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Background/aim: Severity of microlithiasis- and sludge-induced pancreatitis in comparison to gallstone-induced pancreatitis has never been studied for a lack of definition., Materials and Methods: In this retrospective cohort study, 263 patients with acute biliary pancreatitis treated at a tertiary care center from 2005 to 2021 were stratified according to the recent consensus definition for microlithiasis and sludge. The gallstone-pancreatitis cohort was compared to microlithiasis, sludge, and suspected stone passage pancreatitis cohorts in terms of pancreatitis outcome, liver function, and endosonography/endoscopic retrograde cholangiopancreatography results using one-way analysis of variance and χ 2 test. Multinomial logistic regression analysis was performed to correct for bias., Results: Microlithiasis- and sludge-induced pancreatitis, classified according to the revised Atlanta classification, did not present with a milder course than gallstone-induced pancreatitis ( P = 0.62). Microlithiasis and sludge showed an increase in bilirubin on the day of admission to hospital, which was not significantly different from gallstone-induced pancreatitis ( P = 0.36). The likelihood of detecting biliary disease on endosonography resulting in bile duct clearance was highest on the day of admission and day 1, respectively., Conclusions: Microlithiasis and sludge induce gallstone-equivalent impaired liver function tests and induce pancreatitis with similar severity compared with gallstone-induced acute biliary pancreatitis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: With respect to severity and outcome of an index episode of idiopathic acute pancreatitis the current literature reports conflicting retrospective results. One reason might be the retrospective study design precluding in depth analysis resulting in mixed etiologies and combination of index episode versus recurrent idiopathic acute pancreatitis., Methods: In this retrospective monocentric cohort study, we retrieved all patients with a first acute pancreatitis episode treated between 2005 and 2021 at the LMU University Hospital from our clinical information system based on the respective ICD-10 codes. In an initial sample of 1390 presumed idiopathic pancreatitis patients we identified 68 confirmed idiopathic acute pancreatitis patients and compared those to 75 first-time alcohol-induced acute pancreatitis patients and 390 first-time biliary-induced acute pancreatitis patients. Clinical outcome (severity, SIRS, mortality, and re-admission rate) was set as outcome measures. Multinomial logistic regression analysis was performed., Results: In alcohol-induced acute pancreatitis moderate and severe courses occur significantly more often when compared to idiopathic acute pancreatitis (17.33 % vs. 10.29 %; multinomial logistic regression p = 0.0021). There were no significant differences in mortality between first-time alcoholic, idiopathic and biliary pancreatitis (p = 0.6328). Patients with idiopathic acute pancreatitis had significantly more hospital readmissions (within 30 days) compared to alcohol-induced pancreatitis patients (p = 0.0284)., Conclusion: In the context of a first episode of acute pancreatitis, idiopathic acute pancreatitis remains a challenging diagnosis posing an increased risk of recurrence, but not an increased risk for a more severe disease course., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest concerning the research, authorship, and/or publication of this article., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: In up to 20% of patients, the aetiology of acute pancreatitis (AP) remains elusive and is thus called idiopathic. On more detailed review these cases can often be explained through biliary disease and are amenable to treatment. Findings range from biliary sludge to microlithiasis but their definitions remain fluid and controversial., Design: A systematic literature review (1682 reports, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines) analysed definitions of biliary sludge and microlithiasis, followed by an online international expert survey (30 endoscopic ultrasound/hepatobiliary and pancreatic experts; 36 items) which led to definitions of both. These were consented by Delphi voting and clinically evaluated in a retrospective cohort of patients with presumed biliary pancreatitis., Results: In 13% of original articles and 19.2% of reviews, microlithiasis and biliary sludge were used synonymously. In the survey, 41.7% of experts described the term 'sludge' and 'microlithiasis' as identical findings. As a consequence, three definitions were proposed, agreed on and confirmed by voting to distinctly discriminate between biliary sludge (hyperechoic material without acoustic shadowing) and microlithiasis (echorich calculi of ≤5 mm with acoustic shadowing) as opposed to larger biliary stones, both for location in gallbladder and bile ducts. In an initial attempt to investigate the clinical relevance in a retrospective analysis in 177 confirmed cases in our hospital, there was no difference in severity of AP if caused by sludge, microlithiasis or stones., Conclusion: We propose a consensus definition for the localisation, ultrasound morphology and diameter of biliary sludge and microlithiasis as distinct entities. Interestingly, severity of biliary AP was not dependent on the size of concrements warranting prospective randomised studies which treatment options are adequate to prevent recurrence., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) are an established risk factor for cystic fibrosis (CF) and chronic pancreatitis. Whereas patients with CF usually develop complete exocrine pancreatic insufficiency, pancreatitis patients with CFTR mutations have mostly preserved exocrine pancreatic function. We therefore used a strain of transgenic mice with significant residual CFTR function (CFTR tm1HGU ) to induce pancreatitis experimentally by serial caerulein injections. Protease activation and necrosis were investigated in isolated acini, disease severity over 24h, pancreatic function by MRI, isolated duct stimulation and faecal chymotrypsin, and leucocyte function by ex vivo lipopolysaccharide (LPS) stimulation. Pancreatic and lung injury were more severe in CFTR tm1HGU but intrapancreatic trypsin and serum enzyme activities higher than in wild-type controls only at 8h, a time interval previously attributed to leucocyte infiltration. CCK-induced trypsin activation and necrosis in acini from CFTR tm1HGU did not differ from controls. Fluid and bicarbonate secretion were greatly impaired, whereas faecal chymotrypsin remained unchanged. LPS stimulation of splenocytes from CFTR tm1HGU resulted in increased INF-γ and IL-6, but decreased IL-10 secretion. CFTR mutations that preserve residual pancreatic function significantly increase the severity of experimental pancreatitis-mostly via impairing duct cell function and a shift towards a pro-inflammatory phenotype, not by rendering acinar cells more susceptible to pathological stimuli., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Premature intrapancreatic trypsinogen activation is widely regarded as an initiating event for acute pancreatitis. Previous studies have alternatively implicated secretory vesicles, endosomes, lysosomes, or autophagosomes/autophagolysosomes as the primary site of trypsinogen activation, from which a cell-damaging proteolytic cascade originates. To identify the subcellular compartment of initial trypsinogen activation we performed a time-resolution analysis of the first 12 h of caerulein-induced pancreatitis in transgenic light chain 3 (LC3)-GFP autophagy reporter mice. Intrapancreatic trypsin activity increased within 60 min and serum amylase within 2 h, but fluorescent autophagosome formation only by 4 h of pancreatitis in parallel with a shift from cytosolic LC3-I to membranous LC3-II on Western blots. At 60 min, activated trypsin in heavier subcellular fractions was co-distributed with cathepsin B, but not with the autophagy markers LC3 or autophagy protein 16 (ATG16). Supramaximal caerulein stimulation of primary pancreatic acini derived from LC3-GFP mice revealed that trypsinogen activation is independent of autophagolysosome formation already during the first 15 min of exposure to caerulein. Co-localization studies (with GFP-LC3 autophagosomes versus Ile-Pro-Arg-AMC trypsin activity and immunogold-labelling of lysosomal-associated membrane protein 2 [LAMP-2] versus trypsinogen activation peptide [TAP]) indicated active trypsin in autophagolysosomes only at the later timepoints. In conclusion, during the initiating phase of caerulein-induced pancreatitis, premature protease activation develops independently of autophagolysosome formation and in vesicles arising from the secretory pathway. However, autophagy is likely to regulate overall intracellular trypsin activity during the later stages of this disease.

Background & Aims: Pancreatitis starts with primarily sterile local inflammation that induces systemic inflammatory response syndrome, followed by compensatory anti-inflammatory response syndrome (CARS). We investigated the mechanisms of these processes in mice and human serum., Methods: We induced severe acute pancreatitis by partial duct ligation with caerulein stimulation or intraperitoneal injection of l-arginine in mice with deletion of interleukin (IL)12B, NLRP3, or IL18 and in mice given MCC950, a small molecule inhibitor of the NLRP3-inflammasome. Pancreata were collected from mice and analyzed by histology, and cytokine levels were measured in serum samples. We measured activation of adaptive immune responses in mice with pancreatitis by flow cytometry analysis of T cells (CD25 and CD69) isolated from the spleen. Differentiation of T-helper (Th1) cells, Th2 cells, and T-regulatory cells was determined by nuclear staining for TBET, GATA3, and FOXP3. We performed transcriptome analysis of mouse lymph nodes and bone marrow-derived macrophages after incubation with acini. We measured levels of cytokines in serum samples from patients with mild and severe acute pancreatitis., Results: Activation of the adaptive immune response in mice was initiated by macrophage-derived, caspase 1-processed cytokines and required activation of NLRP3 (confirmed in serum samples from patients with pancreatitis). Spleen cells from mice with pancreatitis had increases in Th2 cells but not in Th1 cells. Bone marrow-derived macrophages secreted IL1B and IL18, but not IL12, after co-incubation with pancreatic acini. T-cell activation and severity of acute pancreatitis did not differ significantly between IL12B-deficient and control mice. In contrast, NLRP3- or IL18-deficient mice had reduced activation of T cells and no increase in Th2 cell-mediated responses compared with control mice. The systemic type 2 immune response was mediated by macrophage-derived cytokines of the IL1 family. Specifically, IL18 induced a Th2 cell-mediated response in the absence of IL12. MCC950 significantly reduced neutrophil infiltration, T-cell activation, and disease severity in mice., Conclusions: In mice with severe pancreatitis, we found systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome developed in parallel. Infiltrating macrophages promote inflammation and simultaneously induce a Th2 cell-mediated response via IL18. Inhibition of NLRP3 reduces systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome and might be used to treat patients with severe pancreatitis., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Acute pancreatitis is a common gastrointestinal disorder burdened with a high mortality. Two pathophysiological events during experimental pancreatitis are thought to determine the clinical course: premature digestive protease activation and tissue infiltration by inflammatory cells. We have investigated the effect of AZD8309, a potent and orally bioavailable antagonist of the chemokine receptor CXCR2, which has been proposed to regulate the transmigration of neutrophils., Methods: Male C57BL6 mice (25-30 g) received gavage feeding of AZD8309 (50 mg/kg/BW) or mannitol (controls) twice daily starting 3 h prior to pancreatitis induction. Mild pancreatitis was induced by i.p. caerulein administration (50 μg/kg BW), severe pancreatitis by intraductal taurocholate (2%). Pancreas, lung, and serum was harvested up to 48 h after pancreatitis induction and used for histopathology, amylase, lipase, cathepsin B, trypsin, and elastase activity measurements, myeloperoxidase (MPO) content and cytokine concentrations., Results: Oral administration of AZD8309 significantly reduced MPO in the pancreas and lungs (8 h & 24 h) and reduced intrapancreatic trypsin and elastase activity (8 h) in caerulein-pancreatitis. In taurocholate-pancreatitis AZD8309 reduced cathepsin B activity and MPO. Serum cytokine levels were reduced by AZD8309 as well as histopathological damage., Conclusion: The CXCR2 antagonist AZD8309 reduced the transmigration of neutrophils as well as intrapancreatic protease activation in experimental pancreatitis. This effect was sufficient to reduce the overall severity of the disease. CXCR2 may therefore be a viable therapeutic target and AZD8309 a suitable agent for the treatment of acute pancreatitis., (Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Reactive oxygen radicals, pro-inflammatory mediators and cytokines have been implicated in caerulein induced acute pancreatitis. Nordihydroguaiaretic acid (NDGA), a plant lignin, has marked anti-inflammatory properties. The present study aimed to investigate the possible protective effect of NDGA against caerulein induced pancreatitis. Acute pancreatitis was induced by intraperitoneal administration of eight doses of caerulein in male swiss albino mice. NDGA was administered after 9 h of acute pancreatitis induction. Pancreatic damage and the protective effect of NDGA were assessed by oxidative stress parameters and histopathology of pancreas. The mRNA expression of heat shock proteins (DNAJ C15 and HSPD1) was examined by real-time RT-PCR analysis. Expression of HSP 27, NF-κB, TNF-α, p-p38, Bcl-2, p-PP2A, procaspase-3, caspase-3 and histone modifications were examined by western blotting. NDGA attenuated the oxidative stress, led to increased plasma α-amylase and decreased IGF-1 in AP mice. It modulated the mRNA and protein levels of heat shock proteins and reduced the expression of NF-κB, TNF-α and p-p38. It increased the number of TUNEL positive apoptotic cells in the pancreas of AP mice. In addition, NDGA prevented the changes in modifications of histone H3 in acute pancreatitis. To best of our knowledge, this is the first report which suggests that NDGA prevents the progression of acute pancreatitis by involving alteration of histone H3 modifications and modulating the expression of genes involved in inflammatory/apoptotic cascade, which may be responsible for decreased necrosis and increased apoptosis in this model of acute pancreatitis.