Acute Pancreatitis Research Articles

Trypsin in pancreatitis: The culprit, a mediator, or epiphenomenon?

Pancreatitis is a common, life-threatening inflammatory disease of the exocrine pancreas. Its pathogenesis remains obscure, and no specific or effective treatment is available. Gallstones and alcohol excess are major etiologies of pancreatitis; in a small portion of patients the disease is hereditary. Pancreatitis is believed to be initiated by injured acinar cells (the main exocrine pancreas cell type), leading to parenchymal necrosis and local and systemic inflammation. The primary function of these cells is to produce, store, and secrete a variety of enzymes that break down all categories of nutrients. Most digestive enzymes, including all proteases, are secreted by acinar cells as inactive proforms (zymogens) and in physiological conditions are only activated when reaching the intestine. The generation of trypsin from inactive trypsinogen in the intestine plays a critical role in physiological activation of other zymogens. It was proposed that pancreatitis results from proteolytic autodigestion of the gland, mediated by premature/ inappropriate trypsinogen activation within acinar cells. The intra-acinar trypsinogen activation is observed in experimental models of acute and chronic pancreatitis, and in human disease. On the basis of these observations, it has been considered the central pathogenic mechanism of pancreatitis - a concept with a century-old history. This review summarizes the data on trypsinogen activation in experimental and genetic rodent models of pancreatitis, particularly the more recent genetically engineered mouse models that mimic mutations associated with hereditary pancreatitis; analyzes the mechanisms mediating trypsinogen activation and protecting the pancreas against its’ damaging effects; discusses the gaps in our knowledge, potential therapeutic approaches, and directions for future research. We conclude that trypsin is not the culprit in the disease pathogenesis but, at most, a mediator of some pancreatitis responses. Therefore, the search for effective therapies should focus on approaches to prevent or normalize other intra-acinar pathologic processes, such as defective autophagy leading to parenchymal cell death and unrelenting inflammation.

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.

Risk factors for acute kidney injury in patients with severe acute pancreatitis: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to identify the risk factors for acute kidney injury (AKI) in patients with severe acute pancreatitis (SAP). A comprehensive literature search was conducted using the PubMed, Embase and Cochrane Library databases for case-control studies comparing the clinical characteristics of patients with SAP with and without AKI. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS). Pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated using fixed- or random-effects models, based on heterogeneity. Five studies involving 795 patients with SAP were included, of whom 173 (21.8 %) developed AKI. All studies were of high quality according to the NOS. Among the 17 potential risk factors that were analysed, a history of alcohol consumption (OR = 2.36, 95% CI = 0.54-10.43, p < 0.001), elevated serum amylase (OR = 4.50, 95% CI = 1.77-11.43, p = 0.002) and Acute Physiology and Chronic Health Evaluation II (APACHE II) score (OR = 1.57, 95% CI = 0.49-2.64, p = 0.004) were significantly associated with an increased risk of AKI. However, hypertension (OR = 1.14, 95% CI = 0.60-2.16, p = 0.69) and diabetes (OR = 1.88, 95% CI = 0.51-6.95, p = 0.34) were not significantly associated with AKI risk. Based on funnel plots, no obvious publication bias was detected. A history of alcohol consumption, elevated serum amylase and APACHE II score are significant risk factors for AKI in patients with SAP. For early intervention, clinical physicians should be vigilant about the risk of AKI in patients with SAP with these factors. More high-quality studies are needed to validate these findings and explore other potential risk factors.

Diffusion weighted MRI and neutrophil lymphocyte ratio non-invasively predict infection in pancreatic necrosis: a pilot study.

Infected pancreatic necrosis (IPN) is a major determinant of mortality in acute pancreatitis (AP). Non-invasive diagnosis of IPN could guide the intervention in AP. We aimed to investigate the role of non-invasive methods like diffusion weighted magnetic resonance imaging (DW-MRI) and clinico-laboratory parameters as predictors of IPN. Prospective evaluation for predictors of IPN by diffusion restriction (DR) on DW-MRI and clinico-laboratory parameters was performed. Out of 39 patients included, 31 were analysed after exclusion. Twenty-six (83.8%) patients had moderately severe AP, and the rest had severe disease. They were categorized into Group A: patients with documented infection after intervention (n = 17) and Group B: successfully managed without intervention or negative culture after intervention (n = 14). On univariate analysis, Group A had significantly more incidence of fever (P = 0.020), persistent unwellness (P = 0.003), elevated neutrophil count (P = 0.007), lymphocyte count (P = 0.007), neutrophil lymphocyte ratio (NLR) (P = 0.028), DR on DW-MRI (P = 0.001) and low apparent diffusion coefficient (ADC) (P = 0.086). Multivariate analysis revealed DR on DW-MRI (P = 0.004) and NLR (P = 0.035) as significant predictors of IPN, among other factors. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of DW-MRI were 94.1%, 78.6%, 91.66%, and 84.21%, respectively. The area under curve of NLR on the ROC plot was 0.85 and the best cutoff was >3.5, with sensitivity, specificity, PPV, and NPV of 70.6%, 78.6%, 80%, and 68.7% respectively. DW-MRI and NLR are promising non-invasive tools for accurate prediction of IPN and hence can guide the need for intervention in acute pancreatitis.

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.

Interpretable prediction of 30-day mortality in patients with acute pancreatitis based on machine learning and SHAP.

Severe acute pancreatitis (SAP) can be fatal if left unrecognized and untreated. The purpose was to develop a machine learning (ML) model for predicting the 30-day all-cause mortality risk in SAP patients and to explain the most important predictors. This research utilized six ML methods, including logistic regression (LR), k-nearest neighbors(KNN), support vector machines (SVM), naive Bayes (NB), random forests(RF), and extreme gradient boosting(XGBoost), to construct six predictive models for SAP. An extensive evaluation was conducted to determine the most effective model and then the Shapley Additive exPlanations (SHAP) method was applied to visualize key variables. Utilizing the optimized model, stratified predictions were made for patients with SAP. Further, the study employed multivariable Cox regression analysis and Kaplan-Meier survival curves, along with subgroup analysis, to explore the relationship between the machine learning-based score and 30-day mortality. Through LASSO regression and recursive feature elimination (RFE), 25 optimal feature variables are selected. The XGBoost model performed best, with an area under the curve (AUC) of 0.881, a sensitivity of 0.5714, a specificity of 0.9651 and an F1 score of 0.64. The first six most important feature variables were the use of vasopressor, high Charlson comorbidity index, low blood oxygen saturation, history of malignant tumor, hyperglycemia and high APSIII score. Based on the optimal threshold of 0.62, patients were divided into high and low-risk groups, and the 30-day survival rate in the high-risk group decreased significantly. COX regression analysis further confirmed the positive correlation between high-risk scores and 30-day mortality. In the subgroup analysis, the model showed good risk stratification ability in patients with different gender, renal replacement therapy and with or without a history of malignant tumor, but it was not effective in predicting peripheral vascular disease. the XGBoost model effectively predicts the severity of SAP, serving as a valuable tool for clinicians to identify SAP early.

Acute pancreatitis following asparaginase treatment in pediatric acute lymphoblastic leukemia with a heterozygous SPINK1 c.194 + 2T&gt;C intronic variant: a case report

BackgroundAsparaginase is a critical component of chemotherapy for pediatric acute lymphoblastic leukemia (ALL), but its use is often complicated by asparaginase-associated pancreatitis (AAP). Genetic predispositions, such as variants in the SPINK1 gene, have been linked to an increased risk of pancreatitis. However, the role of genetic factors in relation to asparaginase treatment remains incompletely understood, partly because mutations in pancreatitis-causing genes are rarely found in pediatric ALL.Case descriptionA four-year and three-month-old Chinese girl was admitted to our hospital due to fever for half a day, with no history of significant prior medical history. Initial blood tests revealed hematological abnormalities, including leukopenia, anemia, and thrombocytosis. Bone marrow aspiration identified 81.5% blast cells with B-lymphocyte morphology and immunophenotype, leading to a diagnosis of B-cell acute lymphoblastic leukemia (B-ALL). The patient began treatment under the CCCG-ALL-2015 protocol, which included PEG-asparaginase (PEG-asp). On day 10 of induction, she developed AAP, which was primarily characterized by severe epigastric pain and elevated serum amylase. Despite effective symptom management with analgesics and anti-inflammatory therapy, AAP recurred following administration of L-asparaginase (L-asp). Genetic analysis revealed a heterozygous SPINK1 c.194 + 2T&amp;gt;C variant (rs148954387), a well-known pathogenic variant associated with increased susceptibility to pancreatitis. Sanger sequencing confirmed that the SPINK1 variant was inherited from her asymptomatic mother. The patient's AAP was managed conservatively, and an asparaginase-free regimen ultimately achieved complete remission without recurrence of pancreatitis.ConclusionsThe identification of the SPINK1 c.194 + 2T&amp;gt;C variant, which is recognized as pathogenic, provides valuable information for understanding the heightened risk of AAP in our pediatric ALL patient. Our case underscores the potential role of genetic predisposition in the development of AAP and highlights the importance of considering genetic screening prior to asparaginase therapy in pediatric ALL patients to identify those at increased risk.

Guidelines in Practice: Management of Acute Pancreatitis.

Guidelines in Practice: Management of Acute Pancreatitis.

Therapeutic potential of plant polyphenols in acute pancreatitis.

Acute pancreatitis is a potentially life-threatening inflammatory disorder of the exocrine pancreas characterized by early activation of pancreatic enzymes followed by macrophage-driven inflammation, and pancreatic acinar cell death. The most common causes are gallstones and excessive alcohol consumption. Inflammation and oxidative stress play critical roles in its pathogenesis. Despite increasing incidence, currently, no specific drug therapy is available to treat or prevent acute pancreatitis, in particular severe acute pancreatitis. New therapeutic agents are very much needed. Plant polyphenols have attracted extensive attention in the field of acute pancreatitis due to their diverse pharmacological properties. In this review, we discuss the potential of plant polyphenols in inhibiting the occurrence and development of acute pancreatitis via modulation of inflammation, oxidative stress, calcium overload, autophagy, and apoptosis, based on the currently available in vitro, in vivo animal and very few clinical human studies. We also outline the opportunities and challenges in the clinical translation of plant polyphenols for the treatment of the disease. We concluded that plant polyphenols have a potential therapeutic effect in the management and treatment of acute pancreatitis. Knowledge gained from this review will hopefully inspire new research ideas and directions for the development and application of plant polyphenols for treating this disease.

Comparison of outcomes of index and interval laparoscopic cholecystectomy in mild biliary pancreatitis.

Objective: To compare the outcomes of index and interval laparoscopic cholecystectomy in mild biliary pancreatitis in terms of duration of hospital stay. Study Design: Randomized Controlled Trial. Setting: Surgical Unit 1, Holy Family Hospital, Rawalpindi. Period: January 2023 till June 2023. Methods: Patients were being admitted with acute biliary pancreatitis and undergoing either index or interval cholecystectomy. BISAP scoring system was used for severity of ABP and mild cases were included. Study outcomes in both groups (index and interval cholecystectomy) were determined. For quantitative variables mean and standard deviation were calculated. Frequency and percentages were used to describe qualitative variables. Results: Total of 70 patients divided into two groups were included in this study. Mean age of the study population was 40.44+/-7.90 years. Fifty-three percent of the population had BMI in the overweight category. Mean BISAP score was 1.11+/-0.80. All of the patients included in the study had mild acute pancreatitis. The length of hospital stay was significantly associated with timing of surgery with p-values 0.045. Conclusion: The surgical outcomes of index and interval cholecystectomy in acute mild biliary pancreatitis are comparable. However, early cholecystectomy has shorter duration of hospital stay.

MRG15 promotes cell apoptosis through inhibition of mitophagy in hyperlipidemic acute pancreatitis.

Hyperlipidemia is a common cause of acute pancreatitis (AP), often leading to more severe clinical symptoms. The mortality factor 4-like protein 1 (MORF4L1, also called MRG15) plays a crucial role in regulating lipid metabolism. Therefore, this study aimed to explore the mechanism of MRG15 in hyperlipidemic acute pancreatitis (HAP). Mendelian randomization, transcriptome analysis, and single-cell analysis were employed to explore the association between MRG15 and AP by utilizing publicly available databases. In vivo, hypertriglyceridemia mouse models were created by intraperitoneal injection of P407 or using APOE-deficient mice. Subsequently, the HAP model was induced by cerulean. In vitro, a cell model of HAP was established by initially exposing cells to palmitic acid to simulate a high-fat environment, followed by cerulein treatment. Subsequently, MRG15-related indicators were measured. Through Mendelian randomization, it was discovered that there is a positive correlation between genetic expression of MRG15 and the risk of AP. Transcriptome and single-cell analysis revealed that elevated MRG15 expression in AP contributes to lipid metabolism disorders and the activation of apoptosis pathways in pancreatic acinar cells. MRG15 is found to be significantly upregulated in cases of HAP. Knocking down MRG15 led to an increase in mitophagy and a decrease in apoptosis in pancreatic cells, and this effect was reversed when the mitochondrial Tu translation elongation factor (TUFM) was simultaneously knocked down. MRG15 inhibits mitophagy by degrading TUFM, ultimately promoting cell apoptosis and worsening the progression of HAP.

Identifying the ceRNA Regulatory Network in Early-Stage Acute Pancreatitis and Investigating the Therapeutic Potential of NEAT1 in Mouse Models.

Acute pancreatitis (AP) is a common digestive disorder characterized by high morbidity and mortality. This study aims to uncover differentially expressed long noncoding RNAs (lncRNAs) and mRNAs, as well as related pathways, in the early stage of acute pancreatitis (AP), with a focus on the role of Neat1 in AP and severe acute pancreatitis (SAP). In this study, we performed high-throughput RNA sequencing on pancreatic tissue samples from three normal mice and three mice with cerulein-induced AP to describe and analyze the expression profiles of long non-coding RNAs (lncRNAs) and mRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted on the differentially expressed mRNAs to identify enriched pathways and biological processes. An lncRNA-miRNA-mRNA interaction network was constructed to elucidate potential regulatory mechanisms. Furthermore, we utilized Neat1 knockout mice to investigate the role of Neat1 in the pathogenesis of cerulein-AP and L-arginine-severe acute pancreatitis (SAP). Our results revealed that 261 lncRNAs and 1522 mRNAs were differentially expressed in the cerulein-AP group compared to the control group. GO and KEGG analyses of the differentially expressed mRNAs indicated that the functions of the corresponding genes are enriched in cellular metabolism, intercellular structure, and positive regulation of inflammation, which are closely related to the central events in the pathogenesis of AP. A ceRNA network involving 5 lncRNAs, 226 mRNAs, and 61 miRNAs were constructed. Neat1 was identified to have the potential therapeutic effects in AP. Neat1 knockout in mice inhibited pyroptosis in both the AP/SAP mouse models. We found that lncRNAs, particularly Neat1, play a significant role in the pathogenesis of AP. This finding may provide new insights into further exploring the pathogenesis of SAP and could lead to the identification of new targets for the treatment of AP and SAP.

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.

Ascaris in infected pancreatic pancreatic necrosum: a case report of an intraoperative surprise

Introduction and importance: Ascariasis lumbricoides is a common gastrointestinal tract helminthic disease in developing countries and is also a cause of hepatobiliary and pancreatic disease in endemic areas of the world. Involvement of the pancreatic duct by worms and associated pancreatitis is less common than the hepatic and biliary involvement. Case presentation: A 38-year-old patient was admitted with a diagnosis of alcohol-induced acute pancreatitis and managed conservatively. However, the patient’s condition worsened after 2 weeks, and a CT scan revealed an acute necrotic collection with gas foci. After failed percutaneous pigtail catheter drainage, laparotomy was performed, revealing a necrotic collection in the right paracolic gutter, with the entire area frozen and a worm observed in the necrosum. The colon and small bowel were intact without perforation. The suspicion arose that the worm might have either migrated from a duodenal perforation, which had possibly sealed after the acute phase, or migrated from the major pancreatic duct. Debridement of easily accessible necrotic tissues was performed, and the patient was admitted to the intensive care unit (ICU). Unfortunately, the patient tested positive for COVID-19, and a few days later, blood was observed in the drain. Re-exploration revealed diffuse blood oozing, and the abdomen was closed with packing. Conclusion: The route of ascaris migration to necrosum or its association with severe acute pancreatitis needs to be ensured in endemic areas. Cautious use of antihelminthic therapy in endemic areas could prevent fatal pancreatobiliary complications and its associated mortality.

Outcomes of percutaneous endoscopic versus endoscopic transmural necrosectomy for necrotizing pancreatitis: A propensity score-matched study

BackgroundFew published studies exist that compare the outcomes of different endoscopic necrosectomy methods for necrotizing pancreatitis(NP). We compared the safety and efficacy of percutaneous versus transmural endoscopic necrosectomy for NP patients. MethodsIn this retrospective cohort study, we analyzed adult NP patients who underwent either percutaneous endoscopic necrosectomy(PEN) or endoscopic transmural necrosectomy(ETN), and compared safety and efficacy between the two groups. Propensity score-matched analysis and multivariable logistic regression analysis were conducted. ResultsA total of 280 patients were enrolled, among which 142 underwent PEN and 138 underwent ETN. There were differences in baseline characteristics between the two groups, including body mass index, C-reactive protein, systemic inflammatory response syndrome score. The incidences of sepsis, respiratory failure, and intensive care unit stay were higher among patients who underwent PEN than those who underwent ETN (all P<0.01). Ninety-one pairs were matched with comparable baseline characteristics and severity. The incidence of postoperative complications, open surgery, clinical success, radiological success, collection recurrence, and reintervention were not significantly different between the ETN group and PEN group (all P>0.05). Multivariate analysis also showed that the approaches (PEN vs ETN) was not associated with postoperative complications or mortality. ConclusionsIn real world setting, sicker patients tend to be more effectively managed through PEN compared to ETD. PEN demonstrates comparable efficacy and safety to ETD in the treatment of NP patients.

Circulating Protectin D1 and Neutrophils Extracellular Traps in the Diagnosis and Progression of Acute Pancreatitis

Circulating Protectin D1 and Neutrophils Extracellular Traps in the Diagnosis and Progression of Acute Pancreatitis

Coagulopathy and acute pancreatitis: pathophysiology and clinical treatment

Coagulopathy is a critical pathophysiological mechanism of acute pancreatitis (AP), arising from the complex interplay between innate immune, endothelial cells and platelets. Although initially beneficial for the host, uncontrolled and systemic activation of coagulation cascade in AP can lead to thrombotic and hemorrhagic complications, ranging from subclinical abnormalities in coagulation tests to severe clinical manifestations, such as disseminated intravascular coagulation. Initiation of coagulation activation and consequent thrombin generation is caused by expression of tissue factor on activated monocytes and is ineffectually offset by tissue factor pathway inhibitor. At the same time, endothelial-associated anticoagulant pathways, in particular the protein C system, is impaired by pro-inflammatory cytokines. Also, fibrin removal is severely obstructed by inactivation of the endogenous fibrinolytic system, mainly as a result of upregulation of its principal inhibitor, plasminogen activator inhibitor type 1. Finally, increased fibrin generation and impaired break down lead to deposition of (micro) vascular clots, which may contribute to tissue ischemia and ensuing organ dysfunction. Despite the high burden of coagulopathy that have a negative impact on AP patients’ prognosis, there is no effective treatment yet. Although a variety of anticoagulants drugs have been evaluated in clinical trials, their beneficial effects are inconsistent, and they are also characterized by hemorrhagic complications. Future studies are called to unravel the pathophysiologic mechanisms involved in coagulopathy in AP, and to test novel therapeutics block coagulopathy in AP.

Correlation between gut microbiota and pancreatitis: a bidirectional Mendelian randomization.

The causative role of gut microbiota in pancreatitis remains unknown. This study aimed to investigate potential causal associations between gut microbiota and pancreatitis, using bidirectional Mendelian randomization (MR) analysis. We analyzed genome-wide association study (GWAS) summary statistics for gut microbiota (211 taxa from gut microbiota, n = 18 340) and two types of pancreatitis, namely acute pancreatitis (AP, 5509 cases and 301 383 controls) and chronic pancreatitis (CP, 3002 cases and 301 383 controls). A reverse MR analysis was also performed to assess the possibility of reverse causation. Nine features (one family + eight genera) showed a causal association with AP. According to inverse-variance weighted (IVW) estimates, phylum Firmicutes (P = 4.10 × 10-2), genus Erysipelatoclostridium (P = 4.80 × 10-2), genus Flavonifractor (P = 4.10 × 10-2), genus Methanobrevibacter (P = 3.40 × 10-2), and genus Prevotella9 (P = 4.60 × 10-2) were found to have a protective effect on AP. Additionally, genus Eubacteriumeligensgroup (P = 4.10 × 10-2), genus Eubacteriumfissicatenagroup (P = 4.00 × 10-3), genus Coprococcus3 (P = 4.10 × 10-2), and genus Haemophilus (P = 4.60 × 10-2) exhibited a positive correlation with AP. Four features (two families + two genera) were causally associated with CP. IVW results also confirmed that family Clostridiaceae1 (P = 3.30 × 10-2), genus LachnospiraceaeFCS020group (P = 4.60 × 10-2), and genus Prevotella9 (P = 1.90 × 10-2) were protective factors for CP, whereas the presence of family Victivallaceae (P = 2.60 × 10-2) correlated with CP risk. No causal effects of pancreatitis (AP or CP) on these gut microbiota taxa were found in the reverse MR analysis. This study confirms a potential causal relationship between gut microbiota and pancreatitis, highlighting the gut microbiota-pancreas axis in the pathogenesis of pancreatitis.

Resveratrol improved mitochondrial biogenesis by activating SIRT1/PGC-1α signal pathway in SAP

NLRP3 inflammasomes- pyroptosis axis is activated by microcirculation dysfunction and touched off severe acute pancreatitis (SAP). Activation of PGC-1α can improve microcirculation dysfunction by promoting mitochondrial biogenesis. Resveratrol (RSV), one typical SIRT1 agonist, possesses the ability of alleviating SAP and activing PGC-1α. Therefore, the study was designated to explore whether the protective effect of RSV in SAP was though suppressing NLRP3 inflammasomes- pyroptosis axis via advancing SIRT1/PGC-1α-dependent mitochondrial biogenesis. The models of SAP were induced by treating with sodium taurodeoxycholate in rats and AR42J cells. The pathological injury, water content (dry/wet ratio) and microcirculation function of pancreas, activity of lipase and amylase were used to evaluate pancreatic damage. The expression of inflammatory cytokine was measured by ELISA and RT-PCR. The damage of mitochondrial was evaluated by measuring the changes in Mitochondrial Membrane Potential (ΔΨm), mitochondrial ROS, ATP content and MDA as well as relocation of mtDNA and the activity of SOD and GSH. The expressions of NLRP3 inflammasomes- pyroptosis axis proteins were detected by Western blotting as well as SIRT1/PGC-1α/NRF1/TFAM pathway protein. Moreover, the modification of PGC-1α was measured by co-immunoprecipitation. The results displayed that RSV can significantly improve the damage of pancreas and mitochondrial, decrease the expression of pro-inflammatory factor and the activation of NLRP3 inflammasomes- pyroptosis axis, promote the expression of an-inflammatory factor and the deacetylation of PGC-1α together with facilitating SIRT1/PGC-1α-mediating mitochondrial biogenesis. Therefore, the protective effect of RSV in SAP is though inactivation of NLRP3 inflammasomes- pyroptosis axis via promoting mitochondrial biogenesis in a SIRT1/PGC-1α-dependent manner.