Neutrophil Extracellular Traps Initiate Gallstone Formation.

The presence of gallstones (cholelithiasis) is a highly prevalent and severe disease and one of the leading causes of hospital admissions worldwide. Due to its substantial health impact, we investigated the biological mechanisms that lead to the formation and growth of gallstones. We show that gallstone assembly essentially requires neutrophil extracellular traps (NETs). We found consistent evidence for the presence of NETs in human and murine gallstones and describe an immune-mediated process requiring activation of the innate immune system for the formation and growth of gallstones. Targeting NET formation via inhibition of peptidyl arginine deiminase type 4 or abrogation of reactive oxygen species (ROS) production, as well as damping of neutrophils by metoprolol, effectively inhibit gallstone formation in vivo. Our results show that after the physicochemical process of crystal formation, NETs foster their assembly into larger aggregates and finally gallstones. These insights provide a feasible therapeutic concept to prevent cholelithiasis in patients at risk.

Novel insights into causal effects of serum lipids and lipid-modifying targets on cholelithiasis.

OBJECTIVE: Different serum lipids and lipid-modifying targets should affect the risk of cholelithiasis differently, however, whether such effects are causal is still controversial and we aimed to answer this question. DESIGN: We prospectively estimated the associations of four serum lipids with cholelithiasis in UK Biobank using the Cox proportional hazard model, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Furthermore, we estimated the causal associations of the genetically predicted serum lipids with cholelithiasis in Europeans using the Mendelian randomisation (MR) design. Finally, both drug-target MR and colocalisation analyses were performed to estimate the lipid-modifying targets' effects on cholelithiasis, including HMGCR, NPC1L1, PCSK9, APOB, LDLR, ACLY, ANGPTL3, MTTP, PPARA, PPARD and PPARG. RESULTS: We found that serum levels of LDL-C and HDL-C were inversely associated with cholelithiasis risk and such associations were linear. However, the serum level of TC was non-linearly associated with cholelithiasis risk where lower TC was associated with higher risk of cholelithiasis, and the serum TG should be in an inverted 'U-shaped' relationship with it. The MR analyses supported that lower TC and higher TG levels were two independent causal risk factors. The drug-target MR analysis suggested that HMGCR inhibition should reduce the risk of cholelithiasis, which was corroborated by colocalisation analysis. CONCLUSION: Lower serum TC can causally increase the risk of cholelithiasis. The cholelithiasis risk would increase with the elevation of serum TG but would decrease when exceeding 2.57 mmol/L. The use of HMGCR inhibitors should prevent its risk.

Association of aflatoxin with gallbladder cancer in a case-control study nested within a Chinese cohort.

We evaluated whether aflatoxin B1 (AFB1 ) exposure was associated with later risk of developing gallbladder cancer (GBC). We measured AFB1 -lysine albumin adducts in baseline samples from the Shanghai Cohort Study of 18 244 men aged 45 to 64 years (recruited 1986-1989). We included 84 GBC cases with sufficient serum and 168 controls matched on age at sample collection, date of blood draw and residence. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for detectable vs non-detectable AFB1 -lysine albumin adducts and gallbladder cancer. AFB1 -lysine albumin adducts were detected in 50.0% of GBC cases, and risk of GBC was twice as high in those with detectable vs undetectable levels (OR = 2.0, 95% CI = 1.0-3.9). ORs ranged from 1.8 (95% CI = 0.75-4.3) for 0.5 to <1.75 pg/mg vs undetectable adduct levels to 2.2 (95% CI = 0.91-5.6) for >3.36 pg/mg vs undetectable, suggesting a dose-response (Ptrend = .05). When restricted to cases diagnosed before the median time to diagnosis after blood draw (18.4 years), results were similar (OR = 2.2, 95% CI = 0.80-5.8) to those for the entire follow-up duration. The OR was 9.4 (95% CI = 1.7-51.1) for individuals with detectable AFB1 -lysine albumin adducts and self-reported gallstones compared to individuals with neither. Participants with detectable AFB1 -lysine albumin adducts at baseline had increased risk of developing GBC, replicating the previously observed association between AFB1 exposure and providing the first evidence of temporality.

Global Epidemiology of Gallstones in the 21st Century: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Gallstones are common and associated with substantial health and economic burden. We aimed to comprehensively evaluate the prevalence and incidence of gallstones in the 21st century. METHODS: We systematically searched PubMed and Embase to identify studies reporting the prevalence and/or incidence of gallstones between January 1, 2000, and November 18, 2023. Pooled prevalence and incidence were calculated using DerSimonian and Laird's random-effects model. We performed subgroup analyses and meta-regression based on age, sex, geographic location, population setting, and modality of detection to examine sources of heterogeneity. RESULTS: Based on 115 studies with 32,610,568 participants, the pooled prevalence of gallstones was 6.1% (95% CI, 5.6-6.5). Prevalence was higher in females vs males (7.6% vs 5.4%), in South America vs Asia (11.2% vs 5.1%), in upper-middle-income countries vs high-income countries (8.9% vs 4.0%), and with advancing age. On sensitivity analysis of population-based studies, the prevalence of gallstones was 5.5% (95% CI, 4.1-7.4; n = 44 studies), and when limiting subgroup analysis to imaging-based detection modalities, the prevalence was 6.7% (95% CI, 6.1-7.3; n = 101 studies). Prevalence has been stable over the past 20 years. Based on 12 studies, the incidence of gallstones was 0.47 per 100 person-years (95% CI, 0.37-0.51), without differences between males and females, and with increasing incidence in more recent studies. CONCLUSIONS: Globally, 6% of the population have gallstones, with higher rates in females and in South America. The incidence of gallstones may be increasing. Our findings call for prioritizing research on the prevention of gallstones.

Metagenomic Analysis of Biliary Microbial Flora in Patients with Gallbladder Cancer or Gallstones-Associated Chronic Cholecystitis.

Biliary dysbiosis is associated with gallbladder cancer (GBC). We aimed to look for biliary bacteria specifically detected in GBC patients. We used 16S rRNA-based metagenomic analysis to elucidate biliary microbiota in 30 GBC and 30 gallstones-associated chronic cholecystitis patients. Relative abundance of five genera, Streptococcus, Enterococcus, Halomonas, Escherichia and Caulobacter was significantly associated with GBC. Of 15-species, 7 were detected significantly higher in GBC, Streptococcus anginosus, Streptococcus constellatus, Streptococcus intermedius, Actinomyces bowdenii, Actinomyces israelii, Actinomyces gerencseriae, and Escherichia fergusonii were biosafety level-2 infectious bacteria; other 8 species were biosafety level-1 bacteria. These bacterial species may be involved in pathogenesis of GBC.

Helicobacter pylori CagA Promotes the Formation of Gallstones by Increasing the Permeability of Gallbladder Epithelial Cells.

BACKGROUND: The formation of gallstones is often accompanied by chronic inflammation, and the mechanisms underlying inflammation and stone formation are not fully understood. Our aim is to utilize single-cell transcriptomics, bulk transcriptomics, and microbiome data to explore key pathogenic bacteria that may contribute to chronic inflammation and gallstone formation, as well as their associated mechanisms. METHODS: scRNA-seq data from a gallstone mouse model were extracted from the Gene Expression Omnibus (GEO) database and analyzed using the FindCluster() package for cell clustering analysis. Bulk transcriptomics data from patients with gallstone were also extracted from the GEO database, and intergroup functional differences were assessed using GO and KEGG enrichment analysis. Additionally, 16S rRNA sequencing was performed on gallbladder mucosal samples from asymptomatic patients with gallstone (n = 6) and liver transplant donor gallbladder mucosal samples (n = 6) to identify key bacteria associated with stone formation and chronic inflammation. Animal models were constructed to investigate the mechanisms by which these key pathogenic bacterial genera promote gallstone formation. RESULTS: Analysis of scRNA-seq data from the gallstone mouse model (GSE179524) revealed seven distinct cell clusters, with a significant increase in neutrophil numbers in the gallstone group. Analysis of bulk transcriptomics data from patients with gallstone (GSE202479) identified chronic inflammation in the gallbladder, potentially associated with dysbiosis of the gallbladder microbiota. 16S rRNA sequencing identified Helicobacter pylori as a key bacterium associated with gallbladder chronic inflammation and stone formation. CONCLUSIONS: Dysbiosis of the gallbladder mucosal microbiota is implicated in gallstone disease and leads to chronic inflammation. This study identified H. pylori as a potential key mucosal resident bacterium contributing to gallstone formation and discovered its key pathogenic factor CagA, which causes damage to the gallbladder mucosal barrier. These findings provide important clues for the prevention and treatment of gallstones.

Identification of changes in bile composition in pancreaticobiliary reflux based on liquid chromatography/mass spectrometry metabolomics.

INTRODUCTION: Pancreaticobiliary reflux (PBR) can induce gallstone formation; however, its pathogenic mechanism remains unclear. In this study, we explored the mechanism of PBR by the non-targeted metabolomic analysis of bile in patients with PBR. OBJECTIVE: The aim of this study was to investigate the pathogenic mechanism in PBR by the non-targeted metabolomic analysis of bile collected during surgery. METHODS: Sixty patients who underwent gallstone surgery at our center from December 2020 to May 2021 were enrolled in the study. According to the level of bile amylase, 30 patients with increased bile amylase ( > 110 U/L) were classified into the PBR group, and the remaining 30 patients were classified into the control group (≤ 110 U/L). The metabolomic analysis of bile was performed. RESULTS: The orthogonal projections to latent structure-discriminant analysis of liquid chromatography mass spectrometry showed significant differences in bile components between the PBR and control groups, and 40 metabolites were screened by variable importance for the projection value (VIP > 1). The levels of phosphatidylcholine (PC) and PC (20:3(8Z,11Z,14Z)/14:0) decreased significantly, whereas the levels of lysoPC (16:1(9z)/0:0), lysoPC (15:0), lysoPC (16:0), palmitic acid, arachidonic acid, leucine, methionine, L-tyrosine, and phenylalanine increased. CONCLUSIONS: Significant differences in bile metabolites were observed between the PBR and control groups. Changes in amino acids and lipid metabolites may be related to stone formation and mucosal inflammation.

Association between body roundness index (BRI) and gallstones: results of the 2017-2020 national health and nutrition examination survey (NHANES).

BACKGROUND: Gallstones are associated with obesity, and the BRI is a new obesity index that more accurately reflects body fat and visceral fat levels. The relationship between BRI and gallstone risk is currently unknown, and we aimed to explore the relationship between BRI and gallstone prevalence. METHODS: A cross-sectional study was conducted utilizing data from the 2017-2020 NHANES involving a total of 5297 participants. To assess the association between BRI and gallstones, we used logistic regression analysis, subgroup analysis, and interaction terms. In addition, we performed restricted cubic spline (RCS) analysis and threshold effects analysis to characterize nonlinear relationships. We assessed the ability of BRI and Body mass index (BMI) to identify gallstones using receiver operating curve (ROC) analysis and area under the curve (AUC), and compared them using the Delong test. RESULTS: Of the 5297 participants aged 20 years and older included in the study, 575 had gallstones. In fully adjusted models, a positive association between BRI and gallstone prevalence was observed (OR = 1.16, 95% CI: 1.12-1.20, P < 0.0001). Individuals in the highest quartile of BRI had a 204% increased risk of gallstones compared with those in the lowest quartile (OR = 3.04, 95% CI: 2.19-4.22, P < 0.0001). The correlation between BRI and gallstones persisted in subgroup analyses. RCS analyses showed a nonlinear relationship between BRI and gallstones. The inflection point was further found to be 3.96, and the correlation between BRI and gallstones was found both before and after the inflection point. ROC analysis showed that BRI (AUC = 0.667) was a stronger predictor of gallstones than BMI (AUC = 0.634). CONCLUSIONS: Elevated BRI is associated with an increased risk of gallstones in the U.S. population, and BRI is a stronger predictor of gallstones than BMI. Maintaining an appropriate BRI is recommended to reduce the incidence of gallstones.

Association between weight-adjusted-waist index and gallstones: an analysis of the National Health and Nutrition Examination Survey.

BACKGROUND: The weight-adjusted-waist index (WWI) is a novel obesity index, and gallstones are associated with obesity. This study aimed to investigate the possible relationship between WWI and gallstones. METHODS: The datasets from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 were used in a cross-sectional investigation. Multivariate linear regression models were used to examine the linear connection between WWI and gallstones incidence. Fitted smoothing curves and threshold effect analysis were used to describe the nonlinear relationship. RESULTS: The study comprised 8004 participants over the age of 20, including 833 reported with gallstones. Participants in the higher WWI tertile tended to have a higher gallstones prevalence. In the final adjusted model, a positive association between WWI and gallstones prevalence was observed (OR = 1.34, 95% CI: 1.20‒1.49). Participants in the highest WWI tertile had a significantly 71% higher risk of gallstones than those in the lowest WWI tertile (OR = 1.71, 95% CI: 1.35‒2.17). A nonlinear correlation was found between the WWI and gallstones prevalence, with an inflection point of 12.7. CONCLUSIONS: Our study found that higher WWI levels connected with increased prevalence of gallstones. However, more prospective studies are needed to validate our findings.

Association of metabolic dysfunction-associated fatty liver disease with gallstone development: A longitudinal study.

BACKGROUND AND AIM: The influence of metabolic dysfunction-associated fatty liver disease on gallstone development remains unclear. We aimed to investigate the longitudinal association between metabolic dysfunction-associated fatty liver disease and gallstone development in both men and women. METHODS: This observational cohort study included 5398 patients without gallstones who underwent > 2 health check-ups between April 1, 2014, and March 31, 2020. A generalized estimation equation model was used to analyze the association between metabolic dysfunction-associated fatty liver disease and gallstone development according to repeated measures at baseline and most recent stage. RESULTS: After adjustment, the odds ratios of metabolic dysfunction-associated fatty liver disease for gallstone development in men and women were 3.019 (95% confidence interval [CI]: 1.901-4.794) and 2.201 (95% CI: 1.321-3.667), respectively. Among patients aged ≥ 50 years, the odds ratio for gallstone development was significantly enhanced with increasing metabolic dysfunction-associated fatty liver disease component numbers in both sexes; however, no significance was observed in those aged < 50 years. Other significant risk factors for gallstone development were age (odds ratio: 1.093, 95% CI: 1.060-1.126) and waist circumference (odds ratio: 1.048, 95% CI: 1.018-1.079) in men and age (odds ratio: 1.035, 95% CI: 1.003-1.067) and current smoking (odd ratio: 5.465, 95% CI: 1.881-15.88) in women. CONCLUSION: Although the risk factors for gallstone development differed between sexes, metabolic dysfunction-associated fatty liver disease was common. Paying attention to an increase in the number of metabolic dysfunction-associated fatty liver disease components in patients aged ≥ 50 years is important for gallstone prevention.

Balloon endoscopy-assisted endoscopic retrograde cholangiopancreatography for hepatolithiasis in patients with hepaticojejunostomy.

BACKGROUND AND AIM: Balloon endoscopy-assisted endoscopic retrograde cholangiopancreatography (BE-ERCP) is an emerging procedure for pancreatobiliary diseases in patients with surgically altered anatomy. However, data on BE-ERCP for hepatolithiasis after hepaticojejunostomy (HJS) are still limited. METHODS: Stone removal success, adverse events and recurrence were retrospectively studied in consecutive patients who underwent BE-ERCP for hepatolithiasis after HJS between January 2011 and October 2022. Subgroup analysis was performed to compare clinical outcomes between patients who had undergone HJS over 10 years before (past HJS group) and within 10 years (recent HJS group). RESULTS: A total of 131 patients were included; 39% had undergone HJS for malignancy and 32% for congenital biliary dilation. Scope insertion and complete stone removal were successful in 89% and 73%, respectively. Early adverse events were observed in 9.9%. Four patients (3.1%) developed gastrointestinal perforation but could be managed conservatively. Hepatolithiasis recurrence rate was 17%, 20% and 31% in 1-year, 3-year, and 5-year after complete stone removal. The past HJS group was the only risk factor for failed stone removal (odds ratio 10.4, 95% confidence interval 2.99-36.5) in the multivariable analysis. Failed scope insertion (20%) and failed guidewire or device insertion to the bile duct (22%) were two major reasons for failed stone removal in the past HJS group. CONCLUSIONS: BE-ERCP for hepatolithiasis was effective and safe in cases with HJS but the complete stone removal rate was low in the past HJS group. Recurrent hepatolithiasis was common and careful follow up study is needed even after complete stone removal.

Immunohistochemical inflammation in histologically normal gallbladders containing gallstones.

BACKGROUND: The aim of this study was to establish features of inflammation in histologically normal gallbladders with gallstones and compare the expression of inflammatory markers in acutely and chronically inflamed gallbladders. METHODS: Immunohistochemistry was performed on formalin-fixed paraffin-embedded gallbladders for tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-2R, and substance p in three groups: Group I (n = 60) chronic cholecystitis, Group II (n = 57) acute cholecystitis and Group III (n = 45) histologically normal gallbladders with gallstones. Expression was quantified using the H-scoring system. RESULTS: Median, interquartile range expression of mucosal IL-2R in Groups I (2.65, 0.87-7.97) and II (12.30, 6.15-25.55) was significantly increased compared with group III (0.40, 0.10-1.35, p < 0.05). Submucosal IL-2R expression in Groups I (2.0, 1.12-4.95) and II (10.0, 5.95-14.30) was also significantly increased compared with Group III (0.50, 0.15-1.05, p < 0.05). There was no difference in the lymphoid cell IL-6 expression between Groups I (5.95, 1.60-18.15), II (6.10, 1.1-36.15) and III (8.30, 2.60-26.35, p > 0.05). Epithelial IL-6 expression of Group III (8.3, 2.6-26.3) was significantly increased compared with group I (0.5, 0-10.2, p < 0.05) as was epithelial TNF-α expression in Group III (85.0, 70.50-92.0) compared with Groups I (72.50, 45.25.0-85.50, p < 0.05) and II (61.0, 30.0-92.0, p < 0.05). Lymphoid cell Substance P expression in Groups I (1.90, 1.32-2.65) and II (5.62, 2.50-20.8) was significantly increased compared with Group III (1.0,1.0-1.30, p < 0.05). Epithelial cell expression of Substance P in Group III (121.7, 94.6-167.8) was significantly increased compared with Groups I (75.7, 50.6-105.3, p < 0.05) and II (78.9, 43.5-118.5, p < 0.05). CONCLUSION: Histologically normal gallbladders with gallstones exhibited features of inflammation on immunohistochemistry.

Association between dietary magnesium intake and gallstones: the mediating role of atherogenic index of plasma.

BACKGROUND: Dyslipidemia and abnormalities in cholesterol metabolism are commonly observed in individuals with gallstone disease. Previous research has demonstrated that dietary magnesium can influence lipid metabolism. The atherogenic index of plasma (AIP) has emerged as a novel lipid marker. This study aimed to examine the possible correlation between dietary magnesium intake and gallstones and the potential mediating role of AIP in US adults. METHODS: A total of 4,841 adults were included in this study from the National Health and Nutrition Examination Survey (NHANES) conducted from 2017 to 2020. A variety of statistical techniques such as logistic regression, subgroup analysis, smoothed curve fitting, and causal mediation analysis were utilized to analyze the information collected from the participants. RESULTS: In the fully adjusted model, a statistically noteworthy inverse relationship was observed between dietary magnesium intake and the presence of gallstones, as indicated by an odds ratio (OR) of 0.58 and a 95% confidence interval (CI) of (0.42, 0.81). Causal intermediary analysis revealed that the association between magnesium intake and gallstones was partially mediated by AIP, with a mediation ratio of 3.2%. CONCLUSION: According to this study, dietary magnesium intake had a significant linear negative association with the prevalence of gallstones, in which AIP played a mediating role. This discovery offers novel perspectives on the prevention and management of gallstones.

INDURG TRIAL Protocol: A Randomized Controlled Trial Using Indocyanine Green during Cholecystectomy in Acute Cholecystitis.

INTRODUCTION: Laparoscopic cholecystectomy is one of the most common gastrointestinal surgeries, and bile duct injury is one of its main complications. The use of real-time indocyanine green fluorescence cholangiography allows the identification of extrahepatic biliary structures, facilitating the procedure and reducing the risk of bile duct lesions. A better visualization of the bile duct may help to reduce the need for conversion to open surgery, and may also shorten operating time. The main objective of this study was to determine whether the use of indocyanine green is associated with a reduction in operating time in emergency cholecystectomies. Secondary outcomes are the postoperative hospital stay, the correct intraoperative visualization of the Calot's Triangle structures with the administration of indocyanine green, and the intraoperative complications, postoperative complications and morbidity according to the Clavien-Dindo classification. METHODS: This is a randomized, prospective, controlled, multicenter trial with patients diagnosed with acute cholecystitis requiring emergency cholecystectomy. The control group will comprise 220 patients undergoing emergency laparoscopic cholecystectomy applying the standard technique. The intervention group will comprise 220 patients also undergoing emergency laparoscopic cholecystectomy for acute cholecystitis with prior administration of indocyanine green. CONCLUSION: Due to the lack of published studies on ICG in emergency laparoscopic cholecystectomy, this study may help to establish procedures for its use in the emergency setting.

Cholelithiasis prevalence and risk factors in individuals with severe or profound intellectual and motor disabilities.

BACKGROUND: The prevalence and risk factors of cholelithiasis in individuals with severe or profound intellectual and motor disabilities (SPIMD) are poorly characterised. Thus, we aimed to investigate the prevalence and risk determinants of cholelithiasis in a cohort with SPIMD under medical care in a residential facility. METHODS: We categorised 84 patients in a residential hospital for persons with SPIMD into groups: those with (Group CL) and without (Group N) cholelithiasis. Gallstones were detected via computed tomography, ultrasonography or both. We evaluated gastrostomy status, nutritional and respiratory support, constipation, and bladder and kidney stones. Data were significantly analysed using univariate and multivariate logistic regression analyses. RESULTS: The prevalence rate of cholelithiasis in our SPIMD cohort was 27%. There were no significant differences in sex, age, weight, height, or Gross Motor Function Classification System between the two groups. However, more patients received enteral nutrition (39.13% vs. 6.56%; P = 0.000751) and were on ventilator support (56.52% vs. 19.67%; P = 0.00249) in Group CL than in Group N. Enteral nutrition [odds ratio (OR) 10.4, 95% confidence interval (CI) 1.98-54.7] and ventilator support (OR 20.0, 95% CI 1.99-201.0) were identified as independent risk factors for the prevalence of cholelithiasis in patients with SPIMD. CONCLUSIONS: Patients with SPIMD demonstrated an increased prevalence of cholelithiasis, with a notable association between nutritional tonic use and respiratory support. Therefore, to emphasise the need for proactive screening, it is crucial to devise diagnostic and therapeutic strategies specific to patients with SPIMD. Further investigation is essential to validate our findings and explore causative factors.

Extrahepatic abscess and dropped gallstones: a case report and a narrative review of an unusual delayed complication of laparoscopic cholecystectomy.

BACKGROUND: Laparoscopic cholecystectomy is the most common minimally invasive abdominal surgery procedure performed in Western countries; it offers several advantages over laparotomy but still carries some risks, such as intraoperative spillage of bile and gallstones. Diagnosis of dropped gallstones could be challenging, it is frequently delayed, and this can lead to further complications such as abscesses formation. METHODS: We report the history of a 51-year-old male with persistent dull abdominal pain in association to appetite loss, vomiting episodes and changes in regular bowel habits, a past medical history of laparoscopic cholecystectomy for biliary lithiasis (1.5 years earlier) and minimum elevation of inflammatory markers and gamma-GT values. RESULTS: Ultrasound examination showed perihepatic stones and magnetic resonance imaging revealed the presence of multiple perihepatic abscesses, findings compatible with fibrotic-inflammatory phenomena from 'dropped gallstones'. A re-laparoscopy was then performed with an abscess collection containing multiple gallstones; a liver wedge resection was also required due to strong adhesions. At follow up, the patient had improved both on clinical and biochemical perspective. CONCLUSION: Dropped gallstones are an underreported cause of morbidity and diagnostic dilemmas in subjects who underwent to laparoscopic cholecystectomy, in relation to infectious complications that can occur even several months or years after surgery. Imaging represents a valuable aid in the correct non-invasive diagnostic process, but proper awareness of this insidious condition is necessary. Surgeons and radiologists should always consider this eventuality in the differential diagnosis of a patient presenting with abdominal abscesses and history of cholecystectomy.

Pediatric gallstone disease-Management difficulties in clinical practice.

BACKGROUND: Gallstone disease (GD) is no longer an exclusive condition of adulthood, and its prevalence is increasing in pediatric age. The management and the extent of the etiological investigation of GD in children and adolescents remains controversial. This study aimed to analyze the difficulties in the work-up and management of pediatric GD patients. METHODS: A retrospective study performed in a single tertiary center enrolled sixty-five patients with GD followed from January 2014 to June 2021. Patients were categorized conveniently according to their age at diagnosis: Group A (<10years, n=35) and Group B (≥10years, n=30). We analyzed demographic, clinical and laboratory data, ultrasonographic findings at presentation, therapeutics and complications. RESULTS: Symptoms were more frequent in patients >10years old (p=0.001). Cholecystectomy was performed in 31 patients (47.7%). A multivariate regression logistic model identified the age >10years (OR=6.440, p=0.005) and underlying entities (OR=6.823, p=0.017) as independent variables to perform surgery. Spontaneous resolution of GD was more common in children <2years old. A multivariate regression logistic model showed a trend for those >10years old to develop more complications. Two out of 18 patients were diagnosed with ABCB4 gene mutations in heterozygosity. CONCLUSIONS: Decision-making on cholecystectomy remains challenging in asymptomatic patients. Identifying predictive factors for the development of complications has proven difficult. However, we found a trend toward the development of complications in individuals older than 10years.

Cholecystectomy in Mild and Moderate Acute Pancreatitis: A Retrospective Study.

Background: Cholecystectomy has been a subject of debate regarding its timing and utility in cases of mild and moderately severe acute pancreatitis (AP). We aimed to critically evaluate the role of early cholecystectomy in the management of mild and moderate AP, considering patient's characteristics, associated procedures, and overall impact on patient outcomes. Methods: The study compared the outcomes between patients admitted in a tertiary care surgical center undergoing early ( 96h) versus delayed ( 96h) laparoscopic cholecystectomy (LC) for mild and moderately severe acute gallstone pancreatitis between January 2019 and December 2022. Results: The study included 54 cases [mean (standard deviation) age, 59.4 (16.5) years; 31 (57.4%) years females]. All patients underwent LC, with 29 cases undergoing a two-phase therapeutic regimen for common bile duct (CBD) lithiasis, consisting of endoscopic retrograde cholangiopancreatography followed by sequential LC. The early cholecystectomy group (EC) comprised 17 patients (31.5%), while the delayed cholecystectomy group (DC) included 37 patients (68.5%). EC was significantly correlated with lower length of stay (p-value 0.0001) and significantly lower rate of ERCP usage during perioperative period. Conclusions: EC in the first 4 days after admission provides significant benefits such as prevention of recurrent pancreatitis, reduction in complications, and decreased length of stay for patients with mild and moderately severe AP.

Consensus definition of sludge and microlithiasis as a possible cause of pancreatitis.

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.

Patient selection for urgent endoscopic retrograde cholangio-pancreatography by endoscopic ultrasound in predicted severe acute biliary pancreatitis (APEC-2): a multicentre prospective study.

OBJECTIVE: Routine urgent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy (ES) does not improve outcome in patients with predicted severe acute biliary pancreatitis. Improved patient selection for ERCP by means of endoscopic ultrasonography (EUS) for stone/sludge detection may challenge these findings. DESIGN: A multicentre, prospective cohort study included patients with predicted severe acute biliary pancreatitis without cholangitis. Patients underwent urgent EUS, followed by ERCP with ES in case of common bile duct stones/sludge, within 24 hours after hospital presentation and within 72 hours after symptom onset. The primary endpoint was a composite of major complications or mortality within 6 months after inclusion. The historical control group was the conservative treatment arm (n=113) of the randomised APEC trial (Acute biliary Pancreatitis: urgent ERCP with sphincterotomy versus conservative treatment, patient inclusion 2013-2017) applying the same study design. RESULTS: Overall, 83 patients underwent urgent EUS at a median of 21 hours (IQR 17-23) after hospital presentation and at a median of 29 hours (IQR 23-41) after start of symptoms. Gallstones/sludge in the bile ducts were detected by EUS in 48/83 patients (58%), all of whom underwent immediate ERCP with ES. The primary endpoint occurred in 34/83 patients (41%) in the urgent EUS-guided ERCP group. This was not different from the 44% rate (50/113 patients) in the historical conservative treatment group (risk ratio (RR) 0.93, 95% CI 0.67 to 1.29; p=0.65). Sensitivity analysis to correct for baseline differences using a logistic regression model also showed no significant beneficial effect of the intervention on the primary outcome (adjusted OR 1.03, 95% CI 0.56 to 1.90, p=0.92). CONCLUSION: In patients with predicted severe acute biliary pancreatitis without cholangitis, urgent EUS-guided ERCP with ES did not reduce the composite endpoint of major complications or mortality, as compared with conservative treatment in a historical control group. TRIAL REGISTRATION NUMBER: ISRCTN15545919.