation mechanisms cause a selective, bicarbonate defect in channel function (CFTRBD) affecting organs that utilize CFTR for bicarbonate secretion (e.g. the pancreas, nasal sinus, vas deferens) but do not cause typical CF. To understand the structural and functional requirements of the CFTR bicarbonate-preferring channel, we (a) screened 984 well-phenotyped pancreatitis cases for candidate CFTRBD mutations from among 81 previously described CFTR variants; (b) conducted electrophysiology studies on clones of variants found in pancreatitis but not CF; (c) computationally constructed a new, complete structural model of CFTR for molecular dynamics simulation of wild-type and mutant variants; and (d) tested the newly defined CFTRBD variants for disease in non-pancreas organs utilizing CFTR for bicarbonate secretion. Nine variants (CFTR R74Q, R75Q, R117H, R170H, L967S, L997F, D1152H, S1235R, and D1270N) not associated with typical CF were associated with pancreatitis (OR 1.5, p = 0.002). Clones expressed in HEK 293T cells had normal chloride but not bicarbonate permeability and conductance with WNK1-SPAK activation. Molecular dynamics simulations suggest physical restriction of the CFTR channel and altered dynamic channel regulation. Comparing pancreatitis patients and controls, CFTRBD increased risk for rhinosinusitis (OR 2.3, p<0.005) and male infertility (OR 395, p<<0.0001). WNK1-SPAK pathway-activated increases in CFTR bicarbonate permeability are altered by CFTRBD variants through multiple mechanisms. CFTRBD variants are associated with clinically significant disorders of the pancreas, sinuses, and male reproductive system.

Pancreatitis Quality of Life Instrument: A Psychometric Evaluation.

OBJECTIVES: Chronic pancreatitis is a significant medical problem that impacts a large number of patients worldwide. In 2014, we developed a disease-specific instrument for the evaluation of quality of life in this group of patients: pancreatitis quality of life instrument (PANQOLI). The goal of this study was to evaluate its psychometric properties: its reliability and its construct validity. METHODS: This is a cross-sectional multi-center study that involved 12 pancreatic disease centers. Patients who met the inclusion/exclusion criteria for chronic pancreatitis were invited to participate. Those who accepted were asked to complete seven questionnaires/instruments. Only patients who completed the PANQOLI were included in the study. Its reliability and its construct validity were tested. RESULTS: A total of 159 patients completed the PANQOLI and were included in the study. They had a mean age of 49.03, 49% were male, and 84% were Caucasian. Six of the 24 items on the scale were removed because of lack of inter-item correlation, redundancy, or lack of correlation to quality of life issues. The final 18-item scale had excellent reliability (Cronbach's alpha coefficient: 0.914) and excellent construct validity with good correlation to generic quality of life instruments (SF-12 and EORTC QLQ-C30/QLQ-PAN26) and lack of correlation to non-quality of life instruments (MAST and DAST). Through exploratory factor analysis, the PANQOLI was found to consist of four subscales: emotional function scale, role function scale, physical function scale, and "self-worth" scale. CONCLUSIONS: PANQOLI is the first disease-specific instrument to be developed and validated for the evaluation of quality of life in chronic pancreatitis patients. It has a unique subscale for "self-worth" that differentiates it from other generic instruments. Studies are currently under way to evaluate its use in other populations not included in this study.

Racial Differences in the Clinical Profile, Causes, and Outcome of Chronic Pancreatitis.

OBJECTIVES: Racial differences in susceptibility and progression of pancreatitis have been reported in epidemiologic studies using administrative or retrospective data. There has been little study, however, on the clinical profile, causes, and outcome of chronic pancreatitis (CP) in black patients. METHODS: We analyzed data on black patients with CP prospectively enrolled in the multicenter North American Pancreatitis Studies from 26 US centers during the years 2000-2014. CP was defined by definitive evidence on imaging studies or histology. Information on demographics, etiology, risk factors, disease phenotype, treatment, and perceived effectiveness was obtained from responses to detailed questionnaires completed by both patients and physicians. RESULTS: Of the 1,159 patients enrolled, 248 (21%) were black. When compared with whites, blacks were significantly more likely to be male (60.9 vs. 53%), ever (88.2 vs. 71.8%), or current smokers (64.2 vs. 45.9%), or have a physician-defined alcohol etiology (77 vs. 41.9%). There was no overall difference in the duration of CP although for alcoholic CP, blacks had a longer duration of disease (8.6 vs. 6.97 years; P=0.02). Blacks were also significantly more likely to have advanced changes on pancreatic morphology (calcifications (63.3 vs. 55.2%), atrophy (43.2 vs. 34.6%), pancreatic ductal stricture or dilatation (72.6 vs. 65.5%) or common bile duct stricture (18.6 vs. 8.2%)) and function (endocrine insufficiency 39.9 vs. 30.2%). Moreover, the prevalence of any (94.7 vs. 83%), constant (62.6 vs. 51%), and severe (78.4 vs. 65.8%) pain and disability (35.1 vs. 21.4%) were significantly higher in blacks. Observed differences were in part related to variances in etiology and duration of disease. No differences in medical or endoscopic treatments were seen between races although prior cholecystectomy (31.1 vs. 19%) was more common in white patients. CONCLUSIONS: Differences were observed between blacks and whites in the underlying cause, morphologic expression, and pain characteristics of CP, which in part are explained by the underlying risk factor(s) with alcohol and tobacco being much more frequent in black patients as well as disease duration.

Impact and outcomes of research sponsored by the American Society for Gastrointestinal Endoscopy.

BACKGROUND AND AIMS: Since 1985, the American Society for Gastrointestinal Endoscopy (ASGE) has awarded grants for endoscopic-related research. The goals of this study were to examine trends in ASGE grant funding and to assess productivity of previous recipients of the ASGE grant awards. METHODS: This was a retrospective cohort analysis of all research grants awarded by the ASGE through 2009. Measures of academic productivity and self-assessment of the ASGE awards' impact on the recipients' careers were defined by using publicly available resources (eg, National Library of Medicine-PubMed) and administration of an electronic survey to award recipients. RESULTS: The ASGE awarded 304 grants totaling $12.5 million to 214 unique awardees. Funding increased 7.5-fold between 1985 and 1989 (mean $102,000/year) and between 2005 and 2009 (mean $771,000/year). The majority of awardees were men (83%), were at or below the level of assistant professor (82%), with a median of 3 years of postfellowship experience at the time of the award, and derived from a broad spectrum of institutions as measured by National Institutes of Health funding rank (median 26, interquartile range [IQR] 12-64). Nineteen percent had a master's degree in a research-related field. Awardees' median publications per year increased from 3.5 (IQR 1.2-9.0) before funding to 5.7 (IQR 1.8-9.5) since funding; P = .04, and median h-index scores increased from 3 (IQR 1-8) to 17 (IQR 8-26); P < .001. Multivariate analysis found that the presence of a second advanced degree (eg, masters or doctorate) was independently predictive of high productivity (odds ratio [OR] 2.92; 95% confidence interval [CI], 1.09-7.81). Among 212 unique grant recipients, 82 (40%) completed the online survey. Of the respondents, median peer-reviewed publications per year increased from 3.4 (IQR 1.9-5.5) to 4.5 (IQR 2.0-9.5); P = .17. Ninety-one percent reported that the ASGE grant had a positive or very positive impact on their careers, and 85% of respondents are currently practicing in an academic environment. Most of the grants resulted in at least 1 peer-reviewed publication (67% per Internet-based search and 81% per survey). CONCLUSIONS: The ASGE research program has grown considerably since 1985, with the majority of grants resulting in at least 1 grant-related publication. Overall academic productivity increased after the award, and the majority of awardees report a positive or very positive impact of the award on their careers. Medical professional societies are an important sponsor of clinical research.

Effect of Covered Metallic Stents Compared With Plastic Stents on Benign Biliary Stricture Resolution: A Randomized Clinical Trial.

IMPORTANCE: Endoscopic placement of multiple plastic stents in parallel is the first-line treatment for most benign biliary strictures; it is possible that fully covered, self-expandable metallic stents (cSEMS) may require fewer endoscopic retrograde cholangiopancreatography procedures (ERCPs) to achieve resolution. OBJECTIVE: To assess whether use of cSEMS is noninferior to plastic stents with respect to stricture resolution. DESIGN, SETTING, AND PARTICIPANTS: Multicenter (8 endoscopic referral centers), open-label, parallel, randomized clinical trial involving patients with treatment-naive, benign biliary strictures (N = 112) due to orthotopic liver transplant (n = 73), chronic pancreatitis (n = 35), or postoperative injury (n = 4), who were enrolled between April 2011 and September 2014 (with follow-up ending October 2015). Patients with a bile duct diameter less than 6 mm and those with an intact gallbladder in whom the cystic duct would be overlapped by a cSEMS were excluded. INTERVENTIONS: Patients (N = 112) were randomized to receive multiple plastic stents or a single cSEMS, stratified by stricture etiology and with endoscopic reassessment for resolution every 3 months (plastic stents) or every 6 months (cSEMS). Patients were followed up for 12 months after stricture resolution to assess for recurrence. MAIN OUTCOMES AND MEASURES: Primary outcome was stricture resolution after no more than 12 months of endoscopic therapy. The sample size was estimated based on the noninferiority of cSEMS to plastic stents, with a noninferiority margin of -15%. RESULTS: There were 55 patients in the plastic stent group (mean [SD] age, 57 [11] years; 17 women [31%]) and 57 patients in the cSEMS group (mean [SD] age, 55 [10] years; 19 women [33%]). Compared with plastic stents (41/48, 85.4%), the cSEMS resolution rate was 50 of 54 patients (92.6%), with a rate difference of 7.2% (1-sided 95% CI, -3.0% to ∞; P < .001). Given the prespecified noninferiority margin of -15%, the null hypothesis that cSEMS is less effective than plastic stents was rejected. The mean number of ERCPs to achieve resolution was lower for cSEMS (2.14) vs plastic (3.24; mean difference, 1.10; 95% CI, 0.74 to 1.46; P < .001). CONCLUSIONS AND RELEVANCE: Among patients with benign biliary strictures and a bile duct diameter 6 mm or more in whom the covered metallic stent would not overlap the cystic duct, cSEMS were not inferior to multiple plastic stents after 12 months in achieving stricture resolution. Metallic stents should be considered an appropriate option in patients such as these. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01221311.

A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis.

BACKGROUND: Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). METHODS: In this multicenter, randomized, placebo-controlled, double-blind clinical trial, we assigned patients at elevated risk for post-ERCP pancreatitis to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Patients were determined to be at high risk on the basis of validated patient- and procedure-related risk factors. The primary outcome was post-ERCP pancreatitis, which was defined as new upper abdominal pain, an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least 2 nights. RESULTS: A total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P=0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P=0.03). CONCLUSIONS: Among patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00820612.).

Evaluation of Pharmacologic Prevention of Pancreatitis After Endoscopic Retrograde Cholangiopancreatography: A Systematic Review.

BACKGROUND & AIMS: There is controversy over the efficacy of pharmacologic agents for preventing pancreatitis after endoscopic retrograde cholangiopancreatography (PEP). We performed a systematic review of PEP pharmacoprevention to evaluate safety and efficacy. METHODS: We performed a systematic search of the literature for randomized controlled trials (RCTs) and meta-analyses of PEP pharmacoprevention through February 2014. After identifying relevant studies, 2 reviewers each extracted information on study characteristics, clinical outcomes, and risk of bias. A research classification scale was developed to identify pharmacologic agents ready for clinical use, agents for which a confirmatory RCT should be considered a high priority, agents for which exploratory studies are still necessary, and agents for which additional research should be of low priority. Clinical and research recommendations for each agent were made by consensus after considering research classification results and other important factors such as magnitude of benefit, safety, availability, and cost. RESULTS: After screening 851 citations and 263 potentially relevant articles, 2 reviewers identified 85 RCTs and 28 meta-analyses that were eligible. On the basis of these studies, rectal nonsteroidal anti-inflammatory drugs were found to be appropriate for clinical use, especially for high-risk cases. Sublingual nitroglycerin, bolus-administered somatostatin, and nafamostat were found to be promising agents for which confirmatory research is warranted. Additional research was found to be required to justify confirmatory RCTs for topical epinephrine, aggressive intravenous fluids, gabexate, ulinastatin, secretin, and antibiotics. CONCLUSIONS: On the basis of a systematic review, NSAIDs are appropriate for use in prevention of PEP, especially for high-risk cases. Additional research is necessary to clarify the role of other pharmacologic agents. These findings could inform future research and guide clinical decision-making and policy.

Chronic pancreatitis pain pattern and severity are independent of abdominal imaging findings.

BACKGROUND & AIMS: Chronic pancreatitis is characterized by inflammation, atrophy, fibrosis with progressive ductal changes, and functional changes that include variable exocrine and endocrine insufficiency and multiple patterns of pain. We investigated whether abdominal imaging features accurately predict patterns of pain. METHODS: We collected data from participants in the North American Pancreatitis Study 2 Continuation and Validation, a prospective multicenter study of patients with chronic pancreatitis performed at 13 expert centers in the United States from July 2008 through March 2012. Chronic pancreatitis was defined based on the detection of characteristic changes by cross-sectional abdominal imaging, endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography, or histology analyses. Patients were asked by a physician or trained clinical research coordinator if they had any abdominal pain during the year before enrollment, those who responded "yes" were asked to select from a list of 5 pain patterns. By using these patterns, we classified patients' pain based on timing and severity. Abnormal pancreatitis-associated features on abdominal imaging were recorded using standardized case report forms. RESULTS: Data were collected from 518 patients (mean age, 52 ± 14.6 y; 55% male; and 87.6% white). The most common physician-identified etiologies were alcohol (45.8%) and idiopathic (24.3%); 15.6% of patients reported no abdominal pain in the year before enrollment. The most common individual pain pattern was described as constant mild pain with episodes of severe pain and was reported in 45% of patients. The most common imaging findings included pancreatic ductal dilatation (68%), atrophy (57%), and calcifications (55%). Imaging findings were categorized as obstructive for 20% and as inflammatory for 25% of cases. The distribution of individual imaging findings was similar among patients with different patterns of pain. The distribution of pain patterns did not differ among clinically relevant groups of imaging findings. CONCLUSIONS: Mechanisms that determine patterns and severity of pain in patients with chronic pancreatitis are largely independent of structural variants observed by abdominal imaging techniques. Pancreas-relevant quantitative and qualitative pain measures should be included in the evaluation of patients with chronic pancreatitis to assess pain severity independently of imaging findings.

Success of single-balloon enteroscopy in patients with surgically altered anatomy.

BACKGROUND: Single-balloon enteroscopy (SBE) was introduced in 2007 to diagnose and treat small-bowel disorders. No study to date has evaluated SBE in patients with surgically altered anatomy outside of ERCP. OBJECTIVE: To evaluate the efficacy, yield, and safety of SBE in patients with surgically altered anatomy. DESIGN: Retrospective study. SETTING: Tertiary-care academic medical center. PATIENTS: All patients with altered surgical anatomy who underwent SBE at the Medical University of South Carolina from July 2007 to September 2013. INTERVENTIONS: SBE. MAIN OUTCOME MEASUREMENTS: Diagnostic yield, therapeutic yield, technical success, and adverse events. RESULTS: A total of 48 patients met inclusion criteria. Mean age was 56 years (77% female). Eleven patients underwent single-balloon PEG placement, 8 single-balloon ERCP, 22 non-PEG/non-ERCP anterograde SBE, and 7 retrograde SBE. Previous surgeries included Roux-en-Y gastric bypass (n=26), small-intestine resection (n=6), colon resection (n=5), Whipple procedure (n=4), choledochojejunostomy (n=3), hepaticojejunostomy (n=1), Billroth I (n=1), Billroth II (n=1), and Puestow procedure (n=1). Procedural indications were PEG tube placement (n=11), choledocholithiasis (n=2), biliary stricture (n=2), obstructive jaundice (n=1), cholangitis (n=1), ampullary mass (n=1), sphincter of Oddi dysfunction (n=1), anemia and/or bleeding (n=15), abdominal pain (n=9), radiologic evidence of obstruction (n=3), and Peutz-Jeghers syndrome (n=2). The technical success rate was 73% in single-balloon PEG placement, 88% in single-balloon ERCP, 82% in other anterograde SBEs, and 86% in retrograde SBEs. No intraprocedural or postprocedural adverse events were observed. LIMITATIONS: Single center, retrospective study. CONCLUSION: SBE is safe and effective in patients with surgically altered anatomy.

The risk of post-ERCP pancreatitis and the protective effect of rectal indomethacin in cases of attempted but unsuccessful prophylactic pancreatic stent placement.

BACKGROUND: It is believed, based on limited observational data, that an unsuccessful attempt to place a prophylactic pancreatic stent substantially increases the risk of post-ERCP pancreatitis (PEP). OBJECTIVE: To better understand the risk of PEP in patients with failed pancreatic stent placement (FPS) and the impact of rectal indomethacin on this risk. DESIGN: Secondary analysis of randomized, controlled trial data. SETTING: University of Michigan and Indiana University. PATIENTS: A total of 577 clinical trial participants at elevated risk for PEP. INTERVENTIONS: Pancreatic stent placement. MAIN OUTCOME MEASUREMENTS: Within the placebo group, we compared PEP rates in patients with FPS, patients who underwent successful stent placement, and in those without a stent attempt. We also performed a regression analysis evaluating the association between FPS and PEP. To define the protective effect of indomethacin, we repeated these analyses in the indomethacin group and in the full study cohort. RESULTS: The incidence of PEP among patients in the placebo group who experienced FPS was 34.7%, significantly exceeding rates in patients who underwent successful stent placement (16.4%) and in those without a stent attempt (12.1%). After we adjusted for known PEP risk factors, FPS was found to be independently associated with PEP. Among the indomethacin group and in the full cohort, FPS was not associated with a higher risk of PEP. LIMITATIONS: Low event rate, FPS not prospectively captured. CONCLUSION: FPS appears to confer an increased risk of PEP, which is attenuated by rectal indomethacin administration. These findings highlight the importance of adequate training and proficiency before endoscopists attempt pancreatic stent placement and the routine use of rectal indomethacin in high-risk ERCP cases.

Incidence and predictors of post-ERCP pancreatitis in patients with suspected sphincter of Oddi dysfunction undergoing biliary or dual sphincterotomy: results from the EPISOD prospective multicenter randomized sham-controlled study.

BACKGROUND AND STUDY AIM: Pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP) is a significant and potentially life-threatening adverse event and is common in patients with suspected sphincter of Oddi dysfunction (SOD). Here we aimed to identify predictors of the risk in this population. PATIENTS AND METHODS: The Evaluating Predictors and Interventions in SOD (EPISOD) study prospectively enrolled 214 post-cholecystectomy patients with SOD type III in seven US centers. Patients were randomized, using a 2:1 allocation, to sphincterotomy or sham procedure, irrespective of the results of sphincter of Oddi manometry. Patients in the sphincterotomy arm who had elevated pancreatic sphincter pressure were randomized to biliary only or to dual (biliary and pancreatic) sphincterotomy. All but one patient received prophylactic pancreatic stents, but none received pharmacological prophylaxis. Post ERCP pancreatitis (PEP) was defined as acute pancreatitis within the subsequent 7 days. Blinded research coordinators at each site called patients at 1 week post-procedure. RESULTS: PEP occurred in 26 patients, in 10.6 % (15/141) in the sphincterotomy arm and 15.1 % (11/73) in the sham arm; unadjusted relative risk 0.71 (95 % confidence interval [95 %CI] 0.34 - 1.46). PEP rate was not significantly different in patients who received sphincterotomy compared with those undergoing sham treatment. In addition, the proportion was not statistically different in those who received biliary sphincterotomy alone (12/94; 12.8 % [95 %CI 6.0 % - 19.5 %]) compared with dual sphincterotomy (3/47; 6.4 % [95 %CI 0.0 % - 13.4 %]). Multivariate analysis identified an interaction between duration of ERCP and sedation type (P < 0.02). CONCLUSION: The performance of biliary or dual sphincterotomy does not increase the risk of PEP in patients suspected of SOD. However, the high rate of PEP in patients with suspected SOD, despite pancreatic stenting in expert centers, is confirmed in this prospective study. The combined effect of duration of ERCP and sedation type on the development of PEP should be further explored.Clinicaltrials.gov registration: NCT00688662.

Is Endoscopic Therapy Effective for Angioectasia in Obscure Gastrointestinal Bleeding?: A Systematic Review of the Literature.

GOAL: We aimed to summarize pooled rebleeding rates of angioectasia after therapeutic endoscopy, and compare these to historical control (no intervention) rates. BACKGROUND: Obscure gastrointestinal bleeding continues to be challenging to diagnose and treat; in America, small bowel angioectasias are the most common cause. Technology advances led to higher diagnostic yield for these lesions; however, therapeutic impact of endoscopy remains unclear. STUDY: A PubMed search (June 1, 2006 to September 19, 2013) with 2 independent reviews sought articles reporting rebleeding rates of symptomatic angioectasia without therapy (natural history) and after endoscopic treatment. This study list was added to studies in the 2007 American Gastroenterological Association systematic review. Data on number of patients who underwent endoscopic therapy, type of therapy used, number of patients who experienced rebleeding, and follow-up time were extracted. Rebleeding data were pooled and weighted averages were reported with 95% confidence intervals (CI). RESULTS: Twenty-four articles (n=490 patients) with data on endoscopic therapy for angioectasia and 6 natural history cohorts (n=130) receiving no therapy for angioectasia were eligible. Of the endoscopic therapy patients, 121 at push enteroscopy and 427 at balloon-assisted enteroscopy; 209/490 (42.7%; 95% CI, 38%-47%) rebled. Of the control (no therapy) patients, 64/130 (49.2%; 95% CI, 40%-58%) rebled. Number needed to treat is estimated at 15 to 16. CONCLUSIONS: Rebleeding rate after endoscopic therapy for symptomatic small bowel angioectasia may be comparable to that expected without therapy. Endoscopic therapy may be ineffective; if effective, the needed to treat is estimated to be high. Controlled studies, with intervention-stratified and etiology-stratified outcomes are needed.

Sphincter of Oddi Dysfunction: Updates from the Recent Literature.

Sphincter of Oddi dysfunction (SOD) has long been a controversial topic, starting with whether it even exists, as a sphincterotomy-responsive entity to treat, for either: (1) post-cholecystectomy abdominal pain and/or (2) idiopathic recurrent acute pancreatitis (IRAP). Many of its aspects had required further research to better prove or refute its existence and to provide proper recommendations for physicians to diagnose and treat this condition. Fortunately, there has been major advancement in our knowledge in several areas over the past few years. New studies on challenging the classification, exploring alternative diagnostic methods, and quantifying the role of sphincterotomy in treatment of SOD for post-cholecystectomy pain and for IRAP were recently published, including a randomized trial in each of the two areas. The goal of this paper is to review recent literature on selected important questions and to summarize the results of major trials in this field.