[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).
[Show abstract][Hide abstract] ABSTRACT: Although endoscopic plastic biliary stenting is a clinical procedure routinely carried out in patients with common bile duct stones, the effects of stenting on the sizes or fragmentation of large common bile duct stones have not been formally established and the mechanism of this condition is controversial. We compared the stone sizes of common bile duct stones after biliary stenting in order to develop the mechanism.
Endoscopic plastic biliary stenting was performed in 45 patients with large common bile duct stones or those difficult to extract with conventional endoscopic therapy, including mechanical lithotripsy. The stone diameter was ≥16mm in all patients. Bile duct drainage and endoscopic placement of 7-8.5 Fr plastic biliary stents were established in all patients. Differences of stone sizes and fragmentations after biliary stenting were compared. The complete stone clearance rate after treatment was obtained.
After biliary stenting for 3-6months, the bile stones disappeared or changed to sludge in 10 (10/45) patients, and fragmentation of the stones or decreased stone sizes were seen in 33 patients, whose stone median size was significantly decreased from 23.1mm to 15.4mm in 33 patients (P<0.05). The stones were removed successfully with basket, balloon, mechanical lithotripsy or a combination in 43 (43/45) patients. The remaining two patients (2/45) demonstrated no significant changes in stone sizes.
Plastic biliary stenting may fragment common bile duct stones and decrease stone sizes. This is an effective and feasible method to clear large or difficult common bile duct stones.
[Show abstract][Hide abstract] ABSTRACT: Smoking is an established risk factor for chronic pancreatitis (CP). We sought to identify how often and in which CP patients physicians consider smoking to be a risk factor.
We analyzed data on CP patients and controls prospectively enrolled from 19 US centers in the North American Pancreatitis Study-2. We noted each subject's self-reported smoking status and quantified the amount and duration of smoking. We noted whether the enrolling physician (gastroenterologist with specific interest in pancreatology) classified alcohol as the etiology for CP and selected smoking as a risk factor.
Among 382/535 (71.4%) CP patients who were self-reported ever smokers, physicians cited smoking as a risk factor in only 173/382 (45.3%). Physicians cited smoking as a risk factor more often among current smokers, when classifying alcohol as CP etiology, and with higher amount and duration of smoking. We observed a wide variability in physician decision to cite smoking as a risk factor. Multivariable regression analysis however confirmed that the association of CP with smoking was independent of physician decision to cite smoking as a risk factor.
Physicians often underrecognize smoking as a CP risk factor. Efforts are needed to raise awareness of the association between smoking and CP. and IAP.
[Show abstract][Hide abstract] ABSTRACT: Effectiveness of medical therapies in chronic pancreatitis has been described in small studies of selected patients.
To describe frequency and perceived effectiveness of non-analgesic medical therapies in chronic pancreatitis patients evaluated at US referral centres.
Using data on 516 chronic pancreatitis patients enrolled prospectively in the NAPS2 Study, we evaluated how often medical therapies [pancreatic enzyme replacement therapy (PERT), vitamins/antioxidants (AO), octreotide, coeliac plexus block (CPB)] were utilized and considered useful by physicians.
Oral PERT was commonly used (70%), more frequently in the presence of exocrine insufficiency (EI) (88% vs. 61%, P < 0.001) and pain (74% vs. 59%, P < 0.002). On multivariable analyses, predictors of PERT usage were EI (OR 5.14, 95% CI 2.87-9.18), constant (OR 3.42, 95% CI 1.93-6.04) or intermittent pain (OR 1.98, 95% CI 1.14-3.45). Efficacy of PERT was predicted only by EI (OR 2.16, 95% CI 1.36-3.42). AO were tried less often (14%) and were more effective in idiopathic and obstructive vs. alcoholic chronic pancreatitis (25% vs. 4%, P = 0.03). Other therapies were infrequently used (CPB - 5%, octreotide - 7%) with efficacy generally <50%.
Pancreatic enzyme replacement therapy is commonly utilized, but is considered useful in only subsets of chronic pancreatitis patients. Other medical therapies are used infrequently and have limited efficacy.
[Show abstract][Hide abstract] ABSTRACT: Benign biliary strictures are typically managed endoscopically whereby an increasing size or number of plastic stents is placed at ERCP. Stents are often changed every 3 to 4 months based on the known median patency of a single biliary stent, but patency data for multiple biliary stents are lacking.
To assess the incidence of occlusion-free survival of multiple plastic biliary stents and the rate of premature occlusion if left in longer than 6 months.
Tertiary-care medical center (Charleston, SC).
Consecutive patients who received multiple plastic stents for benign nonhilar biliary strictures from 1994 to 2008 were identified.
Exchange of multiple plastic biliary stents within 6 months (group 1) or 6 months or longer (group 2) after placement.
Symptomatic stent occlusion.
Seventy-nine patients with nonhilar extrahepatic benign biliary stricture underwent 125 ERCPs with multiple plastic biliary stents. Stents were scheduled for removal/exchange within 6 months in 52 patients (86 ERCPs) compared with after 6 months in 22 patients (26 ERCPs). The median interval between multiple stent placement and removal/exchange was 90 days for group 1 and 242 days for group 2. Premature stent occlusion occurred in 4 of 52 (7.7%) patients in group 1 versus 1 of 22 (4.5%) in group 2, with significantly longer occlusion-free survival in group 2 (log-rank P < .0001).
Retrospective study at a single tertiary referral center.
Multiple plastic biliary stents for benign nonhilar strictures were associated with a low rate of premature symptomatic stent occlusion at more than 6 months and a longer occlusion-free survival.
[Show abstract][Hide abstract] ABSTRACT: Chronic pancreatitis is commonly associated with debilitating abdominal pain, in part due to pancreatic duct obstruction. Pancreatic stones are often impossible to extract from the duct with endoscopic retrograde cholangiopancreatography alone. Extracorporeal shock wave lithotripsy (ESWL) is commonly used for fragmentation of obstructing nephrolithiasis and has demonstrated effectiveness in management of pancreatic stones. Our aim was to examine the outcomes of the first 30 patients with symptomatic pancreatic stones treated with a combination of ESWL and endoscopic therapies.
Patients with symptomatic chronic calcific pancreatitis referred for ESWL (2005-2009) were included. Technical success of ESWL was defined as a) stone fragmentation sufficient to allow extraction of main duct stones at ERCP or b) absence of the targeted main pancreatic duct stones on follow-up radiography. Clinical success of ESWL was defined by Patient Global Impression of Improvement (PGII) score of at least slightly improved.
Thirty patients underwent ESWL. One patient was excluded due to adenocarcinoma. Technical success was achieved in 17/29 (58.6%) patients. 25 (86.2%) patients were available for follow-up (median 35 months, range 3-52 months). Fifteen of twenty-five (60%) patients experienced clinical improvement (10 patients very much improved), but there was no significant reduction in the proportion taking narcotics (50% before vs. 44.4% after ESWL). Pancreatic surgery has been avoided to date in 16 (64%) of the 25 patients.
A multidisciplinary approach, combining ERCP and ESWL, to painful obstructing pancreatic duct stones provided symptomatic improvement and allowed pancreatic surgery to be avoided in the majority of patients.
Southern medical journal 06/2010; 103(6):505-8. · 0.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The minor papilla serves as a site of alternative pancreatic duct drainage via the accessory pancreatic duct.
The objectives of this study were to assess the endoscopic appearance of the minor papilla for characteristics that might predict increased accessory pancreatic duct flow and hence suggest pathology of the downstream pancreatic ductal system.
This was a nonrandomized, prospective analysis of consecutively enrolled patients from a tertiary care medical center (Maine Medical Center, Portland, Maine). The study cohort consisted of consecutive patients presenting for endoscopic retrograde cholangiopancreatography (ERCP) without prior pancreaticobiliary endotherapy or ductography.
Sixty-four patients received a minor papilla score prior to ERCP. A normal pancreatogram was found in 37 of 64 (57.8%) patients; the remaining 27 (42.2%) patients had an abnormal pancreatogram. The median minor papilla bulge score was 0.49 (range 0-3) in the normal pancreatogram group and 2 (range 0-3) in the abnormal pancreatogram group (P < 0.0001). The median minor papilla orifice score of those with a normal pancreatogram was 0 (range 0-2) compared to 2 (range 0-3) in the abnormal pancreatogram group (P < 0.001). The median minor papilla cumulative score of 1 (range 0-5) for the normal pancreatogram group was significantly less than that for the abnormal pancreatogram group (3, range 0-6, P < 0.0001), resulting in a sensitivity of 96.3% for an abnormal pancreatogram. The minor papilla orifice was noted to be either gaping or actively dripping pancreatic juice in four out of five patients with pancreas divisum.
A minor papilla without bulging or a visible orifice would suggest a normal pancreatogram at ERP. Conversely, an abnormal minor papilla, particularly a patent minor papilla orifice, should raise suspicion of pancreatic ductal pathology and can help direct pancreatic endotherapy at the major or minor papillae.
Digestive Diseases and Sciences 10/2009; 55(8):2412-6. · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Performance of endoscopic retrograde cholangiopancreatography (ERCP) requires an intraductal contrast agent. The contrast of choice is an iodine-based agent. The alternatives in patients with a severe allergy to iodinated contrast are limited. We undertook a retrospective review of the success and safety of gadolinium as an alternative radiocontrast agent in patients with allergy to iodine-based contrast in a series of five patients in a tertiary care pancreaticobiliary referral center. The five patients underwent a total of six ERCP procedures using a gadolinium chelate as the radiocontrast agent. ERCP was technically successful in all cases, including pancreatic endotherapy. There were no contrast-related adverse reactions. Gadolinium is concluded to be a reasonable alternative to iodine-based ERCP contrast in selected patients. It provides inferior image quality compared to standard iodine-based contrast but was not technically limiting in our small experience.
[Show abstract][Hide abstract] ABSTRACT: Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are associated with alcohol consumption and cigarette smoking. The etiology of RAP and CP is complex, and effects of alcohol and smoking may be limited to specific patient subsets. We examined the current prevalence of alcohol use and smoking and their association with RAP and CP in patients evaluated at US referral centers.
The North American Pancreatitis Study 2, a multicenter consortium of 20 US centers, prospectively enrolled 540 patients with CP, 460 patients with RAP, and 695 controls from 2000 to 2006. Using self-reported monthly alcohol consumption during the maximum lifetime drinking period, we classified subjects by drinking status: abstainer, light drinker (< or =0.5 drink per day), moderate drinker (women, >0.5 to 1 drink per day; men, >0.5 to 2 drinks per day), heavy drinker (women, >1 to <5 drinks per day; men, >2 to <5 drinks per day), or very heavy drinker (> or =5 drinks per day for both sexes). Smoking was classified as never, past, or current and was quantified (packs per day and pack-years).
Overall, participants' mean (SD) age was 49.7 (15.4) years; 87.5% were white, and 56.5% were women. Approximately one-fourth of both controls and patients were lifetime abstainers. The prevalence of very heavy drinking among men and women was 38.4% and 11.0% for CP, 16.9% and 5.5% for RAP, and 10.0% and 3.6% for controls. Compared with abstaining and light drinking, very heavy drinking was significantly associated with CP (odds ratio, 3.10; 95% confidence interval, 1.87-5.14) after controlling for age, sex, smoking status, and body mass index. Cigarette smoking was an independent, dose-dependent risk factor for CP and RAP.
Very heavy alcohol consumption and smoking are independent risks for CP. A minority of patients with pancreatitis currently seen at US referral centers report very heavy drinking.
Archives of internal medicine 06/2009; 169(11):1035-45. · 11.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pancreatic sphincterotomy is one of several factors associated with an increased risk of post-ERCP pancreatitis (PEP). The needle-knife pancreatic sphincterotomy technique (NKS) is purported to result in less-frequent post-ERCP pancreatitis compared with a standard pull-type sphincterotomy (PTS).
Our purpose was to analyze the experience with both endoscopic pancreatic sphincterotomy (EPS) techniques with respect to post-ERCP pancreatitis at a single tertiary-level referral center.
Tertiary-care medical center (Charleston, South Carolina).
Patients without chronic pancreatitis and with normal retrograde pancreatogram who underwent EPS between 1994 and 2007 were identified. Patients were excluded for the following reasons: pancreatic stent not placed, both sphincterotomy techniques used, any balloon dilation of the ampullary orifice, precut or access papillotomy, pancreas divisum.
A total of 481 patients were identified and underwent 510 ERCPs. Indications for ERCP were recurrent pancreatic-type pain (n = 353) or pancreatitis (n = 157). NKS was used for 395 of 510 (77.5%) cases versus 115 of 510 (22.5%) in which PTS was used. The incidence of post-ERCP pancreatitis was no different between NKS (25/395, 6.4%) and PTS (9/115, 7.8%). Most cases were mild pancreatitis; a single episode of severe PEP occurred in each group.
The risk of post-ERCP pancreatitis does not differ between EPS techniques when performed at a high-volume pancreaticobiliary referral center when using routine prophylactic pancreatic duct stent placement.
[Show abstract][Hide abstract] ABSTRACT: Postoperative adhesions create significant morbidity and mortality. Natural orifice transluminal endoscopic surgery (NOTES) procedures may reduce or eliminate adhesions by avoiding disruption of the parietal peritoneum. The primary aim of this pilot study was to compare adhesion formation after performance and subsequent repair of colonic perforation via transgastric, laparoscopic, or open surgical techniques. The secondary aim was to test the feasibility and outcome of transgastric management of bowel perforation in a prepared model.
15 Yorkshire pigs were divided into three groups of five: transgastric (needle-knife entry with balloon dilation over a wire), laparoscopic, and open surgical. Aspects of adhesion formation (density/vascularity, width of bands, and number of organ pairs involved) were compared after perforation and repair during the same procedure. Intra- and postoperative complications were documented during the 21-day survival period.
All 15 pigs recovered fully with no immediate procedural complications. After 21 days, there was a trend towards a lower adhesion burden regarding density/vascularity and number of organ pairs involved, and a significant reduction in the width of the adhesive bands, when the transgastric group was compared with the surgical groups. Additionally, there was a trend towards decreased adhesions to the peritoneum in the transgastric group.
Repair of colonic perforation during transgastric (NOTES) procedures appear feasible and safe in a porcine model. There appears to be a trend towards a lower rate of adhesion formation with the transgastric approach compared with laparoscopic or open surgery.
[Show abstract][Hide abstract] ABSTRACT: Limited published data exist that address the incidence and outcomes of patients with complete pancreatic-duct disruption.
Report on a single-center experience with this entity that emphasizes the feasibility of endoscopic therapy and long-term outcomes.
Tertiary-care medical center (Portland, Maine).
A total of 189 patients with pancreatic-fluid collections and/or pancreatic fistulas were retrospectively evaluated for the presence of a disconnected pancreatic tail. Patients meeting the definition of disconnected pancreatic tail syndrome (DPTS) with a minimum of 6 months' follow-up were analyzed.
Thirty of 189 patients (16%) met criteria for DPTS. Thirty-six drainage procedures were performed on 29 patients (mean 1.2 procedures per patient). In 22 of 29 patients (76%), the initial drainage procedure was successful. However, recurrent fluid collection(s) developed in 11 of 22 patients (50%) and was seen in those treated surgically and endoscopically. Disruption in the tail (n = 3) was uncommon but invariably required no surgical intervention. The median follow-up was 38 months (range 3-94 months). Diabetes mellitus developed in 16 of 30 patients (53%); 15 of 30 patients (50%) had left-sided portal hypertension; 16 of 30 patients (53%) continue in active medical or surgical follow-up for recurrent symptoms attributable to the disconnected pancreatic tail.
Of patients with a pancreatic-fluid collection and/or fistula, 16% will also have a disconnected pancreatic tail. Endoscopic and surgical drainage techniques are typically initially successful, but both suffer from a high rate of recurrence in the setting of DPTS. The majority of patients will require long-term follow-up because of complications and/or ongoing symptoms.
[Show abstract][Hide abstract] ABSTRACT: Placing small stents in the pancreatic duct at endoscopic retrograde cholangiopancreatography reduces the risk of pancreatitis. However, this practice means that a second procedure might be required to remove the stent, and stents can also damage the duct. The aims of this study were to determine the frequency of spontaneous dislodgment and to assess the incidence of stent-induced ductal irregularities.
We performed a retrospective analysis of consecutive patients seen over a 3-year period (2001 - 2004) who had undergone placement of a 3-Fr pancreatic duct stent and in whom the fate of the stent had been documented. Radiographs were reviewed to determine stent passage at 30 days. If applicable, follow-up pancreatograms were reviewed to assess for stent-induced ductal abnormalities. Statistical analysis was performed using chi-squared and Fisher's exact tests for proportions, and 95 % binomial confidence intervals (CI) were calculated.
Records for 125 consecutive patients who had had 3-Fr pancreatic stents placed were reviewed. The stents had passed spontaneously within 30 days in 110/125 patients (88 %). In the remaining 15 patients (12 %, 95 % CI 6.9 % - 19 %), the stents were still present on follow-up radiographs after a median time of 36 days, (range 31 - 116 days). Stent length, pancreatic sphincterotomy, and pancreas divisum had no effect on the likelihood of spontaneous passage. No stent-induced ductal irregularities were observed.
Nearly 90 % of prophylactic 3-Fr pancreatic duct stents pass spontaneously within 30 days, and these stents were not observed to induce changes in the pancreatic duct.