Severe Pancreatitis Research Articles

An Atypical Case of Acute Pulmonary Embolism in a Sri Lankan Patient With Acute Severe Pancreatitis With Heterozygosity for the SPINK 1 Mutation

An Atypical Case of Acute Pulmonary Embolism in a Sri Lankan Patient With Acute Severe Pancreatitis With Heterozygosity for the SPINK 1 Mutation

HPB O05 - Changing paradigms in the management of severe acute pancreatitis: Focused multi-disciplinary working between surgeons and intensivists to mitigate organ failure in order to reduce mortality

Abstract Background Mortality was classically bimodal in severe acute pancreatitis and organ failure is the single most important factor in predicting outcome in severe acute pancreatitis. Initial interventions are supportive often requiring critical care. Subsequently treatments are required to manage necrosis and any organ recovery remains under threat. The outcomes and interventions from surgery and critical care are reviewed to determine how to balance organ failure and the need for necrosectomy in a modern multi-disciplinary tertiary care centre Method The Royal Liverpool provides a tertiary service to all patients with pancreatitis across Merseyside and North Wales. All patients that were transferred to critical care from 2018 – 2023 were analysed using the intensive care national audit and research centre database which contains information on organ failure. The patients with severe pancreatitis were then reviewed using electronic clinical notes and radiology images to determine clinical course and management. Results Of 134 patients, 48 (36%) were admitted locally, 85 (64%) transferred in, occurring 35% <2weeks, 29% 2-4weeks, 28% 4-6weeks and 8% >8weeks. 76 (57%) required necrosis intervention, 58 (43%) were conservatively managed. Mortality was 38% with 35% <4weeks, 22% 4-8weeks, 22% 8-12weeks, 22% >12weeks. No significant difference in mortality between conservative or interventional management (15 (45%) vs 18 (55%)) nor median age (58 vs 57.5 yrs). Survival related to number of failing organs (dead vs alive): nil organs: 10 patients vs 27 patients (20%vs32%), One: 11 vs 45 (22%vs45%), Two: 21 vs 9 (42%vs11%), Three: 8 vs 3 (16%vs4%), p<0.005. Conclusion Of patients deemed fit for ITU admission with necrotising pancreatitis, the classic paradigms of biphasic mortality no longer occur. Differences in mortality from intervention and age of patient has been negated by optimal ITU management for organ failure. For the initial phases and the intervention phases of management, ensuring degree of organ failure is key to survival. There is a significant change when two organs fail in mortality and this stresses the importance of holistic management. Our ITU promotes pancreas specific organ preservation measures of early enteral feeding, cessation/tailoring of antibiotics, early extubation/tracheostomy and most importantly multidisciplinary working

HPB SO45 - Level 1 evidence comparing aggressive versus non-aggressive intravenous fluid therapy in acute pancreatitis

Abstract Background Fluid balance in the management of acute pancreatitis (AP) is challenging and has been described as a “double-edged sword” whereby adequate fluids are required to counteract systemic hypovolaemia whilst excessive fluids may exacerbate systemic oedema. Given that data generated from randomised studies are conflicting, the optimal rate and type of fluid resuscitation for AP are yet to be determined. We aimed to perform a comprehensive meta-analysis of all existing randomized controlled trials (RCTs) to evaluate comparative outcomes of aggressive versus non-aggressive intravenous fluid (IVF) therapy in patients with AP. Method A systematic search of electronic data sources and bibliographic reference lists were conducted. All RCTs reporting outcomes of aggressive versus non-aggressive IVF therapy in AP were included and their risk of bias were assessed. Effect sizes were determined for overall mortality, systemic inflammatory response syndrome (SIRS), sepsis, respiratory failure, pancreatic necrosis, severe pancreatitis, clinical improvement, AKI, and length of stay using random-effects modelling. Trial sequential analysis was conducted to determine risk of types 1 or 2 errors. Results Ten RCTs enrolling 993 patients with AP who received aggressive (n = 475) or non-aggressive (n = 518) IVF therapy were included. Aggressive IVF therapy was associated with significantly higher rate of sepsis (OR:2.68, P=0.0005) and longer length of stay (MD:0.94, P<0.00001). There was no statistically significant difference in mortality (RD:0.02, P=0.31), SIRS (OR:0.93, P=0.89), respiratory failure (OR:2.81, P=0.07), pancreatic necrosis (OR:1.98, P = 0.06), clinical improvement (OR:1.12, P=0.83), severe pancreatitis (OR:1.31, P=0.38) or AKI (OR:1.06, P=0.91). Subgroup analysis demonstrated higher morbidity and mortality with aggressive fluids in severe AP. Trial sequential analysis detected risk of type 2 error. Conclusion Aggressive IVF therapy may be associated with higher morbidity in patients with acute pancreatitis compared with the non-aggressive approach, particularly in patients with more severe disease. It may also prolong length of hospital stay. The available evidence is subject to type 2 error indicating the need for adequately powered RCTs.

HPB SO46 - Risk Stratification for Acute Pancreatitis: A Retrospective Comparative Analysis between Glasgow-Imrie and BISAP Scoring Systems within a District General Hospital

Abstract Background Risk stratification for acute pancreatitis (AP) is an important tool in clinical decision making. The BISAP score has been validated to be a comparable risk prognostication tool to current models[1, 2]. Current trust practice is the Glasgow-Imrie score, which involves more invasive and non-routine investigations, resulting in an increased cost and labour burden. Additionally, a previous local audit demonstrated poor compliance with only 55% of admissions having a documented score, limiting utility and prognostication. By demonstrating non-inferiority, we aim to implement BISAP as the standard of practice with earlier severity assessment, improved patient experience and minimising unnecessary investigations. Method A retrospective analysis of 153 admissions with acute pancreatitis admitted to a single-site district general hospital over a 12-month period was performed, reviewing electronic patient records for documentation, observations and investigations. Both Glasgow-Imrie and BISAP scores were calculated within 48 and 24 hours of admission retrospectively and respectively. Descriptive statistics was used to summarise data and compare trends between both scores and the severity of acute pancreatitis, ICU admissions and mortality. Logistic regression was utilised to model the relationship between both systems and binary outcomes with area under the curve (AUC) and non-inferiority tests derived to determine efficacy. Results The cohort had a mean age of 57 ± 18.53 (52:48 male:female) with an average LOS of 7.25 ± 10.12 days. 6.54% had severe AP, 3.92% required ICU admisison and 3.26% mortality rate. The AUC value for both models was 0.868 in predicting severity (p<0.001) with Glasgow-Imrie performing better in predicting ICU admission (AUC 0.954 > 0.855, p<0.01) and BISAP outperforming Glasgow-Imrie in predicting mortality (AUC 0.903 > 0.867, p<0.01). Bootstrapping resampling demonstrated no significant difference between models in predicting severity (δAUC 0.0007, 95%CI -0.01181, 0.1167), ICU admission (δAUC 0.1010, 95%CI -0.0113, 0.2140) and mortality (δAUC -0.0366, 95%CI -0.0788, 0.0045). Conclusion Both the Glasgow-Imrie and BISAP scoring systems are accurate in predicting the severity of pancreatitis, ICU admission and mortality. The BISAP score is similar in prognostic accuracy to the Glasgow-Imrie score and is advantageous in being simpler to obtain in clinical practice with a higher rate of completeness. We recommend the BISAP score as a non-inferior, pragmatic risk stratification tool in acute pancreatitis.

HPB SO09 - Review of the management and the outcome of acute pancreatitis in a tertiary centre in the United Kingdom

Abstract Background Acute idiopathic pancreatitis (IP) is a challenging condition in surgical practice. We undertook a prospective review of all patients presenting with idiopathic pancreatitis to identify the natural course of the disease. Method Fifty-nine patients were identified within a 12-month period from a prospectively maintained database. Patients were diagnosed with idiopathic pancreatitis (IP) following a standardised protocol excluding other causes of pancreatitis. Results Over one year, a total of 373 new patients with acute pancreatitis were admitted. IP constituted 15.8% of admissions; 15.2 % of which presented with severe pancreatitis. Average LOS for the index IP admission was 7.05 days, compared with 6.4 days for the rest of cohort. 8.47% with IP were re-admitted within 3 months of index admission, increasing to 13.6% over 12 months. Overall, 16.9% developed long term complications including pancreatic insufficiency or chronic pancreatitis over 12 months compared to 15.3% in the rest of AP cohort. The mortality rate was 3.4% and 12.1% in the IP and AP cohort respectively. Conclusion Idiopathic pancreatitis constitutes a larger burden than expected in a large prospective cohort of patients with AP. Patients with IP have a longer LOS and a high risk of long-term sequelae.

HPB SO23 - Implementation and Outcomes of Index Admission Management of Acute Gallstone Pancreatitis on a Specialist Biliary Unit

Abstract Background While the management of acute gallstone pancreatitis (AP) has recognised guidelines, there are wide variations in compliance with these in various institutions for different reasons. The primary objective of this review was to evaluate the effects of implementing proactive management strategies on a specialist biliary firm receiving most biliary emergency admissions by protocol on the incidence of index admission laparoscopic cholecystectomy (LC) for AP. The secondary aims were to study the admission to LC interval, if such policy was safe and how it can help the optimisation of outcomes of AP. Method Analysis of prospectively collected data from AP patients treated by a specialist biliary unit dedicated to index admission LC and single session laparoscopic management of bile duct stones. Almost all patients were referred to the unit as soon as the diagnosis of AP was made. Only patients with severe pancreatitis on imaging or requiring intensive care were not included in the index admission pathway and subsequently underwent delayed surgery. Routine MRCP and ERCP were not part of the management protocol. Following clinical optimisation patients had LC with routine cholangiography (IOC). and if necessary bile duct exploration. Results 495/6140 patients were identified (8%), 70% females. Median age was 55 years. 92.3% had suspected ductal stones, half with jaundice. 11.9% had previous episodes. Only 6.2% had MRCPs and 2% ERCPs. Admission to LC interval was 5 days. 33.2% required bile duct explorations. LC difficulty grade was III to V in 37.2%. The median operative time was 62 minutes with no conversions, ductal injuries or mortality. Complications occurred in 9.2%, including 14 persistent pancreatitis/collections resulting in 6 of 25 readmissions. Two re-operations resulted from t-tube complications. Median hospital stay was 7 days, 72% having had only one admission. Conclusion Index admission LC on all AP patients fit for surgery is perfectly safe in the specialist setting. It optimises preoperative radiological investigations and endoscopic interventions and ,subsequently, a third of the patients require bile duct exploration. Implementing definitive surgical interventions during the index admission for AP offers a substantial reduction in hospital stay, re-admission rates and an overall decrease in hospital attendances. This not only yields significant cost benefits for the health service but also enhances the quality of life for patients.

HPB SO71 - Meta-Anaylsis of Early Endoscopic Retrograde Cholangiopancreatography versus conservative management for gallstone pancreatitis

Abstract Background Acute pancreatitis is one of the most common gastrointestinal causes of hospital admission. The most common cause is transient blockage of the bile or pancreatic duct (or both) by gallstones. Most of the time, pancreatitis responds to conservative management (CM) comprising intravenous fluid hydration and analgesia. ERCP +/_endoscopic sphincterotomy in acute gallstone pancreatitis has been advocated in the past to decrease the number of complications of this condition. However, the role and timing of this procedure are still contentious and an ongoing debate. Method The aim of this study is to compare the clinical outcomes of early urgent ERCP versus conservative management in biliary pancreatitis but not cholangitis. An online search of Medline, Embase, Science citation index, PubMed and Cochrane database of systematic reviews published between 1988 and 2022 was carried out for relevant studies. Statistical analysis was done using Revman 5.4 and Odds ratio with a 95% Confidence interval was used for outcome estimation. There was 14 studies included in the final study consisting a total of 1756 patients with 877 patients in ERCP group while 879 in CM group. Results With random effects model, data showed no significant reduction in mortality in ERCP group as compared to the CM group (OR 0.59, 95% CI 0.30-1.16; p=0.13). However there were overall more local or systemic complications (OR 0.51, 95% CI 0.36-0.71; p<0.002) in the CM group as compared to ERCP group. No statistically significant difference found amongst groups when comparing complications as renal failure(OR-0.99, 95% CI-0.41-2.41, p=0.98), cardiac failure (OR-0.77 95% CI 0.35-1.69, p=0.51) or biliary sepsis (OR-0.56 95%CI 0.15-2.10, p=0.39) but there was more incidence of pseudocyst in CM group patients(OR-0.47, 95% CI 0.25-0.87, p=0.02). Conclusion The above study did show that the mortality rate was not significantly higher in the CM group as compared to the ERCP group however the early ERCP was beneficial in reducing overall complications in the interventional group. Based on this fact, ERCP considered early in the management of acute pancreatitis despite of still being debatable in practice can be considered in severe pancreatitis cases and further high powered randomized controlled trials can be carried out to assess this point.

Use of short single-balloon enteroscopy in patients with surgically altered anatomy: a single-center experience.

Conventional duodenoscopy is challenging to perform in patients with a surgically altered anatomy (SAA). Short single-balloon enteroscopy (SBE) is an innovative alternative. We investigated the performance of short SBE in patients with SAA and explored risk factors for unsuccessful intubation.Patients who underwent short SBE from October 2019 to October 2023 were retrospectively analyzed. Successful enteroscopic intubation was defined as the endoscope reaching the papilla of Vater, the pancreaticobiliary-enteric anastomosis, or the target site of the afferent limb. In total, 99 short SBE procedures were performed in 64 patients (40 men, 24 women) with a mean age of 61 years (range, 36-86 years). The patients had a history of choledochoduodenostomy (n = 1), Billroth II gastrojejunostomy (n = 11), pancreaticoduodenectomy (n = 17), Roux-en-Y reconstruction with hepaticojejunostomy (n = 31), and Roux-en-Y reconstruction with total gastrectomy (n = 4). Successful enteroscopic intubation occurred in 32 of 64 (50.0%) patients, and in 57 of 99 (57.6%) procedures. No perforation or severe pancreatitis occurred. Multivariable analysis showed that Roux-en-Y reconstruction was a risk factor for intubation failure (hazard ratio, 4.2; 95% confidence interval, 1.1-15.8; p = 0.033). Short SBE is efficacious and safe in patients with postsurgical anatomy. Roux-en-Y reconstruction adversely affects the success of short SBE intubation.

Demographic and clinical profile of patients with acute biliary pancreatitis: an experience in Patan academy of health sciences

Background: Acute pancreatitis is one of the most common causes of acute abdomen encountered in emergency department with wide range of severity from mild self-limiting disease to severe and rapidly progressive illness leading to multi organ failure and even death. Gall stones are leading cause of acute pancreatitis. This study has been carried out to find out demographic pattern and clinical profile of patients with acute biliary pancreatitis. Methods: This is a prospective cross-sectional study carried out in the department of surgery in Patan academy of health sciences (PAHS) in the time period between May 1, 2021 and April 30, 2022. The process of data collection was started after obtaining ethical approval from institutional review committee (IRC) of PAHS, and written informed consent was obtained from patients. Total sampling was done and 66 patients were enrolled into the study, who were diagnosed as acute biliary pancreatitis. Data was analyzed with SPSS ver 25 and Microsoft excel 2016. Results: Out of total 66 patients in the study 25 (37.9%) were male and 41 (62.1%) were female with male: female ratio of 1:1.64. Mean age was 48.42±16.62 years. ranging from 16-88 years. Epigastric abdominal pain was predominant presenting symptoms accounting for 57 (86.4%) cases. Pleural effusion was most common complication seen in 17 (25.8%) cases. Mortality occurs in 2 (3%) cases, both of cases had severe pancreatitis. Only 21 (31.8%) patients underwent cholecystectomy among which 13 (19.7%) interval and 8 (12.1%) index cholecystectomy. Conclusions: Female gender with age group of 40-60 years. predominates acute biliary pancreatitis. Though most of the cases are mild and have benign course, severe cases and patients with advanced age are associated with high mortality. Acceptance of index cholecystectomy is very low.

Splenic infarction without thrombosis secondary to severe acute pancreatitis

Abstract Introduction: Acute pancreatitis is a common disease that is usually mild, although in some cases it may present complications, among which are vascular ones such as splenic infarction. Clinical case: A 71 years old woman was admitted for acute pancreatitis, who presented a torpid evolution throughout the first admission with associated acute cholecystitis and an encapsulated necrotic collection that required endoscopic drainage using a luminal apposition prosthesis and endoscopic necrosectomy. A month and a half later, the patient was readmitted for abdominal pain, with abdominal CT scan showing a very thinned splenic vein and patent artery without identifying thrombosis (with 700,000 platelets/mm3), associated splenic infarction as well as worsening of the inflammation of pancreatitis. Given these findings, we were decided to start anticoagulation with enoxaparin at prophylactic doses for splenic vascular stenosis, achieving resolution of the thrombocytosis (410,000 platelets/mm3), disappearance of the splenic necrotic area and improvement of the pancreatic inflammatory component confirmed by CT scan. Conclusion: When splenic infarction is associated with severe pancreatitis with splenic thrombosis, anticoagulation is indicated. However, when there is no splenic thrombosis and the splenic infarction occurs in the context of critical vascular stenosis with high thrombocytosis, the indication for anticoagulation is controversial, with no consensus in the literature. Furthermore, at present it is not establish the active ingredient to be used or its dose, and highlights the need to carry out clinical trials in order to establish clinical or consensus guidelines.

Inhibition of Hedgehog Signaling Ameliorates Severity of Chronic Pancreatitis in Experimental Mouse Models.

Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas with no specific cure. Research highlighting the pathogenesis and especially the therapeutic aspect remains limited. Aberrant activation of developmental pathways in adults have been implicated in several diseases. Hedgehog pathway is a notable embryonic signaling pathway, known to promote fibrosis of various organs when over-activated. The aim of this study is to explore the role of hedgehog pathway in the progression of CP and evaluate its inhibition as a novel therapeutic strategy against CP. CP was induced in mice by repeated injections of L-arginine or Caerulein in two separate models. Mice were administered with the FDA approved pharmacological hedgehog pathway inhibitor, Vismodegib during or after establishing the disease condition to inhibit hedgehog signaling. Various parameters of CP were analyzed to determine the effect of hedgehog pathway inhibition on the severity and progression of the disease. Our study shows that hedgehog signaling was over-activated during CP and its inhibition was effective in improving the histopathological parameters associated with CP. Vismodegib administration not only halted the progression of CP but was also able to resolve already established fibrosis. Additionally, inhibition of hedgehog signaling resulted in reversal of pancreatic stellate cell activation ex vivo. Conclusions: Findings from our study justify conducting clinical trials using Vismodegib against CP and thus, could lead to development of novel therapeutic strategy for the treatment of CP.

Prediction of Severe Acute Pancreatitis at a Very Early Stage of the Disease Using Artificial Intelligence Techniques, Without Laboratory Data or Imaging Tests: The PANCREATIA Study.

To evaluate machine learning models' performance in predicting acute pancreatitis severity using early-stage variables while excluding laboratory and imaging tests. Severe acute pancreatitis (SAP) affects approximately 20% of acute pancreatitis (AP) patients and is associated with high mortality rates. Accurate early prediction of SAP and in-hospital mortality is crucial for effective management. Traditional scores such as APACHE-II and BISAP are complex and require laboratory tests, while early predictive models are lacking. Machine learning (ML) has shown promising results in predictive modelling, potentially outperforming traditional methods. We analysed data from a prospective database of AP patients admitted to Vall d'Hebron Hospital from November 2015 to January 2022. Inclusion criteria were adults diagnosed with AP according to the 2012 Atlanta classification. Data included basal characteristics, current medication, and vital signs. We developed machine learning models to predict SAP, in-hospital mortality, and intensive care unit (ICU) admission. The modelling process included two stages: Stage 0, which used basal characteristics and medication, and Stage 1, which included data from Stage 0 and vital signs. Out of 634 cases, 594 were analysed. The Stage 0 model showed AUC values of 0.698 for mortality, 0.721 for ICU admission, and 0.707 for persistent organ failure. The Stage 1 model improved performance with AUC values of 0.849 for mortality, 0.786 for ICU admission, and 0.783 for persistent organ failure. The models demonstrated comparable or superior performance to APACHE-II and BISAP scores. The ML models showed good predictive capacity for SAP, ICU admission, and mortality using early-stage data without laboratory or imaging tests. This approach could revolutionise AP patients' initial triage and management, providing a personalised prediction method based on early clinical data.

Fibrinogen-Like Protein 2 Protects the Aggravation of Hypertriglyceridemia on the Severity of Hypertriglyceridemia Acute Pancreatitis by Regulating Macrophages.

The mechanisms underlying the increased severity of hypertriglyceridemia acute pancreatitis (HTG-AP) remain poorly understood. Fibrinogen-like protein 2 (FGL2) has been identified as a regulator of macrophage activity, mediating immune suppression. This study aims to examine the role of FGL2 in the susceptibility to severe conditions of HTG-AP. Both wild-type and FGL2 gene knockout C57BL/6 mice were utilized to establish HTG, AP, and HTG-AP models using P-407 and/or caerulein. Serum levels of triglycerides, total cholesterol, amylase, and lipase were assessed via biochemical analysis. Pancreatic and lung tissue injuries were evaluated using hematoxylin and eosin staining. Tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) levels in serum and pancreatic tissues were quantified using enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry was used to assess the expression of FGL2, the macrophage marker CD68, and M1/M2 macrophage markers iNOS/CD163. The animal models were successfully established. Compared to wild-type mice, FGL2 knockout resulted in increased pathological injury scores in the pancreas and lungs, as well as elevated TNF-α, IL-1β, and IL-6 levels in serum and pancreatic tissue in the HTG group, with more pronounced effects observed in the HTG-AP group. The AP group alone did not exhibit significant changes due to FGL2 knockout. Further analysis revealed that FGL2 knockout increased CD68 expression but reduced CD163 expression in the pancreatic tissues in the HTG group. In the HTG-AP group, there was a marked increase in CD68 and iNOS expressions, coupled with a reduction in CD163 expression. FGL2 knockout in HTG and HTG-AP mice resulted in increased inflammatory responses and a significant imbalance in M2 macrophages. These findings suggest that FGL2 plays a crucial role in mitigating the aggravation of HTG on the severity of HTG-AP by modulating macrophage activity.

Clinical significance of peripheral blood DDR1 and CtBP gene methylation detection in patients with acute pancreatitis

ABSTRACT To investigate the clinical value of methylation levels of peripheral blood DDR1 and CtBP genes in evaluating the severity of acute pancreatitis (AP). Collect 90 blood samples from AP patients and healthy volunteers, and test methylation levels of SPINK1, STAT3, KIT, CFTR, DDR1, CtBP1, CtBP2 genes by bisulfite amplicon sequencing (BSAS). The gene methylation and clinical predictors of SAP early prediction were determined by univariate and multifactorial analysis, respectively. (1) The methylation level of CtBP1 gene and MCTSI score were independent predictors of SAP, with AUC values of 0.723 and 0.8895, respectively. (2) The methylation levels of DDR1, CtBP2, CFTR and SPINK1 genes were statistically significant in HC group vs AP group, HC group vs MAP group, and HC group vs SAP group. (3) The combined detection of CtBP1 gene methylation level and MCTSI score predicted the sensitivity, specificity, AUC, and 95%CI of SAP were 0.750, 0.957, 0.902, and 0.816–0.989, respectively. (1) The methylation level of CtBP1 gene in peripheral blood is an independent risk factor for predicting SAP and is a potentially good predictor of SAP, and the combined testing with the MCTSI score does not further significantly improve the early predictive value for SAP. (2) The methylation levels of DDR1, SPINK1, CtBP2, and CFTR genes were potential indicators for recognizing AP.

Comparative Study Of BISAP Score With APACHE-II Scoring System To Determine The Severity Of Acute Pancreatitis

Introduction: Acute pancreatitis (AP) is a significant abdominal emergency characterized by inflammation of the pancreas, primarily due to autodigestion by pancreatic enzymes. Early severity assessment is crucial for management, as severe cases lead to complications and mortality. While various scoring systems exist, the Bedside Index for Severity in Acute Pancreatitis (BISAP) and APACHE-II (Acute Physiology and Chronic Health Evaluation) scores are commonly used, each with unique advantages and limitations in severity prediction. Objective: This study aims to compare the effectiveness of BISAP and APACHE-II scores in predicting acute pancreatitis severity, helping clinicians optimize treatment decisions. Methods: This observational study was conducted at SMS Hospital, Jaipur, involving 76 patients diagnosed with AP based on clinical, biochemical, and imaging criteria. Participants were assessed using both BISAP and APACHE-II scoring within 24 hours of admission, with a focus on accuracy in predicting severe cases and outcomes. Results: Among participants, the mean age was 43 years, and 84.2% were male. Gallstone disease was the leading cause of AP (55.2%), followed by alcohol (34.2%). BISAP scores ≥3 was associated with significantly higher mortality, highlighting BISAP’s predictive accuracy. The mean BISAP score was 1.86 ± 1.09, while the APACHE-II score was 6.97 ± 5.66, indicating more severe classifications using BISAP. The study found a moderate positive correlation between BISAP and APACHE-II scores, though only BISAP scores significantly predicted patient outcomes. Conclusion: BISAP offers a rapid and accurate assessment tool for AP severity, especially suitable for early intervention in high-risk patients. Compared to APACHE-II, BISAP is simpler, cost-effective, and demonstrates a high negative predictive value, making it more practical for acute settings.

Intestinal microflora and metabolites affect the progression of acute pancreatitis (AP)

Specific intestinal metabolites are closely associated with the classification, severity, and necrosis of acute pancreatitis (AP) and provide novel insights for in-depth clinical investigations. In this study, the gut microbiota and metabolites of 49 AP patients at different treatment stages and severities were analysed via 16S rDNA sequencing and untargeted metabolomics to investigate the trends in gut microbiota composition and metabolome profiles observed in patients with severe AP. These findings revealed an imbalance in intestinal flora homeostasis among AP patients characterized by a decrease in probiotics and an increase in opportunistic pathogens, which leads to damage to the intestinal mucosal barrier through reduced short-chain fatty acid (SCFA) secretion and disruption of the intestinal epithelium. This dysbiosis influences energy metabolism, anti-inflammatory responses, and immune regulation, and these results highlight significant differences in energy metabolism pathways. These findings suggest that the differential composition of intestinal flora, along with alterations in intestinal metabolites and metabolic pathways, contribute to the compromised integrity of the intestinal mucosal barrier and disturbances in energy metabolism in patients with severe AP.

Transition of patients with familial chylomicronaemia syndrome from volanesorsen to olezarsen: safety and pharmacokinetic results

Abstract Background Familial chylomicronaemia syndrome (FCS) is a rare genetic disorder of lipoprotein lipase deficiency resulting in severe hypertriglyceridaemia and pancreatitis risk. Volanesorsen is a weekly-injected antisense oligonucleotide (ASO) designed to degrade APOC3 mRNA that is approved as an adjunct to diet to treat FCS in the EU, UK, and Brazil. Olezarsen is an investigational monthly-injected ASO-GalNAC3 conjugate also designed to degrade APOC3 mRNA, but directed to hepatocytes, resulting in more potency and less systemic exposure and making it a potential alternative to volanesorsen for FCS. Purpose This interim analysis of an open-label phase 3 trial evaluated olezarsen safety and pharmacokinetics in patients (pts) with FCS previously treated with volanesorsen. Methods Adults with FCS with prior volanesorsen treatment, or actively participating in an expanded access programme (US and Canada), started olezarsen 80 mg by subcutaneous injection every 4 weeks after a minimum washout of 6 weeks. Historical volanesorsen laboratory and safety data were unavailable. The primary objective was to assess safety from changes vs baseline in platelet count, liver enzymes, and renal function; bleeding events; and adverse events. Pharmacokinetic measurements included plasma volanesorsen and olezarsen concentrations. Immunogenicity was assessed by measuring anti-drug antibodies (Abs). Results Of 24 pts enrolled, the majority were female (n=13; 54.2%) and White (n=21; 87.5%), with mean age of 49.1 years; 20 (83.3%) had genetically and 4 (16.7%) clinically validated FCS, all had history of acute pancreatitis (or symptoms suggestive of pancreatitis requiring hospitalisation or emergency room/urgent care visit; mean, 3.4 episodes within 5 years) and 5 (20.8%) of thrombocytopaenia. Time since last volanesorsen dose was 42—1118 days. Baseline fasting triglyceride (median [interquartile range (IQR)], 18.6 [9.6,34.0] mmol/L [1648 (852,3007) mg/dL]; mean [standard deviation (SD)], 25.5 [20.5] mmol/L [2256 (1812) mg/dL]) and apolipoprotein C-III (median [IQR], 0.2 [0.1,0.4] g/L [16.1 (12.4,39.0) mg/dL]; mean [SD], 0.3 [0.2] g/L [25.9 (19.5) mg/dL]) levels were elevated. During a mean (SD) of 329 (95) days of olezarsen 80 mg treatment, no pts experienced hepatic failure, renal impairment, major bleeding events, or platelet count below the prespecified threshold of 50,000 mm³ (Table 1). Olezarsen levels at trough were elevated during the first 3 months, mainly due to residual volanesorsen levels in pts with washout <90 days (Figure 1). Eleven (45.8%) pts had treatment-emergent anti-olezarsen Abs, of whom 5 (20.8%) had anti-volanesorsen Abs, with no impact on safety or efficacy; pts with vs without anti-drug Abs had higher olezarsen trough levels (mean, 4.4–7.8 ng/mL vs 1.1 ng/mL). Conclusions In this interim analysis, olezarsen was safe and well tolerated in pts with FCS previously treated with volanesorsen after a minimum washout of 6 weeks.

The clinical value of serum creatinine to bilirubin ratio in predicting the severity and prognosis of acute pancreatitis.

Bilirubin (BIL) and creatinine (Cr) have been used as potential early predictors of the severity of many diseases. A recent study found that the Cr to BIL ratio (CTR) was more sensitive and specific than either serum Cr or BIL alone. Our research focused on the clinical significance of CTR in evaluating the severity and prognosticating outcomes of acute pancreatitis (AP) in patients. Patients diagnosed with AP at the First Affiliated Hospital of Guangdong Pharmaceutical University between July 1, 2016, and December 31, 2020 were included. The analysis then focused on examining the relationship between CTR levels and the severity of the illness, the occurrence of complications, and the prognosticating outcomes for individuals diagnosed with AP. A total of 286 AP patients were enrolled. Multivariate regression analyses showed that patients with AP with increased CTR levels had a poorer disease (easier to develop severe AP); higher Ranson, and Acute Physiology and Chronic Health Evaluation (APACHE-II) scores; higher incidence of organ failure (acute heart failure, acute kidney injury and acute myocardial infarction ); and leading to a worse prognosis characterized more by frequent use of vasoactive and diuretic agents. When CTR >14.05, AP patients had increased occurrence of AHF and AKI, higher 30-day all-cause mortality rates, more frequently using vasoactive agent and diuretic agent. Besides, the disease severity scores and hospital stays were markedly increased. Patients with AP who exhibit higher CTR levels tend to experience escalating disease severity, more complications, and a poorer outcome compared with those with lower CTR levels.

Restoring CFTR function with Orkambi decreases the severity of alcohol-induced acute pancreatitis.

Heavy alcohol intake is one of the most common causes of acute pancreatitis (AP). We have previously shown that ethanol (EtOH) decreases the expression and activity of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a key role in alcohol-induced AP development. The prescription drug, Orkambi (a combination of ivacaftor and lumacaftor) can correct impaired CFTR function and expression in cystic fibrosis (CF) patients. Thus, the present study aimed to investigate whether Orkambi can mitigate alcohol-induced AP. Intact guinea-pig pancreatic ducts were pre-treated with different concentrations of ethanol (EtOH; 30, 50 and 100mm) for 12h alone or in combination with ivacaftor (VX770) and/or lumacaftor (VX-809), and CFTR expression and activity were evaluated by immunostaining and by the patch clamp technique, respectively. Alcoholic AP was induced in Orkambi-treated guinea-pigs, and standard laboratory and histological parameters were measured. Ivacaftor and lumacaftor alone or in combination dose-dependently restored the apical expression and activity of CFTR after EtOH treatment in vitro. Oral administration of Orkambi reduced the severity of alcohol-induced AP and restored impaired CFTR activity and expression. Orkambi is able to restore the CFTR defect caused by EtOH and decreases the severity of alcohol-induced pancreatitis. This is the first in vivo pre-clinical evidence of Orkambi efficacy in the treatment of alcohol-induced AP. KEY POINTS: Acute pancreatitis is one of the leading causes of hospital admission among gastrointestinal diseases in which the lack of a specific drug therapy plays a crucial role. The cystic fibrosis transmembrane conductance regulator (CFTR) plays an essential role in pancreatic ductal HCO3 - secretion; inappropriate CFTR function, as seen in heavy alcohol consumption, increases the risk of pancreatitis development. CFTR modulators are able to prevent the inhibitory effect of ethanol and reduce pancreatic ductal injury and the severity of alcohol-induced pancreatitis. CFTR modulators present a novel option in the pharmacotherapy of alcohol-induced pancreatitis by enhancing pancreatic functions or preventing recurrence.

Heme Oxygenase-1 Protected Against Severe Acute Pancreatitis by Inhibiting Inflammatory Response

Abstract Background Activation of NLPR3 inflammasome promotes the maturation and secretion of IL-1β and IL-18, leading to a series of inflammatory reactions, while inhibition of NLRP3 inflammasome alleviates the severity of Severe Acute Pancreatitis (SAP). An inducible enzyme responsible for heme decomposition, heme oxygenase-1 (HO-1), has anti-inflammatory, antioxidant, and anti-proliferative effects. HO-1 activity profoundly affects the host ability to forbear infection by reducing tissue damage or affecting resistance and increasing the capacity to pathogen load. We postulated that hemin, a strong HO-1 inducer, could decrease NLRP3 inflammasome activation, which would alleviate the severity of SAP and acute lung injury caused by pancreatitis. Methods By administering intraperitoneal injections of caerulein (Cae) and lipopolysaccharide (LPS), the SAP rat model was created. Then, the SAP rats were pretreated with Hemin or zinc protoporphyrin IX (Znpp, a HO-1 inhibitor) to stimulate or inhibit the HO-1 enzyme respectively, and the effects and mechanisms were investigated. Results The pancreas and lung tissue of the SAP rats suffered considerable pathological damage after Cae and LPS injection, with significant increases of amylase, lipase, IL-1β and IL-18 levels in the serum. Hemin pretreatment decreased IL-1β and IL-18 release in the serum and prevented pancreatic and pulmonary damage. Hemin dramatically reduced oxidative stress, downregulated the expression of NLRP3, ASC, and Caspase-1, and elevated HO-1 expression. On the contrary, there were no discernible changes between the SAP control and Znpp treated groups. Conclusion These results showed that hemin prevented Cae and LPS-induced lung and pancreatic injury through suppression of the inflammatory response. The impact of hemin on the activity of the NLRP3 inflammasome was depending critically on HO-1 activity. The protective role and mechanism HO-1 against the acute and severe inflammatory responses may provide a novel and effective therapeutic approach for SAP treatment.