Understanding bacterial infiltration of the pancreas through a deformable pancreatic duct.

Tiny amount of bacteria are found in the pancreas in pancreatitis and cancer, which seemed involved in inflammation and carcinogenesis. However, bacterial infiltration from the duodenum is inhibited by the physical defense mechanisms such as bile flow and the sphincter of Oddi. To understand how the bacteria possibly infiltrate the pancreas through a deformable pancreatic duct, influenced by the periodic contractions of the sphincter of Oddi, a mathematical model of bacterial infiltration is developed that considered large deformation, fluid flow, and bacterial transport in a deformable pancreatic duct. In addition, the sphincter's contraction wave is modeled by including its propagation from the pancreas toward the duodenum. Simulated structure of the deformed duct with the relaxed sphincter and simulated bile distribution agreed reasonably well with the literature, validating the model. Bacterial infiltration from the duodenum in a deformable pancreatic duct, following the sphincter's contraction, is counteracted by a gradual peristalsis-like deformation of the pancreatic duct, due to an antegrade contraction wave propagation from the pancreas to the duodenum, Parametric sensitivity analysis demonstrated that bacterial infiltration is increased with lower bile and pancreatic juice flow rate, greater contraction amplitude and frequency, thinner wall thickness, and retrograde contraction wave propagation. Since contraction waves following retrograde propagation are increased in patients with common bile duct stones and pancreatitis, they may possibly be factors for continuum inflammation of pancreas. (224 words).

The efficacy and safety of endoscopic sphincterotomy in patients with Sphincter of Oddi dysfunction: a systematic review and meta-analysis.

OBJECTIVE: Sphincter of Oddi dysfunction (SOD) has been used to describe patients with RUQ abdominal pain without an etiology. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of ES (endoscopic sphincterotomy) for SOD. METHODS: The study methodology follows the PRISMA guidelines. A comprehensive search was conducted using MEDLINE and EMBASE databases for RCTs with ES in patients with SOD. The primary outcome assessed was the improvement of abdominal pain after ES/sham. A random effects model was used to calculate pooled estimates for each outcome of interest. RESULTS: Of the initial 55 studies, 23 were screened and thoroughly reviewed. The final analysis included 3 studies. 340 patients (89.7% women) with SOD were included. All patients had a cholecystectomy. Most included patients had SOD type II and III. The pooled rate of technical success of ERCP was 100%. The average clinical success rate was 50%. The pooled cumulative rate of overall AEs related to all ERCP procedures was 14.6%. In the sensitivity analysis, only one study significantly affected the outcome or the heterogeneity. CONCLUSION: ES appears no better than placebo in patients with SOD type III. Sphincterotomy could be considered in patients with SOD type II and elevated SO basal pressure.

Transduodenal Sphincteroplasty: A Visual Case Study.

BACKGROUND: Sphincter of Oddi dysfunction is a challenging and rare clinical entity resulting in pancreatobiliary pain and stasis of bile and pancreatic juice. This problem was classically treated with surgical therapy, but as classification of the disease has changed and newer methods of endoscopic evaluation and therapy have evolved, operative transduodenal sphincteroplasty is now generally reserved as a final therapeutic option for these patients. In this video and manuscript, we describe our approach to operative transduodenal sphincteroplasty in a patient with type I Sphincter of Oddi dysfunction. METHODS: A 50-year-old female with history of Roux-en-Y gastric bypass presented with episodic right-upper-quadrant and epigastric abdominal pain with associated documented elevations in liver chemistries. Preoperative cross-sectional imaging demonstrated dilation of her common bile duct. After multidisciplinary discussion, the decision was made to pursue operative transduodenal sphincteroplasty. RESULTS: All key operative steps of the transduodenal sphincteroplasty are demonstrated in the embedded video. Key operative steps include laparotomy, generous Kocher maneuver, and duodenotomy over the ampulla, allowing access for sequential biliary and pancreatic sphincterotomies and sphincteroplasties with absorbable suture. The duodenotomy and abdominal fascia are then closed. Our patient underwent sequential diet advancement and was discharged to home on postoperative day five. At clinic follow-up, pancreatobiliary-type pain had resolved. CONCLUSION: The embedded video demonstrates a case of operative transduodenal sphincteroplasty, which can provide durable results in appropriate patient populations.

Pancreatic duct pressure: A review of technical aspects and clinical significance.

Pancreatic duct pressure (PDP) dynamics comprise an intricately modulated system that helps maintain homeostasis of pancreatic function. It is affected by various factors, including the rate of pancreatic fluid secretion, patency of the ductal system, sphincter of Oddi function, and pancreatic fluid characteristics. Disease states such as acute and chronic pancreatitis can alter the normal PDP dynamics. Ductal hypertension or increased PDP is suspected to be involved in the pathogenesis of pancreatic pain, endocrine and exocrine pancreatic insufficiency, and recurrent pancreatitis. This review provides a comprehensive appraisal of the available literature on PDP, including the methods used in the measurement and clinical implications of elevated PDP.

Protocol of a randomised controlled phase II clinical trial investigating PREoperative endoscopic injection of BOTulinum toxin into the sphincter of Oddi to reduce bile leakage after hepatic resection: the PREBOT-II trial.

INTRODUCTION: Bile leakage represents a major cause of morbidity following hepatic resection. Although most patients can be managed non-operatively, this complication requires diagnostics and therapeutic interventions. Preoperative endoscopic injection of botulinum toxin (BTX) into the sphincter of Oddi represents an innovative approach to prevent bile leakage. The aim of the PREBOT-II trial is to generate the first randomised controlled trial data on the safety, feasibility and efficacy of preoperative endoscopic BTX injection into the sphincter of Oddi to prevent bile leakage following hepatic resection. METHODS AND ANALYSIS: The PREBOT-II trial is an investigator-initiated, exploratory, multicentre, randomised, controlled, open-label, phase II clinical trial with two parallel study groups. 70 patients scheduled for hepatic resection will be randomised to either the intervention or the control group. Patients of the intervention group will undergo preoperative endoscopic injection of BTX into the sphincter of Oddi 3-10 days before surgery, whereas in the control group only hepatic resection will be performed. The primary endpoint is the occurrence of a postoperative bile leakage within 30 days after hepatic resection according to the definition of the International Study Group of Liver Surgery. The secondary endpoints comprise further postoperative morbidity parameters such as severity of postoperative bile leakage, post-hepatectomy haemorrhage or liver failure, mortality and quality of life up to 3 months after hepatic resection. Safety and feasibility of the procedure will also be recorded. ETHICS, FUNDING AND DISSEMINATION: The PREBOT-II trial has been approved by the German Federal Institute for Drugs and Medical Devices (reference number 4044932) and the Ethics Committee of Heidelberg University (reference number AFmu-558/2021). This trial is supported by the German Federal Ministry of Education and Research. The results will be presented at national and international conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: DRKS00024061, EudraCT: 2020-006001-35.

Sphincter of Oddi dysfunction that could not be diagnosed with Rome IV: a case report.

A 30-year-old female patient presented with monthly episodes of severe intermittent upper abdominal pain, especially after consuming fatty meals. Over a period of 5 years, she visited the emergency department 21 times due to the intensity of the pain. Although the pain appeared consistent with biliary pain, both blood and imaging tests showed no abnormalities. Despite not meeting the Rome IV criteria, we suspected sphincter of Oddi dysfunction (SOD). To further investigate, we conducted hepatobiliary scintigraphy (HBS), which revealed a clear delay in bile excretion. With the patient's informed consent, we performed endoscopic sphincterotomy (EST) and as of 10 months later, there have been no recurrences. This case demonstrates an instance of SOD that could not be diagnosed using the Rome IV criteria alone but was successfully identified through HBS. It underscores the possibility of hidden cases of SOD among patients who regularly experience severe epigastric pain, where routine blood or imaging tests may not provide a diagnosis. HBS may be a useful non-invasive test in confirming the presence of previously undiagnosed SOD. As SOD can be easily treated with EST, updating the current diagnostic criteria to include such types of SOD should be considered in the future.

A Comparison of the Efficacy of Plastic Stent Placement Above and Across the Sphincter of Oddi for Benign Biliary Hilar Stricture.

We investigated the efficacy and safety of endoscopic plastic stent (PS) placement for hilar benign biliary strictures (BBSs) and compared cases with PS placement above (inside stent, IS) and across (usual stent, US) the sphincter of Oddi. Patients who underwent initial endoscopic PS placement for hilar BBSs between August 2012 and December 2021 were retrospectively analyzed. Hilar BBSs in 88 patients were investigated. Clinical success was achieved in 81 of these cases (92.0%), including 38 patients in the IS group and 43 patients in the US group. Unexpected stent exchange (uSE) before the first scheduled PS exchange occurred in 18 cases (22.2%). The median time from first stent placement to uSE was 35 days. There was no significant difference in the rate and median time to uSE between the two groups. The rates of adverse events such as pancreatitis or cholangitis in the two groups did not significantly differ. However, the rate of difficult stent removal in the IS group (15.8%) was significantly higher than that in the US group (0%) (p=0.0019). US placement is preferable to IS placement for scheduled stent exchange, as it offers the same effectiveness and risk of adverse events with easier stent removal.

Effect of sphincter of Oddi dysfunction on the abundance of biliary microbiota (biliary microecology) in patients with common bile duct stones.

Objective: Biliary calculi, a common benign disease of the gastrointestinal tract, are affected by multiple factors, including diet, lifestyle, living environment, and personal and genetic background. Its occurrence is believed to be related to a change in biliary microbiota. Approximately 10%-20% of symptomatic patients with cholecystolithiasis have choledocholithiasis, resulting in infection, abdominal pain, jaundice, and biliary pancreatitis. This study aimed to determine whether a dysfunction in the sphincter of Oddi, which controls the outflow of bile and separates the bile duct from the intestine, leads to a change in biliary microbiota and the occurrence of biliary calculi. Methods: Forty patients with cholecystolithiasis and choledocholithiasis were prospectively recruited. Bile specimens were obtained, and biliary pressure was measured during and after surgery. The collected specimens were analyzed with 16S rRNA gene to characterize the biliary microbiota. The risk factors of common bile duct calculi were analyzed numerically combined with the pressure in the sphincter of Oddi. Results: Different biliary microbiota were found in all cases. Patients with sphincter of Oddi dysfunction had significantly increased biliary microbiota as well as significantly higher level of systemic inflammation than patients with normal sphincter of Oddi. Conclusions: The systemic inflammatory response of patients with sphincter of Oddi dysfunction is more severe, and their microbial community significantly differs from that of patients with normal sphincter of Oddi, which makes biliary tract infection more likely; furthermore, the biliary tract of patients with sphincter of Oddi dysfunction has more gallstone-related bacterial communities.

Hepatic Abscess following Yttrium-90 Radioembolization in Patients with Surgical Bilioenteric Anastomosis or Compromised Sphincter of Oddi: A Tertiary Cancer Center Experience.

Purpose: We describe our experience with the development of hepatobiliary infection in patients with prior surgical, percutaneous, or endoscopic biliary interventions who are receiving transarterial radioembolization (TARE) with yttrium-90 (90Y) for primary or metastatic hepatobiliary lesions. Methods: Records of 15 patients with a history of prior biliary intervention and liver malignancy subsequently treated with TARE at the participating medical center from November 2009 to September 2015 were reviewed. The primary endpoint was the development of a hepatic abscess or cholangitis in a patient after radioembolization. Results: A total of 15 patients comprising 9 men and 6 women, with a median age of 49 years (range 30-73), underwent 17 TARE with 90Y procedures. Of the 15 patients, 2 (13.3%) of them developed a hepatobiliary infection. A single patient (6.6%) developed a hepatobiliary abscess. Conclusion: Our study shows a low incidence rate of hepatic abscess following TARE in patients with prior biliary intervention.

α-Subunit Tyrosine Phosphorylation Is Required for Activation of the Large Conductance Ca2+-Activated Potassium Channel in the Rabbit Sphincter of Oddi.

Large conductance Ca2+-activated potassium (BKCa) channels are regulated by intracellular free Ca2+ concentrations ([Ca2+]i) and channel protein phosphorylation. In hypercholesterolemia (HC), motility impairment of the sphincter of Oddi (SO) is associated with abnormal [Ca2+]i accumulation in smooth muscle cells of the rabbit SO (RSOSMCs), which is closely related to BKCa channel activity. However, the underlying mechanisms regulating channel activity remain unclear. In this study, an HC rabbit model was generated and used to investigate BKCa channel activity of RSOSMCs via SO muscle tone measurement in vitro and manometry in vivo, electrophysiological recording, intracellular calcium measurement, and Western blot analyses. BKCa channel activity was decreased, which correlated with [Ca2+]i overload and reduced tyrosine phosphorylation of the BKCa α-subunit in the HC group. The abnormal [Ca2+]i accumulation and decreased BKCa channel activity were partially restored by Na3VO4 pretreatment but worsened by genistein in RSOSMCs in the HC group. This study suggests that α-subunit tyrosine phosphorylation is required for [Ca2+]i to activate BKCa channels, and there is a negative feedback between the BKCa channel and the L-type voltage-dependent Ca2+ channel that regulates [Ca2+]i. This study provides direct evidence that tyrosine phosphorylation of BKCa α-subunits is required for [Ca2+]i to activate BKCa channels in RSOSMCs, which may be the underlying physiological and pathologic mechanism regulating the activity of BKCa channels in SO cells.

[Pay attention to endoscopic diagnosis and treatment for confluence disease of pancreaticobiliary ducts].

The confluence of pancreaticobiliary ducts refers to the area between the end of common bile duct, the opening of main pancreatic duct and duodenal papilla. Those confluence diseases of pancreaticobiliary ducts will cause obstruction of biliary and pancreatic outflow tract, cholestasis, pancreatic juice deposition or pancreaticobiliary reflux, and thus induce gallstones, cholangitis, pancreatitis and other diseases. Endoscopic ampullary sphincterotomy is an important way to treat biliary and pancreatic diseases, but the length of incision is determined by the anatomy of Oddi sphincter. The endoscopic approach aims to relieve biliary and pancreatic outflow tract obstruction and pancreatic biliary reflux, and avoid enterobiliary reflux.

Stent placement above the sphincter of Oddi is a useful option for patients with inoperable malignant hilar biliary obstruction.

BACKGROUND AND AIMS: Endoscopic biliary drainage (EBD) is essential for the management of malignant hilar biliary obstruction (MHBO). We prospectively evaluated the efficacy and safety of "inside-stent" therapy, where a plastic stent is placed above the sphincter of Oddi without endoscopic sphincterotomy, in patients with inoperable MHBO. METHODS: This study was a multicenter, single-blinded, randomized controlled trial at three centers. Patients with inoperable MHBO were enrolled in this study, and randomly assigned to receive an inside-stent or conventional-stent therapy. The primary endpoint was cumulative stent patency of the initial stent. The secondary endpoints were second stent patency, technical and clinical success rate, adverse events, re-intervention rate, and overall patient survival. RESULTS: Forty-three patients were randomly assigned to the inside-stent group (n = 21) or the conventional-stent group (n = 22). The median cumulative stent patency of the initial stent was 123 days in the inside-stent group and 51 days in the conventional-stent group (P = .031). For patients with the initial stent dysfunction in the conventional-stent group, the inside-stent was placed as a second stent, and its patency was significantly longer than that of the initial stent (P = .0001). The technical and clinical success rate, re-intervention rate, second stent patency, adverse events, and survival probability did not differ between the groups. CONCLUSIONS: Inside-stent therapy appears to be useful not only as an initial stent but also as a second stent for patients with inoperable MHBO. TRIAL REGISTRATION NUMBER: UMIN000004587.

Characteristics of Patients Undergoing Endoscopic Retrograde Cholangiopancreatography for Sphincter of Oddi Disorders.

The concept that sphincter of Oddi dysfunction (SOD) can cause attacks of biliary-type pain in postcholecystectomy patients and those with unexplained recurrent acute pancreatitis, and that endoscopic sphincterotomy can ameliorate symptoms, remains unproven. The Evaluating Predictors and Interventions in Sphincter of Oddi Dysfunction (EPISOD) study of patients without objective evidence for biliary obstruction showed no difference in outcomes between those who underwent sphincterotomy or sham treatment.1 To date, there have been no studies examining the characteristics of patients who still are being offered endoscopic retrograde cholangiopancreatography (ERCP) for SOD since the EPISOD publication, although the absolute number appears to have declined.2.

The Next EPISOD: Trends in Utilization of Endoscopic Sphincterotomy for Sphincter of Oddi Dysfunction from 2010-2019.

BACKGROUND & AIMS: For years, the endoscopic management of the disorder formerly known as Type III Sphincter of Oddi Dysfunction (SOD) had been controversial. In 2013, the results of the Evaluating Predictors and Interventions in Sphincter of Oddi Dysfunction (EPISOD) trial demonstrated that there was no benefit associated with endoscopic sphincterotomy for patients with Type III SOD. We aimed to assess the utilization of endoscopic sphincterotomy for patients with SOD in a large population database from 2010-2019. METHODS: We searched a large electronic health record (EHR)-based dataset incorporating over 300 individual hospitals in the United States (Explorys, IBM Watson health, Armonk, NY). Using Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT) we identified patients with a first-ever diagnosis of "disorder of Sphincter of Oddi" annually from 2010-2019. Subclassification of SOD types was not feasible using SNOMED-CT codes. Stratified by year, we identified the proportion of patients with newly-diagnosed SOD undergoing endoscopic sphincterotomy and those receiving newly-prescribed medical therapy. RESULTS: A total of 39,950,800 individual patients were active in the database with 7,750 index diagnoses of SOD during the study period. The incidence rates of SOD increased from 2.4 to 12.8 per 100,000 persons from 2010-2019 (P < .001). In parallel, there were reductions in the rates of biliary (34.3% to 24.5%) and pancreatic sphincterotomy (25% to 16.4%), respectively (P < .001). Sphincter of Oddi manometry (SOM) was infrequently utilized, <20 times in any given year, throughout the study duration. There were no significant increases in new prescriptions for TCAs, nifedipine, or vasodilatory nitrates. CONCLUSIONS: Among a wide range of practice settings which do not utilize routine SOM, a sudden and sustained decrease in rates of endoscopic sphincterotomy for newly-diagnosed SOD was observed beginning in 2013. These findings highlight the critical importance of high-quality, multi-center, randomized controlled trials in endoscopy to drive evidence-based changes in real-world clinical practice.

Common bile duct pressure in patients with and without cholelithiasis: A case-control study.

BACKGROUND: The reflux of pancreatic enzymes into the bile duct and the gallbladder is an abnormal phenomenon that plays a role in lithogenesis and carcinogenesis. Because the pressure of the common bile duct depends on the pressures of the sphincter of Oddi, its dysfunction would be reflected in an increase in the pressure of the common bile duct in patients with cholelithiasis. The objective of this study was to measure the pressures of the common bile duct in patients with and without cholelithiasis and to relate them to the presence of pancreatobiliary reflux. METHODS: A prospective case-control study was designed. The study universe was constituted by all patients undergoing total gastrectomy for gastric cancer stages I and II over 30 months. The primary outcome measure was to establish differences between common bile duct pressures in patients with and without cholelithiasis. RESULTS: Common bile duct pressures in patients with gallstones showed a significant elevation (16.9 mmHg) compared to patients without gallstones (3.3 mm Hg) (p < 0.0001). These pressures correlated with the levels of amylase and lipase in gallbladder bile; higher levels were found in patients with gallstones compared to patients without gallstones (P < 0.0001). CONCLUSIONS: Common bile duct pressure in patients with cholelithiasis was significantly higher compared to patients without cholelithiasis leading to pancreatobiliary reflux.

Biliary type-II sphincter of Oddi dysfunction with a pancreatic duct dilation: a case report and review of the literature.

BACKGROUND: The double-duct sign is defined as dilation of both the common bile duct and pancreatic duct, which usually indicates pancreatic malignancy. However, benign causes have also been reported to cause a double-duct sign. CASE PRESENTATION: We present the case of a 59-year-old Caucasian female patient admitted to the Gastroenterology Department with intermittent right epigastric abdominal pain and an intact gallbladder. A double-duct sign was seen on endoscopic ultrasound. The suspicion of pancreatic malignancy was excluded through follow-up investigations. Biliary type II sphincter of Oddi dysfunction was diagnosed with an association of the double-duct sign. Sphincterotomy was performed to reduce pain, and there was no recurrence of symptoms during follow-up. CONCLUSIONS: This is the third reported case in the literature of the double-duct sign associated with sphincter of Oddi dysfunction. This case emphasizes that the double-duct sign is not always caused by a local malignancy. The literature review of the reported cases has been summarized to help in the diagnosis of future similar cases.

Axin2+ Peribiliary Glands in the Periampullary Region Generate Biliary Epithelial Stem Cells That Give Rise to Ampullary Carcinoma.

BACKGROUND & AIMS: Peribiliary glands (PBGs), clusters of epithelial cells residing in the submucosal compartment of extrahepatic bile ducts, have been suggested as biliary epithelial stem/progenitor cell niche; however, evidence to support this claim is limited because of a lack of PBG-specific markers. We therefore sought to identify PBG-specific markers to investigate the potential role of PBGs as stem/progenitor cell niches, as well as an origin of cancer. METHODS: We examined the expression pattern of the Wnt target gene Axin2 in extrahepatic bile ducts. We then applied lineage tracing to investigate whether Axin2-expressing cells from PBGs contribute to biliary regeneration and carcinogenesis using Axin2-CreERT mice. RESULTS: Wnt signaling activation, marked by Axin2, was limited to PBGs located in the periampullary region. Lineage tracing showed that Axin2-expressing periampullary PBG cells are capable of self-renewal and supplying new biliary epithelial cells (BECs) to the luminal surface. Additionally, the expression pattern of Axin2 and the mature ductal cell marker CK19 were mutually exclusive in periampullary region, and fate tracing of CK19+ luminal surface BECs showed gradual replacement by CK19- cells, further supporting the continuous replenishment of new BECs from PBGs to the luminal surface. We also found that Wnt signal enhancer R-spondin3 secreted from Myh11-expressing stromal cells, corresponding to human sphincter of Oddi, maintained the periampullary Wnt signal-activating niche. Notably, introduction of PTEN deletion into Axin2+ PBG cells, but not CK19+ luminal surface BECs, induced ampullary carcinoma whose development was suppressed by Wnt inhibitor. CONCLUSION: A specific cell population receiving Wnt-activating signal in periampullary PBGs functions as biliary epithelial stem/progenitor cells and also the cellular origin of ampullary carcinoma.