Risk factors for biliary tract events during elective cholecystectomy waiting time after endoscopic retrograde cholangiopancreatography for choledocholithiasis.

Objectives: Endoscopic lithotripsy and elective cholecystectomy, followed by endoscopic retrograde cholangiopancreatography, are the first-line treatments for patients with common bile duct (CBD) stones (CBDS) and gallstones. However, this approach entails acute cholecystitis and recurrent cholangitis risk while patients await surgery. We aimed to identify acute cholecystitis and cholangitis risk factors during the waiting time for elective cholecystectomy. Methods: This study comprised 151 patients with CBDS combined with gallstones who underwent cholecystectomy within 90 days of the first endoscopic retrograde cholangiopancreatography at two tertiary care centers between January 2019 and October 2021. Results: The incidence of biliary tract events (acute cholecystitis, acute cholangitis, or any complications requiring unplanned cholangiopancreatography) was 28% (43 cases). In univariate and multivariate analyses, plastic stent placement as a bridge to surgery for the first treatment of CBDS was an independent risk factor for biliary tract events during the waiting time for surgery (odds ratio 4.25, p = 0.002). A subgroup analysis among those with plastic stent placement revealed a CBD diameter of ≤ 10 mm as an independent risk factor for acute cholecystitis (odds ratio 4.32; p = 0.027); a CBD diameter ≥ 11 mm was an independent risk factor for acute cholangitis and unplanned re-endoscopic retrograde cholangiopancreatography (odds ratio 5.66; p = 0.01). Conclusions: Plastic stent placement for CBDS before elective cholecystectomy increases the risk of acute cholecystitis or acute cholangitis during the waiting time for elective cholecystectomy.

A Case of Robotic Cholecystectomy in a Patient With Decompensated Cirrhosis and Portal Hypertension.

In patients with liver cirrhosis, approximately one-third experience pigmented cholelithiasis. In parallel to this, cirrhotics consequently encounter a greater prevalence of acute cholecystitis. Traditionally, the definitive treatment for acute cholecystitis in non-cirrhotic patients is cholecystectomy. However, decompensated cirrhosis and portal hypertension pose a surgical challenge, as these comorbidities increase the risk of postoperative complications such as bleeding, infection, and multi-organ failure. Therefore, it is of utmost importance to consider patient risk factors, anatomy, and acuity of patient cholecystitis on an individual basis and develop a surgical (or non-surgical) plan that minimizes risk to patients with decompensated cirrhosis and portal hypertension. We present the management strategies of a case of a 50-year-old male who presents with a history of decompensated liver cirrhosis and portal hypertension complicated by acute cholecystitis. Upon initial presentation, he was critically ill, and a percutaneous cholecystostomy tube was placed for management and the patient was instructed to follow up in the clinic. Then, the patient later returned to the emergency department with a fever, UTI, and sepsis. At that time, his cholecystostomy tube continued to have bilious drainage and he had tenderness in the right upper quadrant. The decision was made to proceed with surgery. Because of his significant comorbid conditions and underlying cirrhosis, surgery posed an increased risk. For this patient, it was especially important to evaluate the risk of complications and the decision of open vs laparoscopic cholecystectomy. In this patient, robotic-assisted laparoscopic cholecystectomy was eventually performed. Due to the patient's hepatomegaly, splenomegaly, and portal hypertension, special consideration was needed for trocar placement. In this case, we aim to exemplify that is of utmost importance to consider patient anatomy by using imaging and marking organ borders to inform trocar placement as part of the surgical approach.

The impact of routine cholangiography for asymptomatic patients after cholecystostomy insertion for acute cholecystitis.

BACKGROUND: We aim to investigate the impact of routine cholangiography on asymptomatic patients with percutaneous cholecystostomy (PCC) for acute cholecystitis (AC). METHODS: The study included all patients treated with PCC for AC from 2017 to 2020 â€‹at a single academic center. Patients who underwent routine cholangiography within 30 days post-discharge while asymptomatic were compared to patients who were only followed clinically. RESULTS: The groups (cholangiography group, n â€‹= â€‹44, and control group, n â€‹= â€‹145) were similar in terms of age, comorbidities, and clinical presentation. The readmission rate for biliary disease in the cholangiography group was nearly half that of the control group (22.7 â€‹% vs. 40.7 â€‹%, p â€‹= â€‹0.05) over an average follow-up of 10.4 months. The time to drain removal, cholecystectomy rate, and time to operation were comparable between the groups (42 vs. 40 days, p â€‹= â€‹0.47, 52.3 â€‹% vs 53.1 â€‹%, p â€‹= â€‹NS and 69 vs. 82 days, p â€‹= â€‹0.17, respectively). CONCLUSIONS: Routine cholangiography can help reduce biliary disease readmissions among asymptomatic patients with PCC for AC without delaying further treatment.

Combined laser and mechanical lithotripsy for endoscopic management of Bouveret's syndrome: A case report.

Bouveret's syndrome (BS) represents an exceedingly rare clinical entity characterized by gastric outlet obstruction induced by a gallstone passing through a cholecystoduodenal, cholecystogastric or choledochoduodenal fistula and impacting in the duodenum or pylorus. Endoscopy is the preferred first-line therapy. It has a favorable safety profile, but requires high level of expertise to achieve stone clearance.

Management of Gallstone Disease.

Gallstone disease has plagued humanity since antiquity. Its recognition and treatment has been refined through decades as surgical technique and imaging capabilities have advanced. With the rise of the obesity epidemic and metabolic syndrome, its prevalence is also increasing. This review provides an overview of the various manifestations of gallstone disease and treatment modalities appropriate for its resolution.

Management of the Difficult Gallbladder.

Cholecystectomies are very common in general surgery practice. A small percentage of these will present with factors that pose operative difficulty. The surgeon should have a high index of suspicion based on preoperative factors of patients that may present an operative challenge and have necessary equipment available and the surgical skill to provide the best surgical outcome for the patient if a total cholecystectomy is unable to be performed.

Acute cholecystitis management at a tertiary care center: are we following current guidelines?

PURPOSE: After the Tokyo 2018 guidelines (TG2018) were published, evidence from the 2018 CHOCOLATE RCT supported early cholecystectomy for acute cholecystitis (AC), even in high-risk patients. This study aims to investigate AC management at our tertiary care center in the years following these publications. METHODS: A retrospective cohort study was performed on patients admitted from 2018 to 2023. AC severity was graded using TG2018 definitions. Comorbidities were summarized using Charlson Comorbidity Index (CCI) and frailty using the 5-item modified Frailty Index (5mFI). Compliance with TG2018 recommendations for management strategy was investigated. Outcomes were compared between patients who underwent surgery versus non-operative management (NOM). Subset analysis based on patients' age, frailty, and comorbidities was performed. RESULTS: Among 642 AC patients, 57% underwent cholecystectomy and 43% NOM (22% percutaneous cholecystostomy, 21% antibiotics only). NOM patients had greater length of stay (LOS), complications, deaths, readmissions, and discharge to nursing/rehab versus surgery patients. In 70% of patients managed non-operatively, TG2018 were not followed. Patients managed non-operatively despite TG2018 were more likely to undergo delayed cholecystectomy compared to those in whom guidelines were followed (17% vs. 4%). In subset analysis, healthy octogenarians were significantly less likely to be managed according to TG2018 (9.4%); patients undergoing surgery had a trend towards shorter LOS (3.1 vs. 4.8 days) than those managed non-operatively but no difference in other outcomes. CONCLUSION: Most patients undergoing NOM could potentially undergo cholecystectomy if guidelines are considered. A more objective approach to risk assessment may optimize patient selection and outcomes.

Preoperative predictors of difficult early laparoscopic cholecystectomy among patients with acute calculous cholecystitis in Egypt.

BACKGROUND: Early laparoscopic cholecystectomy (ELC) in the setting of acute calculous cholecystitis (ACC) requires to be performed by highly-skilled surgeons to avoid complications. The purpose of this study is to identify preoperative factors that would predict difficult ELC among patients with ACC prior to proceeding with surgery. METHODS: We retrospectively reviewed all patients who received ELC within 10 days from the onset of symptoms of ACC between August 1, 2018, and December 31, 2022. They were divided into 2 groups according to the difficulty of surgery. RESULTS: 149 patients with ACC received ELC during the study period. ELC was considered difficult in 52 patients (35%). Five preoperative factors were identified as significant predictors of difficult ELC (DELC) on multivariate analysis: duration of acute attack ≥ 4 days from the onset of symptoms till surgery (OR 34.4, P < 0.001), ultrasound showing largest gallstone size > 20 mm (OR 20.2, P = 0.029), ultrasound showing gallstone impaction in Hartmann's pouch (OR 7.2, P = 0.017), history of prior episode(s) of acute attack (OR 6.8, P = 0.048), and diabetes mellitus (OR 5.8, P = 0.046). CONCLUSION: Careful preoperative assessment of patients with ACC is crucial among junior surgeons with limited surgical expertise prior to proceeding with ELC to identify those at risk of DELC to potentially reduce postoperative morbidity and mortality. If encountered, a management plan should be made, and surgery should proceed only upon confirming the availability of experienced surgeons in the field of biliary and laparoscopic surgery to supervise or assist in the procedure. Alternatively, such group of patients should rather be transferred to more advanced surgical centers which offer higher level of care to maintain patient safety and optimal surgical outcomes. More importantly, bail-out procedures should always be resorted to whenever DELC is encountered intraoperatively to prevent further surgical damage.

Methylnaltrexone's Effect on Cholestasis in Trauma Patients.

Introduction Cholestasis in hospitalized patients receiving opiates has the potential to have devastating outcomes including acalculous cholecystitis, sepsis, or even death. In this study, we evaluate the outcomes of trauma patients treated with methylnaltrexone. Methods We conducted the study at Desert Regional Medical Center, a level 1 trauma center in Palm Springs, California. Our electronic medical record was queried for all trauma patients between January 1, 2018 and January 1, 2024. Patients were excluded if they were under 18 years old or had a documented history of cirrhosis, congestive heart failure, or cardiac arrest during their admission. Those not excluded were divided into a treatment group including those who received at least one dose of methylnaltrexone and those who never received a dose of methylnaltrexone. A control group was created matching by randomly selecting one patient from the non-treatment group for each patient in the treatment group. The control and treatment groups were then analyzed using SPSS (IBM Corp., Armonk, NY). Demographic data was compared using student t-test between the two groups including age, sex, length of stay, ICU length of stay, ventilator days, and mortality. A p-value is reported as a test statistic. The incidence of cholestasis was measured by either laboratory evidence of hyperbilirubinemia, radiologic evidence of cholecystitis, diagnosis code of cholecystitis, or procedural intervention for cholecystitis. The two groups were compared for incidence of cholestasis using student t-test. Results are reported below. Results A total of 9894 patients were evaluated for inclusion in the study. Of those patients, 1292 patients met the exclusion criteria, and 8602 patients were analyzed for administration of the study drug. Fifty-six patients received at least one dose of methylnaltrexone. The remaining 8597 patients did not receive the treatment. Fifty-six patients were selected randomly for the control group. The median age between the treatment and control groups did not show statistically significant differences. Sex was also not statistically different between the two groups with 38 males and 18 females in the treatment group as compared to 39 males and 17 females in the control group with a p-value of 0.86. The median hospital length of stay was longer in the treatment group at 13 days compared to only one day in the control group which was statistically different with a p-value of <.001. ICU length of stay was also found to be statistically different between the treatment and control groups with 4 and 0 days respectively and a p-value of <.001. Mortality between the two groups was also higher in the treatment group with five patients in the treatment group not surviving to discharge as compared to one patient in the control group (p-value = .044). Both groups had one patient who met the criteria for cholestasis representing an overall incidence of 1.8% for each group. Conclusion Our data suggests that patients who received the medication were overall sicker with longer hospital stays, increased mortality, and more likely to have required surgery. We did not show a significant difference in incident of cholestasis or acalculous cholecystitis between the two groups but suggest that a larger study is warranted to study a causal relationship.

Unexpected intraoperative finding of a hyalinizing cholecystitis in a patient with gallbladder calculi.

Hyalinizing cholecystitis is a rare subtype of chronic cholecystitis in which the gallbladder tissue is replaced with hyaline sclerosis, more or less, and has a characteristic intraoperative appearance. Preoperative diagnosis is hard to establish. The entity is strongly associated with gallbladder carcinoma. Therefore, the pathologist should perform a thorough microscopic analysis. We present a case of an unusual intraoperative finding in a male patient with chronic cholecystitis which was proved to be a hyalinizing cholecystitis.

Gallbladder disease in transgender individuals: associations with gender-affirming hormone therapy.

Background: Transgender individuals frequently undergo gender-affirming hormone therapy (GAHT) during their gender transition which plays a vital role in gender identity affirmation. Cholelithiasis, a common condition affecting 10-15% of the US population, has been linked to estrogen therapy in cisgender women. Despite the fact that hormonal profiles achieved after GAHT are not always identical to cisgender individuals, the effects of GAHT on gallbladder disease (GBD) risk have not been evaluated in transgender populations. This research aims to address this gap utilizing a large nationwide database. Methods: The study analyzed medical records data from the TrinetX database from 52,847 trans men and 38,114 trans women. Four cohorts were created: trans women and men either receiving either hormone therapy or no intervention. Descriptive statistics were calculated before matching to estimate disease burden. The groups were then propensity score matched on known risk factors (age, race, BMI, etc.) and rates of GBD were compared. Results: Before matching, trans women on hormone therapy (TWHT) had a significantly higher 10-year GBD probability than those naïve to therapy (TWNI) (4.69% vs 1.88%). For trans men, there was no significant difference in 10-year rates between those on therapy (TMHT) and those not (TMNI) (3.15% vs 3.87%). Cholecystectomy rates were significantly higher for TWHT than TWNI (1.10% vs. 0.57%), but similar between TMHT and TMNI (0.95% vs. 1.10%). After accounting for risk factors, TWHT had increased GBD risk (HR 1.832), while TMHT showed no significant change. Discussion: This study suggests a link between estrogen GAHT and increased GBD risk in transgender women. Notably, testosterone GAHT did not offer protection against GBD in transgender men, contrary to expectations. This study is, to our knowledge, the first to describe the burden of GBD in the transgender population and to investigate the effects of GAHT on GBD risk.

Benefits of endoscopic gallbladder stenting following percutaneous transhepatic gallbladder drainage.

BACKGROUND: Endoscopic transpapillary gallbladder drainage is challenging because of the complexity of the procedure and high incidence of adverse events (AEs). To overcome these problems, endoscopic gallbladder stenting (EGBS) after percutaneous transhepatic gallbladder drainage (PTGBD) can be effective, as it mitigates inflammation and adhesion. AIM: To examine the benefits of EGBS after PTGBD to assess its efficacy and impact on AEs. METHODS: We retrospectively analyzed data from 35 patients who underwent EGBS after PTGBD at a single center between January 2016 and December 2023. The primary outcomes were technical success and AEs, and the rate of recurrent cholecystitis was evaluated. In addition, the reasons for the failure of the procedure were identified. RESULTS: Among the 35 patients, the technical success rate was 77.1% and the final contrast of the cystic duct was successful in 97.1% of patients. The incidence of early AEs was relatively low (11.4%), with no instances of cystic duct perforation. The rate of recurrent cholecystitis was 3.7%, and no other biliary events were observed. CONCLUSION: EGBS after PTGBD may be significantly beneficial, with a substantial success rate and minimal AEs in both short- and long-term follow-ups.

Multicenter analysis of the efficacy of early cholecystectomy and preoperative cholecystostomy for severe acute cholecystitis: a retrospective study of data from the multi-institutional database of the Hiroshima Surgical Study Group of Clinical Oncology.

BACKGROUND: Severe acute cholecystitis (AC) is a challenging disease because it comprises coexisting systemic infections that lead to vital organ dysfunction. This study evaluated the optimal surgical timing and efficacy of preoperative percutaneous cholecystostomy (PC) for patients with severe AC. METHODS: Data of 142 patients who underwent cholecystectomy for severe AC between 2011 and 2021 were retrospectively collected from the multi-institutional database of the Hiroshima Surgical Study Group of Clinical Oncology. Patients were divided into the early cholecystectomy (EC) group (within 72 h of symptom onset) and delayed cholecystectomy (DC) group. They were also subdivided into the upfront cholecystectomy group and preoperative PC before cholecystectomy group. The diagnosis and severity of AC were graded according to the Tokyo Guidelines 2018. Clinicopathological variables and outcomes were compared. RESULTS: No significant differences in age, body mass index, American Society of Anesthesiologists (ASA) classification, and Charlson comorbidity index between the EC and DC groups were observed. Preoperative drainage was more commonly performed for the DC group than for the EC group. Local severe AC features were more commonly detected in the DC group than in the EC group. The postoperative outcomes of the EC and DC groups were comparable. Compared to the PC before cholecystectomy group, the upfront cholecystectomy group included more patients with ASA physical status ≥ 3 and more patients who used oral warfarin. Warfarin usage and cardiovascular dysfunction rates of the PC after cholecystectomy group were higher than those of the upfront cholecystectomy group. PC was associated with significantly less intraoperative bleeding and shorter hospital stays. CONCLUSIONS: Patients who can tolerate general anesthesia are good candidates for EC. Patients who use warfarin and those with cardiovascular dysfunction are considered to be at high risk for postoperative complications; therefore, to prevent AC recurrence during the waiting period, PC before cholecystectomy during the same admission is more appropriate than upfront cholecystectomy for these patients.

Hemorrhagic Cholecystitis Due to Rupture of Underlying Anomalous Duplicated Cystic Arteries.

Hemorrhagic cholecystitis (HC) is a rare complication that can become rapidly fatal. Patients may present with hematemesis or melena, in addition to other common symptoms of acute cholecystitis. Delay in diagnosing HC postpones early intervention, and patients can quickly decompensate. We present a 33-year-old man with hematemesis and downtrending hemoglobin. Imaging revealed underlying anomalies of duplicate cystic arteries that ruptured, an occurrence never reported in the literature before. Bilateral cystic arteries were embolized successfully. This case demonstrates the importance of early consideration of HC as a differential. Recognition and timely diagnosis prompt urgent intervention, which can reduce morbidity.

Heart failure misdiagnosed as acute cholecystitis: a case report.

BACKGROUND: Heart failure is a clinical syndrome characterized by decreased cardiac output, leading to systemic organ hypoxia and resulting in dyspnea, pulmonary edema, organ congestion, and pleural effusion. Owing to the diverse clinical manifestations of heart failure, early diagnosis can be challenging, and misdiagnosis may occur occasionally. The use of echocardiography and blood brain natriuretic peptide can aid in obtaining a more accurate diagnosis. CASE PRESENTATION: This article presents two case reports of patients who were misdiagnosed with acute cholecystitis. Both patients were young Mongolia males (age 26 and 39 years) who presented to the emergency department with acute upper abdominal pain, abdominal ultrasound revealed gallbladder enlargement, and blood tests suggested mild elevation of bilirubin levels. However, despite the absence of procalcitonin and C-reactive protein elevation, the patients were admitted to the general surgical department with a diagnosis of "acute cholecystitis." Both patients were given treatment for cholecystitis, but their vital signs did not improve, while later examinations confirmed heart failure. After treatment with diuretics and cardiac glycosides, both patients' symptoms were relieved. CONCLUSION: We aim to highlight the clinical manifestations of heart failure and differentiate it from rare conditions such as acute cholecystitis. Physicians should make accurate diagnoses on the basis of physical examinations, laboratory testing and imaging, and surveys while avoiding diagnostic heuristics or mindsets. By sharing these two case reports, we hope to increase awareness to prevent potential complications and improve patient outcomes.

International Delphi consensus on the management of percutaneous choleystostomy in acute cholecystitis (E-AHPBA, ANS, WSES societies).

BACKGROUND: There has been a progressive increase in the use of percutaneous cholecystostomy (PC) in acute cholecystitis (AC) over the last decades due to population aging, and the support of guidelines (Tokyo Guidelines (TG), World Society of Emergency Surgery (WSES) Guidelines) as a valid therapeutical option. However, there are many unanswered questions about the management of PCs. An international consensus on indications and PC management using Delphi methodology with contributions from experts from three surgical societies (EAHPBA, ANS, WSES) have been performed. METHODS: A two-round Delphi consensus, which included 27 questions, was sent to key opinion leaders in AC. Participants were asked to indicate their 'agreement/disagreement' using a 5-point Likert scale. Survey items with less than 70% consensus were excluded from the second round. For inclusion in the final recommendations, each survey item had to have reached a group consensus (≥ 70% agreement) by the end of the two survey rounds. RESULTS: 54 completed both rounds (82% of invitees). Six questions got > 70% and are included in consensus recommendations: In patients with acute cholecystitis, when there is a clear indication of PC, it is not necessary to wait 48 h to be carried out; Surgery is the first therapeutic option for the TG grade II acute cholecystitis in a patient suitable for surgery; Before PC removal a cholangiography should be done; There is no indication for PC in Tokyo Guidelines (TG) grade I patients; Transhepatic approach is the route of choice for PC; and after PC, laparoscopic cholecystectomy is the preferred approach (93.1%). CONCLUSIONS: Only six statements about PC management after AC got an international consensus. An international guideline about the management of PCs are necessary.

Rare finding of ectopic pancreas in a cholecystectomy specimen: case report and literature review.

Ectopic pancreatic tissue (EPT) is a rare condition in which pancreatic tissue is situated outside its normal position. It is commonly found in the stomach and small bowel, typically asymptomatic, and is usually discovered incidentally during histopathological analysis. Although fewer than 40 cases of ectopic pancreatic tissue in the gallbladder have been reported, its significance relies on the risk of malignant transformation, highlighting the need for a thorough pathological study. This case report describes the presence of EPT in the gallbladder incidentally found during the pathological examination following a laparoscopic cholecystectomy of a 37-year-old female due to chronic cholecystitis.

Immune cell traits and causal relationships with cholecystitis: a mendelian randomization analysis.

Cholecystitis, characterized by inflammation of the gallbladder, is intricately linked to immune cells and the cytokines they produce. Despite this association, the specific contributions of immune cells to the onset and progression of cholecystitis remain to be fully understood. To delineate this relationship, we utilized the Mendelian randomization (MR) method to scrutinize the causal connections between 731 immune cell phenotypes and cholecystitis. By conducting MR analysis on 731 immune cell markers from public datasets, this study seeks to understand their potential impact on the risk of cholecystitis. It aims to elucidate the interactions between immune phenotypes and the disease, aiming to lay the groundwork for advancing precision medicine and developing effective treatment strategies for cholecystitis. Taking immune cell phenotypes as the exposure factor and cholecystitis as the outcome event, this study used single nucleotide polymorphisms (SNPs) closely associated with both immune cell phenotypes and cholecystitis as genetic instrumental variables. We conducted a two-sample MR analysis on genome-wide association studies (GWAS) data. Our research thoroughly examined 731 immune cell markers, to determine potential causal relationships with susceptibility to cholecystitis. Sensitivity analyses were performed to ensure the robustness of our findings, excluding the potential impacts of heterogeneity and pleiotropy. To avoid reverse causality, we conducted reverse MR analyses with cholecystitis as the exposure factor and immune cell phenotypes as the outcome event. Among the 731 immune phenotypes, our study identified 21 phenotypes with a causal relationship to cholecystitis (P < 0.05). Of these, eight immune phenotypes exhibited a protective effect against cholecystitis (odds ratio (OR) < 1), while the other 13 immune phenotypes were associated with an increased risk of developing cholecystitis (OR > 1). Additionally, employing the false discovery rate (FDR) method at a significance level of 0.2, no significant causal relationship was found between cholecystitis and immune phenotypes. Our research has uncovered a significant causal relationship between immune cell phenotypes and cholecystitis. This discovery not only enhances our understanding of the role of immune cells in the onset and progression of cholecystitis but also establishes a foundation for developing more precise biomarkers and targeted therapeutic strategies. It provides a scientific basis for more effective and personalized treatments in the future. These findings are expected to substantially improve the quality of life for patients with cholecystitis and mitigate the impact of the disease on patients and their families.

Role of Intraoperative Near-Infrared Indocyanine Green Fluorescence Cholangiography in the Management of Acute Gangrenous Cholecystitis Secondary to Empyema of the Gallbladder in Mirizzi's Syndrome.

Mirizzi syndrome, although rare, is a potential complication of long-standing gallstone disease, particularly cholecystolithiasis. Due to the nonspecific nature of its symptoms, this condition often remains undiagnosed prior to surgery in most cases. While minimally invasive approaches are generally safe in expert hands, they can be challenging and entail the risk of bile duct injuries, often necessitating conversion to bail-out procedures. Delayed management of Mirizzi syndrome can lead to serious consequences, such as empyema of the gallbladder (GB), gangrene of the GB wall, perforation, and sepsis. Intraoperative indocyanine green fluorescence imaging during laparoscopic cholecystectomy can help delineate the biliary anatomy and prevent biliary tract injuries in difficult GBs like Mirizzi syndrome.

Hypoglycemic drugs, circulating inflammatory proteins, and gallbladder diseases: A mediation mendelian randomization study.

BACKGROUND: The relationship of hypoglycemic drugs, inflammatory proteins and gallbladder diseases remain unknown. METHODS: Four hypoglycemic drugs were selected as exposure: glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and metformin. The outcome were two gallbladder diseases: cholecystitis and cholelithiasis. Mendelian Randomization (MR) was employed to determine the association between hypoglycemic drugs and gallbladder diseases. RESULTS: DPP-4i and SGLT-2i had no effect on cholecystitis and cholelithiasis. However, a causal relationship was found between inhibition of ETFDH gene, a target of metformin expressed in cultured fibroblasts, and cholelithiasis (OR: 0.84, 95 %CI: (0.72,0.97), p = 0.021), as well as between GLP1R expression in the brain caudate basal ganglia and cholecystitis (OR: 1.29, 95 %CI: (1.11,1.49), p = 0.001). The effect of ETFDH inhibition on cholelithiasis through Interleukin-10 receptor subunit beta (IL-10RB) levels and Neurotrophin-3 (NT-3) levels, with a mediated proportion of 8 % and 8 %, respectively. CONCLUSION: Metformin plays a protective role in cholelithiasis, while GLP-1RA have a harmful effect on the risk of cholecystitis. Metformin may reduce the risk of cholelithiasis by modulating the levels of Neurotrophin-3 (NT-3) and Interleukin-10 receptor subunit beta (IL-10RB). Further clinical and mechanistic studies are required to confirm these findings.