Pancreatic Exocrine Secretion Research Articles

Impacts of pancreatic exocrine insufficiency on gut microbiota.

Pancreatic exocrine insufficiency (PEI) can be induced by various kinds of diseases, including chronic pancreatitis, acute pancreatitis, and post-pancreatectomy. The main pathogenetic mechanism of PEI involves the decline of trypsin synthesis, disorder of pancreatic fluid flow, and imbalance of secretion feedback. Animal studies have shown that PEI could induce gut bacterial overgrowth and dysbiosis, with the abundance of Lactobacillus and Bifidobacterium increasing the most, which could be partially reversed by pancreatic enzyme replacement therapy. Clinical studies have also confirmed the association between PEI and the dysbiosis of gut microbiota. Pancreatic exocrine secretions and changes in duodenal pH as well as bile salt malabsorption brought about by PEI may affect and shape the abundance and composition of gut microbiota. In turn, the gut microbiota may impact the pancreatic exocrine acinus through potential bidirectional crosstalk. Going forward, more and higher-quality studies are needed that focus on the mechanism underlying the impact of PEI on the gut microbiota.

The Modulation of Euglycemic Endocrine and Exocrine Pancreatic Secretions in Iron Deficiency

Objectives: The contribution of pancreatic secretions in iron metabolism has been elucidated, but the clinical outcomes of iron deficiency on pancreatic function are debatable. This study aimed to investigate the modulation of euglycemic endocrine and exocrine pancreatic excretions in response to variations in iron availability. Subjects and Methods: Serum levels of insulin, glucagon, insulin-to-glucagon ratio (IGR), and amylase were determined in 170 adult subjects with variable levels of serum iron. Results: Control (n = 46) and iron-deficient (n = 124) subjects had significant differences (p r = −0.645, p r = 0.653, p Conclusion: Iron deficiency is associated with an adaptive modulation of euglycemic endocrine and exocrine secretions that is consistent with a status of insulin resistance.

Selective and Concentrative Enteropancreatic Recirculation of Antibiotics by Pigs.

Antibiotics that are efficacious for infectious pancreatitis are present in pancreatic exocrine secretion (PES) after intravenous administration and above minimal inhibitory concentrations. We measured concentrations of four antibiotics by tandem liquid chromatography-mass spectroscopy in plasma and PES after enteral administration to juvenile pigs with jugular catheters and re-entrant pancreatic-duodenal catheters. Nystatin, which is not absorbed by the intestine nor used for infectious pancreatitis (negative control), was not detected in plasma or PES. Concentrations of amoxicillin increased in plasma after administration (p = 0.035), but not in PES (p = 0.51). Metronidazole and enrofloxacin that are used for infectious pancreatitis increased in plasma after enteral administration and even more so in PES, with concentrations in PES averaging 3.1 (±0.5)- and 2.3 (±0.6)-fold higher than in plasma, respectively (p's < 0.001). The increase in enrofloxacin in PES relative to plasma was lower after intramuscular administration (1.8 ± 0.5; p = 0.001). The present results demonstrate the presence of a selective and concentrative enteropancreatic pathway of secretion for some antibiotics. Unlike the regulated secretion of bile, the constitutive secretion of PES and intestinal reabsorption may provide a continuous exposure of pancreas tissue and the small intestine to recirculated antibiotics and potentially other therapeutic molecules. There is a need to better understand the enteropancreatic recirculation of antibiotics and the associated mechanisms.

Pancreatic Exocrine Secretion and Weight Gain After Pancreas Transplantation.

Weight gain after pancreas transplant is a poorly understood phenomenon thought to be related to increased posttransplant insulin production, immunosuppressive medications, and appetite changes. No study has investigated the effect of increased exocrine secretion posttransplant. We hypothesized that exocrine function, measured by fecal elastase-1 (FE-1), was normal posttransplant and not correlated with weight gain. Our primary aim was to investigate changes in FE-1 levels with pancreas transplantation and to correlate this with weight gain. Establishing weight trends and identifying additional correlating factors were secondary aims. Forty-two patients that underwent simultaneous pancreas and kidney or pancreas after kidney transplant at a single center between 2013 and 2021 were included. Fecal elastase was measured prospectively in each patient at a single time point, with >500 µg/g categorized as high. Weight and C-peptide values were obtained. All the patients were on steroid-free immunosuppression. Nineteen patients (45%) had fecal elastase levels >500 µg/g, with a maximum of 3910 µg/g; 43% had levels greater than twice the upper limit of normal. The biggest increase in weight occurred between years 1 and 2, which continued to a median weight gain of 14% at 3 years. There was no correlation between weight gain and FE-1, pretransplant C-peptide levels, or duration of diabetes. This study demonstrated supranormal fecal elastase levels and weight gain posttransplant; however, there was no correlation. Future study with serial FE-1 before and after transplant is needed to better assess its correlation with weight gain.

Ultrasound histography in assessing the degree of pancreatic fibrosis in chronic pancreatitis

Aim: to analyze the clinical and pathogenetic significance of ultrasound histography in pancreatic fibrosis in patients with chronic pancreatitis (CP).&#x0D; Materials and methods. One hundred and eighty-six patients with CP were examined. Complete blood count, urinalysis, biochemical blood and urine tests, duodenal intubation test, coproscopy, enzyme immunoassay, and radioimmune assay were performed. The levels of blood transforming growth factor β1 (TGFβ1) and fecal elastase 1 were measured. Ultrasonography and ultrasound histography of the pancreas and liver, Doppler sound study of the abdominal aorta, celiac trunk, and superior mesenteric artery were carried out.&#x0D; Results. There were correlations suggesting decreased exocrine pancreatic function as its fibrosis progressed, which was indirectly reflected in the increased L index of an ultrasound histogram. The positive correlation between L index and TGFβ1 also showed increased L index in more severe pancreatic fibrosis. CP exacerbation was accompanied by decreased Kgst and N, which were confirmed by evident hyperenzymemia (the blood enzyme deviation) with the decrease of those indices. The clinical signs of CP, especially the rise in the number of dyspeptic complaints that show decreased pancreatic exocrine secretion, revealed pancreatic fibrosis. This was also shown by the fact that the debit hour of lipase and the activity of fecal elastase 1 decreased as the L index increased. There were signs that decreased blood flow in the pancreas made the fibrosis and insufficiency of the organ worse. Furthermore, ultrasound histographic findings reflected a positive correlation between pancreatic and hepatic fibrosis.&#x0D; Conclusion. An examination of pancreatic ultrasound histographic correlations led to the conclusion that this technique could be used to estimate the degree of pancreatic fibrosis and CP exacerbation indirectly.

Changes in pancreatic exocrine function, fat and fibrosis in diabetes mellitus: analysis using MR imaging.

To evaluate the relationships between hemoglobin A1c (HbA1c) levels with exocrine pancreatic function using cine-dynamic magnetic resonance cholangiopancreatography (MRCP) and the pancreatic parenchyma using fat-suppressed T1 mapping and the proton density fat fraction (PDFF). Patients who underwent 3T-MRI and HbA1c measurement were retrospectively recruited. MRI included cine-dynamic MRCP with a spatially selective inversion-recovery (SS-IR) pulse, fat-suppressed Look-Locker T1 mapping and multiecho 3D Dixon-based PDFF mapping. The pancreatic exocrine secretion grade on cine-dynamic MRCP, T1 values, and PDFF were analyzed in non-diabetic (n = 32), pre-diabetic (n = 44) and diabetic (n = 23) groups defined using HbA1c. PDFF was weakly correlation with HbA1c (ρ = 0.30, p = 0.002). No correlations were detected between HbA1c and secretion grade (ρ = - 0.16, p = 0.118) or pancreatic parenchymal T1 (ρ = 0.13, p = 0.19). The secretion grade was comparable between the three groups. The T1 value was higher in diabetic (T1 = 1006.2+/- 224.8 ms) than in non-diabetic (T1 = 896.2+/- 86.3 ms, p = 0.010) and pre-diabetic (T1 = 870.1+/- 91.7 ms, p < 0.010) patients. The PDFF was higher in diabetic (FF = 11.8+/- 8.7 %) than in non-diabetic (FF = 6.8+/- 4.2 %, p = 0.014) patients. Pancreatic exocrine function, T1, and FF showed no correlation with HbA1c. Pancreatic T1 and fat fraction is increased in patients with Type 2 diabetes mellitus. This study demonstrates unaffected exocrine function in pre-diabetes and diabetes and confirms that pancreatic parenchymal T1 and FF are increased in patients with diabetes.

Intestinal Enterokinase Deficiency in Pediatrics

Abstract: Congenital enteropeptidase deficiency (CEP), also known as enterokinase deficiency. CEP is an uncommon autosomal recessive genetic disorder mostly characterized by severe chronic diarrhoea after delivery, hypoproteinemia, and failure to grow. Enteropeptidase activity is anticipated to play a significant role in protein digestion. For growth and appropriate development in newborns with a congenital lack of the enzyme, pancreatic enzyme replacement treatment or an amino acid combination must be given. Only 13 cases of enterokinase insufficiency have been recorded since it was originally characterized in 1969. Couples should be informed that prenatal screening is an option and that EKD has a favourable prognosis. However, if an EKD patient is born, parents should be aware of the feeding issue and offer the proper pancreatic exocrine secretion medication. One research found that all patients had been diagnosed as newborns 25 years ago. Even when the pancreatic-enzyme replacement was stopped, they appeared to lead regular lives as adults, free of gastrointestinal issues and with normal body weight. This can be explained by the fact that trypsin, once liberated from its precursor, encourages additional trypsinogen activation in a positive-feedback manner. Better pharmaceutical preparations such as enteric-coated minimicrospheres and delayed-release capsules are used for better results as it maintains the enzyme and prevents its breakdown by stomach acidity. This review aims to summarise current knowledge of pathophysiology, causes, and treatment of Intestinal Enterokinase Deficiency in Pediatrics

S1838 Spontaneous Gastro-pancreatic Fistula: A Rare Complication of Acute Pancreatitis

Introduction: Although Gastrointestinal fistula is a well-recognized complication of acute pancreatitis, it has been rarely reported. Here we present a rare case of spontaneous gastro-pancreatic fistula following acute pancreatitis. Case Description/Methods: 42 y/o female with PMH of SLE with a recent prolonged hospitalization for acute drug-induced pancreatitis with pseudocyst came to ED with fever, abdominal pain, nausea, and vomiting. She was tachycardic, had leukocytosis, and was positive for COVID-19. CT Scan A/P showed multiple infected peripancreatic collections with communication of the left upper quadrant collection with the gastric lumen (Figure). The patient was hospitalized, Kept NPO, and started on fluids and antibiotics. IR evaluated and put 2 pigtail catheters for drainage of peripancreatic collections. The tip of the pigtail catheter in the left peripancreatic/retroperitoneal collection was in the gastric lumen. The surgery team recommended continuing with conservative treatment with parenteral nutrition, and IV antibiotics as the patient were nontoxic with no signs of free perforation, and pancreatitis would more likely erode a staple or suture line and would put the patient at further risk of free perforation if repair attempted. IR was successful in pulling the drain out of the gastric lumen on the second attempt to allow gastric perforation to heal. Antibiotics were upgraded as per the culture and sensitivity results of the drain fluid. Repeated multiple bedside leak tests and CT scans with oral contrast continue to be positive for patent gastro-pancreatic fistula. Pigtails catheter continues to drain significant necrotic collection. The patient continues to be hospitalized and is being managed conservatively with Parenteral nutrition, and IV antibiotics. Discussion: Fistula of the GI tract following acute pancreatitis can be caused by multiple reasons. Necrosis of the bowel may occur concomitantly with the pancreatic or peripancreatic tissue. Furthermore, enzyme-rich fluid and necrosis can lead to vascular thrombosis, which compromises the blood supply of the segmental GI tract, eventually leading to bowel necrosis. GI fistulas are more common in patients with necrotizing pancreatitis with infected pancreatic necrosis. Despite pharmacologic suppression of pancreatic exocrine secretion and advances in endoscopic and percutaneous therapeutic techniques, pancreatic fistula continues to be a source of morbidity and mortality following pancreatitis and requires multidisciplinary treatment.Figure 1.: Peripherally enhancing fluid collection in the left upper quadrant/gastric wall. There is a communication between this collection with the gastric lumen.

P12.07: The Role of Pancreatic Exocrine Secretion in Weight Gain Following Pancreas Transplantation

Introduction: Weight gain after pancreas transplant is a growing concern. Weight gain can lead to post-transplant comorbidities such as diabetes type 2. A few small studies have investigated weight gain after pancreas transplantation, but none have considered the role of the exocrine pancreas. At the time of pancreas transplant, some patients maintain normal exocrine function from their native pancreas. Therefore, we hypothesized that the presence of two exocrine pancreases (native and graft) may contribute to post-transplant weight gain via supranormal levels of pancreatic exocrine secretions within the GI tract, which may contribute to increased nutrient absorption. Methods: We performed a single-center descriptive study including patients that received pancreas transplant between June 2013 through January 2021. The operative technique was the same in all patients, with systemic vascular drainage from graft portal vein to recipient inferior vena cava, and enteric drainage of the pancreas via an anastomosis between graft duodenum and recipient proximal jejunum. Stool samples were collected from all patients at a single time-point in the post-transplant period. Stool was used to measure fecal elastase-1 (FE-1) in order to quantify the exocrine function of native and/or graft pancreas. Levels of FE-1 were correlated with levels of post-transplant weight gain. Results: 42 patients were included in the study (Figure 1). The median FE-1 was 432 ug/g. For those with excessive weight gain (defined by >7% body weight), median was 409 ug/g. For those without excessive weight gain, FE-1 was 405 ug/g. There was no correlation between FE-1 and weight gain post-transplant. There was an inverse correlation between FE-1 and time from transplant (p=0.02), which can be seen in Figure 2. Post-transplant weight trends were similar to prior studies, where patients lost up to 8% of body weight at 1-month post-transplant and returned to baseline weight by 6 months. The largest increase in weight occurred post-transplant between years one and two. Conclusion: Exocrine secretions appear to decrease over time following pancreas transplant. Additional prospective research, with evaluation of pre- and post-transplant FE-1 will be required to determine the influence of exocrine function on weight gain following pancreas transplantation.Funding provided by the Department of Surgery, Rush University Medical Center.

Ghrelin as a promising biological marker in cardiovascular disease

This review highlights the current literature data on the peptide hormone ghrelin. Ghrelin is a 28-amino-acid peptide, which is the only known peptide hormone modified with fatty acids. Ghrelin is a natural receptor ligand that stimulates the secretion of growth hormones. In addition to the stomach, ghrelin is expressed in many organs such as the duodenum, jejunum, ileum, colon, lungs, heart, pancreas, kidneys, testicles, pituitary gland, and hypothalamus. The main biological functions of this peptide include growth hormone secretion, appetite stimulation, modulation of gastric acid secretion and motility, and an increase in endocrine and exocrine pancreatic secretions. Reference intervals for ghrelin are 8.50216.6 pg/mL. The studies analyzed have shown a strong relationship between ghrelin and cardiovascular system function. Studies have also described the cardioprotective effects of ghrelin. However, the molecular mechanisms underlying the effects of ghrelin on the heart are not fully understood. A further deeper understanding of the role of ghrelin and future clinical studies are necessary to determine the diagnostic, prognostic, and possibly therapeutic significance of this biomarker.

Metabolic effects of truncal vagotomy when combined with bariatric-metabolic surgery

Bariatric-metabolic surgery (BMS) in patients with obesity frequently leads to remission of concurrent type 2 diabetes mellitus (T2DM), even before body weight loss takes place. This is probably based on the correction of a dysmetabolic cycle in the gastrointestinal physiology of T2DM that includes increased vagus-dependent exocrine pancreatic secretion (EPS) and, hence, amplified digestion and nutrient absorption. The resultant chronic exposure of tissues to high plasma levels of glucose, fatty acids and amino acids causes tissue resistance to the actions of insulin and, at a later stage, β-cell dysfunction and reduction of insulin release. We hypothesize that the addition of a surgical truncal vagotomy (TV) may improve and solidify the beneficial results of BMS on T2DM by stably decreasing EPS, − hence reducing the digestion and absorption of nutrients -, and increasing incretin secretion as a result of increased delivery of unabsorbed nutrients to the distal intestine. This hypothesis is supported by surgical data from gastrointestinal malignancies and peptic ulcer operations that include TV, as well as by vagal blockade studies. We suggest that TV may result in a stable reduction of EPS, and that its combination with the appropriate type of BΜS, may enhance and sustain the salutary effects of the latter on T2DM.

Multiple roles for cholinergic signaling in pancreatic diseases.

Cholinergic nerves are widely distributed throughout the human body and participate in various physiological activities, including sensory, motor, and visceral activities, through cholinergic signaling. Cholinergic signaling plays an important role in pancreatic exocrine secretion. A large number of studies have found that cholinergic signaling overstimulates pancreatic acinar cells through muscarinic receptors, participates in the onset of pancreatic diseases such as acute pancreatitis and chronic pancreatitis, and can also inhibit the progression of pancreatic cancer. However, cholinergic signaling plays a role in reducing pain and inflammation through nicotinic receptors, but enhances the proliferation and invasion of pancreatic tumor cells. This review focuses on the progression of cholinergic signaling and pancreatic diseases in recent years and reveals the role of cholinergic signaling in pancreatic diseases.

Neurotensin and xenin stimulates pancreatic exocrine secretion through the peripheral cholinergic nerves in conscious sheep

The present study aimed to clarify the effects of neurotensin and xenin on pancreatic exocrine secretion in conscious sheep and their mechanism of actions. The animals were equipped with two silastic cannulae in the common bile duct to separately collect pancreatic fluid and bile, and a silastic cannula in the proximal duodenum to continuously return the mixed fluids. NT and xenin were intravenously injected at range of 0.01–3.0 nmol/kg during the phase I of duodenal migrating motor complex. A single intravenous NT injection significantly and dose-dependently increased pancreatic fluid, protein, and bicarbonate outputs. The effect of NT at 1 nmol/kg was completely inhibited by a background intravenous infusion of atropine methyl nitrate at a dose of 10 nmol/kg/min, however, the effect was not altered by a prior injection of the neurotensin receptor subtype (NTR)-1 antagonist SR 48692 at 60 nmol/kg. Moreover, a single intravenous xenin-25 injection significantly and dose-dependently increased pancreatic fluid and protein output, whereas the effect of xenin-25 did not clearly show dose-dependence. The prior SR 48692 injection at 30 nmol/kg did not significantly alter the effects of xenin-25 at 0.3 nmol/kg, while the atropine infusion significantly inhibited the increase in fluid secretion. Under the atropine infusion, xenin-25 at 0.3 nmol/kg did not increase protein and bicarbonate outputs, whereas the inhibitory effect of the atropine was not significant compared to that of the single injection of xenin-25. A single intravenous injection of NTR-2 agonist levocabastine at 0.1–3 nmol/kg did not alter pancreatic exocrine secretion. These results suggest that both NT and xenin-25 effectively stimulates pancreatic exocrine secretion through the peripheral cholinergic system in sheep and that NTR-2 is not involved in the regulation of pancreatic exocrine secretion, however, we did not precisely determine the role of NTR-1 in the actions of both the peptides on pancreatic exocrine secretion.

1451-P: Peri-Islet Fibrosis in Cystic Fibrosis Is Associated with Altered Alpha-Cell Phenotype

Cystic fibrosis (CF) is caused by CF transmembrane conductance regulator mutations leading to impaired epithelial cell anion transport and thickened pancreatic exocrine secretions. CF-related diabetes commonly ensues through impact of pancreatic exocrine pathology on islet cell mass and function although specific mechanisms remain unclear. Paraffin-embedded blocks obtained post mortem from pancreatic body in 9 donors with CF (6 (67%) male; age: 0-27 years) were studied. Following haematoxylin and eosin staining, CF changes were scored as early, advanced or end-stage and islet microenvironment was evaluated for presence of surrounding fibrosis and adipocyte replacement. Four donors were categorised as ‘early’ pathology with 0 (1) % (median (IQR)) of islets surrounded by uninterrupted fibrosis and 0 (0) % by adipocyte replacement; 1 donor was categorised as ‘advanced’ with 100% fibrosis, 0% adipocyte replacement; and 4 donors were categorised as ‘end-stage’ with 65 (46) % fibrosis, 12 (32) % adipocyte replacement. Presence of glucagon/vimentin co-expressing cells was demonstrated by immunofluorescence staining / confocal microscopy in 1 (25%) donor with ‘early’ CF pathology and in all with more advanced exocrine changes. All islets with altered alpha-cell phenotype had peri-islet fibrosis. In pancreata with &amp;lt;50% fibrosis (11±17% (mean±SD) ; n=6) altered alpha-cell phenotype was seen in 11±14% of islets vs. pancreata with &amp;gt;50% fibrosis (93±7%; n=3) with altered alpha-cell phenotype in 65±10% islets (p&amp;lt;0.001) . Analysis of a chronic pancreatitis resection with incrementally increasing fibrosis from head to tail showed parallel increase in islet proportion with altered alpha-cell phenotype (head: 28%; body: 80%; tail: 78%) . We have demonstrated that peri-islet fibrosis is associated with aberrant islet glucagon/vimentin co-expression providing further evidence for exocrine-endocrine signalling in human pancreatic pathology. Disclosure N.Kattner: None. Y.Al-selwi: None. D.Tiniakos: None. G.Klöppel: None. J.A.Shaw: None. Funding Cystic Fibrosis Trust (SRC 019)

Overlap esophagojejunostomy with multi-mode modifications in totally laparoscopic total gastrectomy: safety and feasibility of 152 cases from a single center

Objective: Currently, the Overlap anastomosis is one of the most favored reconstruction methods of intracorporeal esophagojejunostomy (EJS). Despite many advantages of the method, it remains some shortcomings to be improved when it comes to the retraction of the esophagus stump, the insertion of the anvil fork of the linear stapler into a "pseudo" lumen, and the closure of the common entry hole. This study aims to investigate the safety and feasibility of a multi-mode modified Overlap anastomosis. Methods: A descriptive case series study was conducted. Medical records of 152 consecutive patients who underwent totally laparoscopic total gastrectomy (TLTG) with our multi-mode modified Overlap EJS method by the same surgical team at our department from February 2017 to June 2020 were retrospectively analyzed. The multi-mode modified Overlap method mainly included (1) After ensuring the safety of tumor resection margin (proximal margin was at least 3 cm from the tumor), the esophagus was partially transected from left to right (with 5-8 mm width esophagus continuation). The specimen was then placed in a plastic bag which was tied up at the mouth using strings with a part of the esophageal wall poking through. Then the plastic bag containing the specimen was transferred to the right lumbar region, while the patient's body position was adjusted so that the abdominal esophagus could be pulled by the gravity of the specimen. (2) Using the "three-direction traction" method. The esophageal lumen was properly exposed, then guided by the gastric tube, the anvil fork was accurately placed into the esophageal lumen for completing the side-to-side EJS. (3) The 3-0 barbed suture was used in the closure of the common entry hole of the stapler from dorsally to ventrally with simple one-layer continuous suture (the stitch going from inside to inside) followed by continuous Lembert's suture (the stitch going from outside to outside). Combined with clinicopathological characteristics, the perioperative outcomes and postoperative complications of the whole group were analyzed and evaluated. Results: The study cohort included 129 men and 23 women, with a mean age of (60.2±9.1) years and a mean body mass index (BMI) of (23.2±3.1) kg/m(2). Of the 152 patients, 23 patients (15.1%) had a history of previous abdominal surgery; dentate line was invaded by tumor in 21 patients (13.8%). The mean length of the proximal resection margin was (3.3±0.3) cm and the postoperative pathological examination indicated negative resection margin tumor. The mean operative time and anastomotic time were (302.1±39.9) minutes and (29.8±5.4) minutes, respectively. The mean estimated blood loss was (87.9±46.4) ml. The mean length of postoperative hospital stay was (12.3±7.3) days. The overall severe postoperative complications (Clavien-Dindo ≥ II) occurred in 22 patients (14.5%). Six cases of pancreatic leakage were successfully recovered by adequate drainage, inhibition of pancreatic exocrine secretion and nutritional support. Ten cases of pneumonia and three cases of abdominal infection were cured with anti-infection and physical therapy. Two patients developed anastomotic leakage postoperatively. One case was caused by excessive tension of the Roux loop of the jejunum and excessive opening on the side of the jejunum after side-to-side anastomosis, and the other case was caused by an accidental intraoperative occurrence of "nasogastric tube stapled to the side-to-side anastomosis". Both of them recovered after conservative treatment including adequate drainage, anti-infection, and adequate nutritional support. One patient underwent immediate open surgery because of Peterson's hernia 7 days after TLTG, and the patient died due to extensive small bowel necrosis. Conclusions: Multi-mode modified overlap method simplifies the operation and reduces the difficulty of EJS. It is a safe and feasible method for EJS.

Bile acid- and ethanol-mediated activation of Orai1 damages pancreatic ductal secretion in acute pancreatitis.

Regardless of its aetiology, sustained intracellular Ca2+ overload is a well-known hallmark of acute pancreatitis (AP). Toxic Ca2+ elevation induces pancreatic ductal cell damage characterized by impaired ion and fluid secretion - essential to wash out the protein-rich fluid secreted by acinar cells while maintaining the alkaline intra-ductal pH under physiological conditions - and mitochondrial dysfunction. While prevention of ductal cell injury decreases the severity of AP, no specific drug target has yet been identified in the ductal cells. Although Orai1, a store-operated Ca2+ influx channel, is known to contribute to sustained Ca2+ overload in acinar cells, details concerning its expression and function in ductal cells are currently lacking. In this study, we demonstrate that functionally active Orai1 channels reside predominantly in the apical plasma membrane of pancreatic ductal cells. Selective CM5480-mediated Orai1 inhibition impairs Stim1-dependent extracellular Ca2+ influx evoked by bile acids or ethanol combined with non-oxidative ethanol metabolites. Furthermore, prevention of sustained extracellular Ca2+ influx protects ductal cell secretory function in vitro and decreases pancreatic ductal cell death. Finally, Orai1 inhibition partially restores and maintains proper exocrine pancreatic secretion in in vivo AP models. In conclusion, our results indicate that Orai1 inhibition prevents AP-related ductal cell function impairment and holds the potential of improving disease outcome. KEY POINTS: Sustained intracellular Ca2+ overload in pancreatic acinar and ductal cells is a hallmark of biliary and alcohol-induced acute pancreatitis, which leads to impaired ductal ion and fluid secretion. Orai1 is a plasma membrane Ca2+ channel that mediates extracellular Ca2+ influx upon endoplasmic reticulum Ca2+ depletion. Results showed that Orai1 is expressed on the luminal plasma membrane of the ductal cells and selective Orai1 inhibition impaired Stim1-dependent extracellular Ca2+ influx evoked by bile acids or ethanol combined with non-oxidative ethanol metabolites. The prevention of sustained extracellular Ca2+ influx protected ductal cell secretory functions in in vitro models and maintained exocrine pancreatic secretion in in vivo acute pancreatitis models. Orai1 inhibition prevents the bile acid- and alcohol-induced damage of the pancreatic ductal secretion and holds the potential of improving the outcome of acute pancreatitis.

Proton Pump Inhibitors Were Associated With Reduced Pseudocysts in Acute Pancreatitis: A Multicenter Cohort Study.

Background: Acute pancreatitis (AP) is a systemic inflammatory disorder with a wide spectrum of clinical symptoms that can range from mild to severe. Previous preclinical study results suggest that proton pump inhibitors (PPIs) can inhibit exocrine pancreatic secretion and exert anti-inflammatory properties, which might in turn improve the outcome of AP. Aim: We conducted this multicenter, retrospective cohort study to investigate the potential effects of PPIs on the mortality, and total duration of hospital stay and local complication occurrence of patients with AP. Methods: A total of 858 patients with AP were included. All patients presented to the hospital within 48 h of symptom onset and were divided into the following two groups: patients who were treated with PPIs (n = 684) and those not treated with PPIs (n = 174). We used propensity score matching (PSM) analysis to reduce confounding bias before comparing the outcomes between the two groups. Results: Before PSM analysis, there were significant differences in a number of parameters between the two groups, including age, sex, hematocrit, blood urea nitrogen, peritonitis signs, Ranson’s score, and Acute Physiology Chronic Health Evaluation II score and organ failure occurrence. Before PSM, the PPIs group had a higher rate of mortality than the control group [RR = 1.065; 95% confidence ratio (CI) 1.045–1.086; p = 0.001]. After PSM, there was no significant difference in mortality (RR = 1.009; 95% CI, 0.999–1.019; p = 0.554) or total hospital stay (p = 0.856), although the PPIs group had a lower occurrence of pancreatic pseudocyst (RR = 0.416; 95% CI 0.221–0.780; p = 0.005). Conclusion: This study showed that PPIs therapy was not associated with reduced mortality or total hospital stay, but was associated with a reduction in the occurrence of pseudocysts in patients with acute pancreatitis.

Prenatal development of sympathetic innervation of the human pancreas

BackgroundThe sympathetic nervous system plays an important role in the regulation of pancreatic exocrine and endocrine secretion. The results of experimental studies also demonstrate the involvement of the sympathetic nervous system in the regulation of endocrine cell differentiation and islet formation during the development of the pancreas. However, the prenatal development of sympathetic innervation of the human pancreas has not yet been studied. Material and methodsPancreatic autopsy samples from 24 human fetuses were examined using immunohistochemistry with antibodies to tyrosine hydroxylase (TH). The density, concentration, and size (width, length, perimeter and area) of the TH-positive sympathetic nerves were compared in four developmental periods: pre-fetal (8–11 weeks post conception (w.p.c.), n = 6), early fetal (13–20 gestational weeks (g.w.), n = 7), middle fetal (21–28 g.w., n = 6) and late fetal (29–40 g.w., n = 5) using morphometric methods and statistical analysis (Multiple Comparisons p values). Double immunofluorescence with antibodies to TH and either insulin or glucagon and confocal microscopy were applied to analyze the interaction between the sympathetic nerves and endocrine cells, and the co-localization of TH with hormones. ResultsTH-positive sympathetic nerves were detected in the fetal pancreas starting from the early stages (8 w.p.c.). The developmental dynamics of sympathetic nerves was follows: from the pre-fetal period, the amount of TH-positive nerves gradually increased and their branching occurred reaching the highest density and concentration in the middle fetal period, followed by a decrease in these parameters in the late fetal period. From the 14th g.w. onwards, thin TH-positive nerve fibers were mainly distributed in the vicinity of blood vessels and around the neurons of intrapancreatic ganglia, which is similar in adults. There were only rare TH-positive nerve fibers adjacent to acini or located at the periphery of some islets. The close interactions between the TH-positive nerve fibers and endocrine cells were observed in the neuro-insular complexes. Additionally, non-neuronal TH-containing cells were found in the pancreas of fetuses from the pre-fetal and early fetal periods. Some of these cells simultaneously contained glucagon. ConclusionsThe results demonstrate that sympathetic innervation of the human pancreas, including the formation of perivascular and intraganglionic nerve plexuses, extensively develops during prenatal period, while some processes, such as the formation of sympathetic innervation of islet capillaries, may occur postnatally. Non-neuronal TH-containing cells, as well as the interactions between the sympathetic terminals and endocrine cells observed in the fetal pancreas may be necessary for endocrine pancreas development in humans.

S3476 Workup of a Suspected Pancreaticopleural Fistula in a Young Male

Introduction: Pancreatic fistulas are an abnormal connection between the pancreas and an adjacent or distant structure or organ. These can be characterized as internal or external depending if the pancreatic duct communicates with the skin or not. The most common cause of an internal pancreatic fistula is pancreatitis associated with chronic alcohol. Pancreatopleural fistulas develop by leakage of pancreatic exocrine secretions through the openings in the diaphragm. Here we present a case, where there was concern for a pancreatopleural fistula. Case Description/Methods: A 31-year-old male with past medical history of chronic recurrent pancreatitis complicated by enlarging pseudocysts and portal vein thrombosis was transferred to our facility from outside hospital for hemorrhagic pancreatic pseudoaneurysm status post IR embolization. He had been bleeding from the hemorrhagic pseudoaneurysm at the previous hospital and had been treated with an initial IR embolization procedure for this 4-5 days before arriving at our facility. He underwent repeat IR embolization procedure with repositioning of the malpositioned coil 6 days after admission and subsequently underwent EGD with endoscopic ultrasound and cysgastrectomy for treatment of his associated pancreatic pseudocyst 12 days after admission. Pleural effusion seen on Xray was thought to be secondary to pancreatic fluid accumulation. Thoracentesis was subsequently performed due to patient complaints of dyspnea and analysis showed > 12,000U/L of amylase and black fluid concerning for a pancreatic pleural fistula (Figure A). Patient had a repeat X-ray the following day with accumulation of the pleural effusion (Figure B). Patient was started on TPN and Octreotide for treatment. Repeat thoracentesis yielded amber colored fluid and a CT chest, abdomen and pelvis did not show evidence of fistula formation. It was determined that the initial thoracentesis performed on the patient was actually placed into the pancreatic pseudocyst due to severe elevation of the hemidiaphragm. The patient was ultimately discharged with plans to follow-up with general surgery as an outpatient for possible pancreatectomy. Discussion: We believe that our findings during the care of this patient are important for Gastroenterologists as they provide an excellent opportunity to review both the common and obscure complications of pancreatitis. entity that can occur in patients with acute pancreatitis and is characterized by small, left sided pleural effusions.Figure 1.: Figure A. Thoracentesis fluid obtained from patient concerning for a pancreatic pleural fistula. Figure B. Repeat chest x-ray showing re-accumulation of large left-sided pleural effusion.

Pharmachologic Prophylaxis for Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis

Post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) is one of the most burdensome adverse events, occurs in about 3 to 15 percent of patients after the procedure. Various and extensive attempts have been made to find proper prophylaxis for PEP. Nowadays, pharmacologic agents consist one of the pivotal axis for prophylaxis for PEP. In this review article, we tried to overview pharmacologic prophylaxis including non-steroidal anti-inflammatory drugs, aggressive hydration, protease inhibitors, exocrine pancreatic secretion inhibitors, and nitrates from recent updated results of randomized controlled studies and key meta-analyses.