[Establishment and Validation of a Predictive Model for Gallstone Disease in the General Population: A Multicenter Study]. / èƒ†ç»“çŸ³æ‚£ç— é£Žé™©é¢„æµ‹æ¨¡åž‹çš„æž„å»ºå’Œå¤šä¸­å¿ƒéªŒè¯ç ”ç©¶.

Objective: Gallstone disease (GSD) is one of the common digestive tract diseases with a high worldwide prevalence. The effects of GSD on patients include but are not limited to the symptoms of nausea, vomiting, and biliary colic directly caused by GSD. In addition, there is mounting evidence from cohort studies connecting GSD to other conditions, such as cardiovascular diseases, biliary tract cancer, and colorectal cancer. Early identification of patients at a high risk of GSD may help improve the prevention and control of the disease. A series of studies have attempted to establish prediction models for GSD, but these models could not be fully applied in the general population due to incomplete prediction factors, small sample sizes, and limitations in external validation. It is crucial to design a universally applicable GSD risk prediction model for the general population and to take individualized intervention measures to prevent the occurrence of GSD. This study aims to conduct a multicenter investigation involving more than 90000 people to construct and validate a complete and simplified GSD risk prediction model. Methods: A total of 123634 participants were included in the study between January 2015 and December 2020, of whom 43929 were from the First Affiliated Hospital of Chongqing Medical University (Chongqing, China), 11907 were from the First People's Hospital of Jining City (Shandong, China), 1538 were from the Tianjin Medical University Cancer Institute and Hospital (Tianjin, China), and 66260 were from the People's Hospital of Kaizhou District (Chongqing, China). After excluding patients with incomplete clinical medical data, 35976 patients from the First Affiliated Hospital of Chongqing Medical University were divided into a training data set (n=28781, 80%) and a validation data set (n=7195, 20%). Logistic regression analyses were performed to investigate the relevant risk factors of GSD, and a complete risk prediction model was constructed. Factors with high scores, mainly according to the nomograms of the complete model, were retained to simplify the model. In the validation data set, the diagnostic accuracy and clinical performance of these models were validated using the calibration curve, area under the curve (AUC) of the receiver operating characteristic curve, and decision curve analysis (DCA). Moreover, the diagnostic accuracy of these two models was validated in three other hospitals. Finally, we established an online website for using the prediction model (The complete model is accessible at https://wenqianyu.shinyapps.io/Completemodel/, while the simplified model is accessible at https://wenqianyu.shinyapps.io/Simplified/). Results: After excluding patients with incomplete clinical medical data, a total of 96426 participants were finally included in this study (35876 from the First Affiliated Hospital of the Chongqing Medical University, 9289 from the First People's Hospital of Jining City, 1522 from the Tianjin Medical University Cancer Institute, and 49639 from the People's Hospital of Kaizhou District). Female sex, advanced age, higher body mass index, fasting plasma glucose, uric acid, total bilirubin, gamma-glutamyl transpeptidase, and fatty liver disease were positively associated with risks for GSD. Furthermore, gallbladder polyps, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and aspartate aminotransferase were negatively correlated to risks for GSD. According to the nomograms of the complete model, a simplified model including sex, age, body mass index, gallbladder polyps, and fatty liver disease was constructed. All the calibration curves exhibited good consistency between the predicted and observed probabilities. In addition, DCA indicated that both the complete model and the simplified model showed better net benefits than treat-all and treat-none. Based on the calibration plots, DCA, and AUCs of the complete model (AUC in the internal validation data set=74.1% [95% CI: 72.9%-75.3%], AUC in Shandong=71.7% [95% CI: 70.6%-72.8%], AUC in Tianjin=75.3% [95% CI: 72.7%-77.9%], and AUC in Kaizhou=72.9% [95% CI: 72.5%-73.3%]) and the simplified model (AUC in the internal validation data set=73.7% [95% CI: 72.5%-75.0%], AUC in Shandong=71.5% [95% CI: 70.4%-72.5%], AUC in Tianjin=75.4% [95% CI: 72.9%-78.0%], and AUC in Kaizhou=72.4% [95% CI: 72.0%-72.8%]), we concluded that the complete and simplified risk prediction models for GSD exhibited excellent performance. Moreover, we detected no significant differences between the performance of the two models (P>0.05). We also established two online websites based on the results of this study for GSD risk prediction. Conclusions: This study innovatively used the data from 96426 patients from four hospitals to establish a GSD risk prediction model and to perform risk prediction analyses of internal and external validation data sets in four cohorts. A simplified model of GSD risk prediction, which included the variables of sex, age, body mass index, gallbladder polyps, and fatty liver disease, also exhibited good discrimination and clinical performance. Nonetheless, further studies are needed to explore the role of low-density lipoprotein cholesterol and aspartate aminotransferase in gallstone formation. Although the validation results of the complete model were better than those of the simplified model to a certain extent, the difference was not significant even in large samples. Compared with the complete model, the simplified model uses fewer variables and yields similar prediction and clinical impact. Hence, we recommend the application of the simplified model to improve the efficiency of screening high-risk groups in practice. The use of the simplified model is conducive to enhancing the self-awareness of prevention and control in the general population and early intervention for GSD.

Symptomatic uncomplicated gallstone disease is associated with a high short-term risk of gallstone-related complications: a contemporary cohort study.

BACKGROUND: The natural history of symptomatic uncomplicated gallstone disease is largely unknown. We examined the risk of progressing from symptomatic uncomplicated to complicated gallstone disease in a large regional cohort of patients, where disruptions in elective surgical capacities have led to the indefinite postponement of surgery for benign conditions, including cholecystectomies. METHODS: Patients with radiologically diagnosed incident symptomatic and uncomplicated gallstone disease were identified from outpatient clinics and emergency departments on the Island of Funen, Denmark. The absolute risk of complications (cholecystitis, cholangitis, pancreatitis, acute cholecystectomy for unremitting pain) was calculated using death and elective cholecystectomies as competing risks using the Aalen-Johansen method. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) of gallstone complications associated with patient and gallstone characteristics. RESULTS: Two hundred eighty-six patients diagnosed with incident symptomatic, uncomplicated gallstone disease from 1 January 2020 to 1 July 2023 were identified. During 79,170 person-years of observation, 176 (61.5%) patients developed a gallstone-related complication. The 6-, 12- and 24-month risk of developing gallstone-related complications were 36%, 55% and 81%. The risk of developing complications related to common bile duct stones was lowest with larger stones (aHR per millimeter increase = 0.89 (0.82-0.97), p < 0.01), while no covariates were statistically significantly associated with the risk of cholecystitis. Eighty-five (30%) patients underwent elective laparoscopic cholecystectomy, with one patient (1.2%) developing a gallstone-related complication afterward. CONCLUSIONS: The risk of developing complications to symptomatic gallstones in a general Scandinavian population is high, and prophylactic cholecystectomy should be considered.

Multi-biobank Mendelian randomization analyses identify opposing pathways in plasma low-density lipoprotein-cholesterol lowering and gallstone disease.

Plasma low-density lipoprotein (LDL)-cholesterol is positively associated with coronary artery disease risk while biliary cholesterol promotes gallstone formation. Different plasma LDL-cholesterol lowering pathways may have distinct effects on biliary cholesterol and thereby gallstone disease risk. We conducted a Mendelian randomization (MR) study using data from the UK Biobank (30,547 gallstone disease cases/336,742 controls), FinnGen (34,461 cases/301,383 controls) and Biobank Japan (9,305 cases/168,253 controls). We first performed drug-target MR analyses substantiated by colocalization to investigate the effects of plasma LDL-cholesterol lowering therapies on gallstone disease risk. We then performed clustered MR analyses and pathway analyses to identify distinct mechanisms underlying the association of plasma LDL-cholesterol with gallstone disease risk. For a 1-standard deviation reduction in plasma LDL-cholesterol, genetic mimics of statins were associated with lower gallstone disease risk (odds ratio 0.72 [95% confidence interval 0.62, 0.83]), but genetic mimics of PCSK9 inhibitors and targeting apolipoprotein B were associated with higher risk (1.11 [1.03, 1.19] and 1.23 [1.13, 1.35]). The association for statins was supported by colocalization (posterior probability 98.7%). Clustered MR analyses identified variant clusters showing opposing associations of plasma LDL-cholesterol with gallstone disease risk, with some evidence for ancestry-and sex-specific associations. Among variants lowering plasma LDL-cholesterol, those associated with lower gallstone disease risk were mapped to glycosphingolipid biosynthesis pathway, while those associated with higher risk were mapped to pathways relating to plasma lipoprotein assembly, remodelling, and clearance and ATP-binding cassette transporters. This MR study provides genetic evidence that different plasma LDL-cholesterol lowering pathways have opposing effects on gallstone disease risk.

Association Between Gallstone Disease and Risk of Mortality of Cardiovascular Disease and Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Gallstone disease (GD) is increasing in the world and has various complications. OBJECTIVE: This study aims to examine the relationship between GD and the risk of mortality from cardiovascular disease (CVD) and cancer using a systematic review and meta-analysis approach. METHODS: A comprehensive and systematic search was done in various databases, such as Web of Science (WOS), Scopus, MEDLINE/PubMed, Cochrane, and Embase. The search included studies published from 1980 to December 2023. Heterogeneity was assessed using Chi-square, I2, and forest plots, while publication bias was evaluated through Begg's and Egger's tests. All analyses were performed using Stata 15, with statistical significance set at p <0.05. RESULTS: A pooled analysis of five studies involving 161,671 participants demonstrated that individuals with GD had a significantly higher risk of mortality from CVD (RR 1.29, 95% CI: 1.11-1.50, p <0.001). Importantly, no evidence of publication bias was found based on the results of Begg's test (p =0.806) and Egger's test (p =0.138). Furthermore, the pooled analysis of seven studies, encompassing a total of 562,625 participants, indicated an increased risk of cancer mortality among individuals with GD (RR 1.45, 95% CI: 1.16-1.82, p <0.001). Similarly, no publication bias was detected through Begg's test (p =0.133) and Egger's test (p =0.089). CONCLUSION: In this study, the evidence of a significant association between GD and an elevated risk of mortality from CVD and cancer is provided. These findings suggest that implementing targeted interventions for individuals with gallstone disease could reduce mortality rates among these patients.

Presence and significance of telocytes in cholelithiasis and biliary dilatation in benign biliary disorders.

Telocytes are closely associated with the regulation of tissue smooth muscle dynamics in digestive system disorders. They are widely distributed in the biliary system and exert their influence on biliary motility through mechanisms such as the regulation of CCK and their electrophysiological effects on smooth muscle cells. To investigate the relationship between telocytes and benign biliary diseases,such as gallbladder stone disease and biliary dilation syndrome, we conducted histopathological analysis on tissues affected by these conditions. Additionally, we performed immunohistochemistry and immunofluorescence double staining experiments for telocytes. The results indicate that the quantity of telocytes in the gallbladder and bile duct is significantly lower in pathological conditions compared to the control group. This reveals a close association between the decrease in telocyte quantity and impaired gallbladder motility and biliary fibrosis. Furthermore, further investigations have shown a correlation between telocytes in cholesterol gallstones and cholecystokinin-A receptor (CCK-AR), suggesting that elevated cholesterol levels may impair telocytes, leading to a reduction in the quantity of CCK-AR and ultimately resulting in impaired gallbladder motility.Therefore, we hypothesize that telocytes may play a crucial role in maintaining biliary homeostasis, and their deficiency may be associated with the development of benign biliary diseases, including gallstone disease and biliary dilation.

SLC10A1 rs2296651 variant (S267F mutation) predicts biochemical traits, hepatitis B virus infection susceptibility and the risk of gallstone disease.

Sodium taurocholate co-transporting polypeptide (NTCP), a bile acid transporter, plays a crucial role in regulating bile acid levels and influencing the risk of HBV infection. Genetic variations in the SLC10A1 gene, which encodes NTCP, affect these functions. However, the impact of SLC10A1 gene variants on the metabolic and biochemical traits remained unclear. We aimed to investigate the association of SLC10A1 gene variants with the clinical and biochemical parameters, and the risk of different HBV infection statuses and gallstone disease in the Taiwanese population. Genotyping data from 117,679 Taiwan Biobank participants were analyzed using the Axiom genome-wide CHB arrays. Regional-plot association analysis demonstrated genome-wide significant association between the SLC10A1 rs2296651 genotypes and lipid profile, gamma glutamyl transferase (γGT) level and anti-HBc-positivity. Genotype-phenotype association analyses revealed significantly lower total cholesterol, low-density lipoprotein (LDL) cholesterol and uric acid levels, a higher γGT level and a higher gallstone incidence in rare rs2296651-A allele carrier. Participants with the rs2296651 AA-genotype exhibited significantly lower rates of anti-HBc-positivity and HBsAg-positivity. Compared to those with the GG-genotype, individuals with non-GG-genotypes had reduced risks for various HBV infection statuses: the AA-genotype showed substantially lower risks, while the GA-genotype demonstrated modestly lower risks. Predictive tools also suggested that the rs2296651 variant potentially induced protein damage and pathogenic effects. In conclusion, our data revealed pleiotropic effects of the SLC10A1 rs2296651 genotypes on the levels of biochemical traits and the risk of HBV infection and gallstone disease. This confirms SLC10A1's versatility and implicates its genotypes in predicting both biochemical traits and disease susceptibility.

Association between triglyceride glucose index-related indices with gallstone disease among US adults.

BACKGROUND: Triglyceride glucose (TyG) index combined with obesity-related indicators [triglyceride glucose-body mass index (TyG-BMI), triglyceride glucose-waist to height ratio (TyG-WHtR), triglyceride glucose-waist circumference (TyG-WC)], represents emerging methodologies for assessing insulin resistance. The objective of this investigation was to explore the correlation between TyG-related indices and gallstone disease. METHODS: The study included 3740 adults from the 2017-2020 period of the National Health and Nutrition Examination Survey. TyG-BMI, TyG-WC, and TyG-WHtR were integrated as both continuous and categorical variables within the multivariate logistic model, respectively to evaluate the connection between various TyG-related indices and gallstone disease. Additionally, restriction cubic splines and subgroup analysis were employed to deepen our understanding of this relationship. RESULTS: When analyzed as continuous variables, positive correlations were observed between TyG-BMI, TyG-WC, TyG-WHtR and gallstone disease. The OR(95%CI) were 1.063(1.045,1.082) for TyG-BMI (per 10-unit), 1.026(1.018,1.034) for TyG-WC (per 10-unit) and 1.483(1.314,1.676) for TyG-WHtR (per 1-unit), respectively. When categorized into quartiles, these three TyG-related indices still show statistically significant associations with gallstone disease. Descending in order, the diagnostic capability for gallstone disease is demonstrated as follows: TyG-WHtR (AUC = 0.667), TyG-BMI (AUC = 0.647), and TyG-WC (AUC = 0.640). CONCLUSION: There were significantly positive associations between TyG-related indices, including TyG-BMI, TyG-WC, and TyG-WHtR, and gallstone disease. Of these indices, TyG-WHtR demonstrated the most favorable performance in identifying the risk of gallstone disease.

The Association between Healthy Eating Index-2015 and Serum Metabolic Parameters in Women with Gallstone Disease: A Case-Control Study.

Background: One of the most prevalent gastrointestinal tract ailments is gallstone disease (GD). Diet has been acknowledged as a modifiable GD risk factor. The Healthy Eating Index (HEI) is a scale for evaluating the quality of diets; therefore, this study aimed to determine whether the HEI-2015 score was associated with serum metabolic parameters in women with GD. Methods: This case-control study was conducted on a sample of 75 women diagnosed with GD and 75 healthy women at the Gastroenterology and Hepatology Clinic of Shahid Beheshti University of Medical Science in Tehran, Iran. Standard laboratory methods were employed to measure the biochemical parameters. The participants' habitual dietary intake was assessed using a validated food frequency questionnaire (FFQ). The HEI-2015 score was computed for all participants. The study employed multivariate logistic regression to identify the optimal predictor of GD. The Pearson Correlation was employed to determine the correlation between the HEI-2015 and serum metabolic parameters. Results: The study found a significant negative association between the risk of GD and serum HDL-c (OR: 0.84; 95% CI: 0.76-0.95, P=0.008). Moreover, a significant positive association was detected between HOMAIR (OR: 3.27; 95% CI: 1.16-9.19, P=0.025), and the risk of GD. The study did not find a statistically significant correlation between the HEI-2015 and serum parameters. Conclusion: While an association was discovered between certain serum metabolic parameters and the risk of GD, the results do not provide a significant association between serum metabolic parameters and HEI-2015 score.

Burden of gallstone disease in the United States population: Prepandemic rates and trends.

BACKGROUND: Gallstone disease is one of the most common digestive disorders in the United States and leads to significant morbidity, mortality, and health care utilization. AIM: To expand on earlier findings and investigate prepandemic rates and trends in the gallstone disease burden in the United States using national survey and claims databases. METHODS: The National Ambulatory Medical Care Survey, National Inpatient Sample, Nationwide Emergency Department Sample, Nationwide Ambulatory Surgery Sample, Vital Statistics of the United States, Optum Clinformatics® Data Mart, and Centers for Medicare and Medicaid Services Medicare 5% Sample and Medicaid files were used to estimate claims-based prevalence, medical care including cholecystectomy, and mortality with a primary or other gallstone diagnosis. Rates were age-adjusted (for national databases) and shown per 100000 population. RESULTS: Gallstone disease prevalence (claims-based, 2019) was 0.70% among commercial insurance enrollees, 1.03% among Medicaid beneficiaries, and 2.09% among Medicare beneficiaries and rose over the previous decade. Recently, in the United States population, gallstone disease contributed to approximately 2.2 million ambulatory care visits, 1.2 million emergency department visits, 625000 hospital discharges, and 2000 deaths annually. Women had higher medical care rates with a gallstone disease diagnosis, but mortality rates were higher among men. Hispanics had higher ambulatory care visit and hospital discharge rates compared with Whites, but not mortality rates. Blacks had lower ambulatory care visit and mortality rates, but similar hospital discharge rates compared with whites. During the study period, ambulatory care and emergency department visit rates with a gallstone disease diagnosis rose, while hospital discharge and mortality rates declined. Among commercial insurance enrollees, rates were higher compared with national data for ambulatory care visits and hospitalizations, but lower for emergency department visits. Cholecystectomies performed in the United States included 605000 ambulatory laparoscopic, 280000 inpatient laparoscopic, and 49000 inpatient open procedures annually. Among commercial insurance enrollees, rates were higher compared with national data for laparoscopic procedures. CONCLUSION: The gallstone disease burden in the United States is substantial and increasing, particularly among women, Hispanics, and older adults with laparoscopic cholecystectomy as the mainstay treatment. Current practice patterns should be monitored for better health care access.

Elevated LDL-c may warn of the risk of gallbladder stones in the patients with metabolic dysfunction-associated steatotic liver disease: A case-control study.

PURPOSE: This study aimed to explore the relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and the development of new-onset gallbladder stone disease (GSD) and to identify factors that influence the occurrence of new-onset GSD in patients with MASLD. METHODS: In this retrospective case-control study, patients who underwent asymptomatic GSD screening during annual routine health check-ups at two hospitals in China between August 2017 and July 2022 were included. Patients with new-onset GSD and controls without GSD were matched 1:1 based on age, sex, race, occupation, diet, drinking habits, systolic blood pressure, diastolic blood pressure, and fasting blood glucose levels. RESULTS: The study comprised 1200 patients with new-onset GSD and 1200 controls without GSD. Patients with new-onset GSD had higher rates of MASLD (33.8% vs. 22.2 %, P < 0.001) and hypercholesterolemia (12.6% vs. 7.2 %, P < 0.001) compared to controls. Waist circumference (WC) (OR = 1.042, 95 % CI: 1.022-1.063, P < 0.001), high-density lipoprotein cholesterol (HDL-c) (OR = 0.048, 95 % CI: 0.037-0.062, P < 0.001), triglycerides (OR = 0.819, 95 % CI: 0.699-0.958, P = 0.013), and hypercholesterolemia (OR = 5.023, 95 % CI: 2.735-9.225, P < 0.001) were independently associated with new-onset GSD. Among patients with MASLD, WC (OR = 1.075, 95 % CI: 1.026-1.127, P = 0.003), total cholesterol (TC) (OR = 2.094, 95 % CI: 1.259-3.484, P = 0.004), HDL-c (OR = 0.088, 95 % CI: 0.054-0.142, P < 0.001), and low-density lipoprotein cholesterol (LDL-c) (OR = 4.056, 95 % CI: 2.669-6.163, P < 0.001) were independently associated with new-onset GSD. CONCLUSIONS: The findings indicate that hypercholesterolemia is independently associated with GSD. Among patients with MASLD, hypercholesterolemia also showed an independent association with GSD. Notably, this study is the first to identify serum LDL-c levels as potentially the most significant risk factor for GSD, highlighting that elevated LDL-c could serve as an important indicator for individuals with MASLD.

The association between trajectory of serum cholesterol, statin dosage, and the risk of recurrent biliary stone diseases.

BACKGROUND: Statins may reduce the risk of recurrent gallstone disease by decreasing bile cholesterol saturation and pathogenicity. However, limited studies have investigated this issue. This study aimed to assess whether statin doses and serum cholesterol levels were associated with a decreased risk of recurrent biliary stone diseases after the first event index, with a follow-up time of 15 years. METHODS: Based on the Chang Gung Research Database (CGRD) between January 1, 2001, and December 31, 2020, we enrolled 68,384 patients with the International Classification of Diseases, Ninth and Tenth Revision codes of choledocholithiasis. After exclusions, 32,696 patients were divided into non-statin (<28 cDDD, cumulative defined daily doses) (n = 27,929) and statin (≥28 cDDD) (n = 4767) user groups for analysis. Serum cholesterol trajectories were estimated using group-based trajectory modeling (n = 8410). RESULTS: The statin users had higher Charlson Comorbidity Index (CCI) scores than the non-statin users. Time-dependent Cox regression analysis showed that statin use >365 cDDD was associated with a significantly lower risk of recurrent biliary stones (adjusted hazard ratio [aHR] = 0.28, 95% CI, 0.24-0.34; p < 00.0001), acute pancreatitis (aHR = 0.24, 95% CI, 0.17-0.32, p < 00.0001), and cholangitis (aHR = 0.28, 95% CI, 0.25-0.32, p < 00.0001). Cholecystectomy was also a protective factor for recurrent biliary stones (aHR = 0.41, 95% CI, 0.37-0.46; p < 00.0001). The higher trajectory serum cholesterol group (Group 3) had a lower risk trend for recurrent biliary stones (aHR = 0.79, p = 0.0700) and a lower risk of cholangitis (aHR = 0.79, p = 0.0071). CONCLUSION: This study supports the potential benefits of statin use and the role of cholecystectomy in reducing the risk of recurrent biliary stone diseases.

Surgeon-Performed Percutaneous Endoscopic Biliary Lithectomy: Description of a Novel Technique and Initial Results.

Introduction: Percutaneous endoscopic biliary lithectomy (PEBL) can be performed through preexisting drain tracts, offering ductal clearance and definitive management for patients with complicated gallstone disease unable to undergo conventional therapy. The technique has not been widely adopted by general surgeons. Herein, we describe our technique with surgeon-performed PEBL and present initial results. Materials and Methods: A single institutional retrospective review of the electronic medical record was performed for patients who underwent percutaneous choledochoscopy between February 2019 and November 2020. All operations were performed by 1 of 2 board-certified general surgeons with fellowship training in surgical endoscopy. Preoperative, operative, and postoperative variables were analyzed using descriptive statistics. Results: Thirteen patients underwent PEBL. Seventeen total procedures were performed; 4 patients underwent repeat intervention. The diagnoses leading to PEBL were: cholelithiasis (8), choledocholithiasis (4), and recurrent pancreatitis (1). Complete ductal clearance was achieved in 9 patients (69.2%) during the initial procedure. The remaining 4 patients (30.8%) underwent repeat PEBL, at which point complete ductal clearance was then achieved. The percutaneous drain was removed at the time of final procedure in 5 patients (38.5%) or within 5 weeks in the remaining 8 (61.5%). No intraoperative complications occurred, and no pancreatic or biliary postoperative complications or recurrences were noted with a mean follow-up of 279 ± 240 days. Conclusion: Surgeon-performed PEBL is a safe and effective method of achieving biliary ductal clearance. The technique is readily achieved following basic endoscopic and fluoroscopic principles and should be understood by all physicians managing gallstone disease.

Individual and joint associations of per- and polyfluoroalkyl substances (PFAS) with gallstone disease in adults: A cross-sectional study.

Disturbances in the enterohepatic circulation are important biological mechanisms for causing gallstones and also have important effects on the metabolism of Per- and polyfluoroalkyl substances (PFAS). Moreover, PFAS is associated with sex hormone disorder which is another important cause of gallstones. However, it remains unclear whether PFAS is associated with gallstones. In this study, we used logistic regression, restricted cubic spline (RCS), quantile g-computation (qg-comp), Bayesian kernel machine regression (BKMR), and subgroup analysis to assess the individual and joint associations of PFAS with gallstones and effect modifiers. We observed that the individual associations of perfluorodecanoic acid (PFDeA) (OR: 0.600, 95% CI: 0.444 to 0.811), perfluoroundecanoic acid (PFUA) (OR: 0.630, 95% CI: 0.453 to 0.877), n-perfluorooctane sulfonic acid (n-PFOS) (OR: 0.719, 95% CI: 0.571 to 0.906), and perfluoromethylheptane sulfonic acid isomers (Sm-PFOS) (OR: 0.768, 95% CI: 0.602 to 0.981) with gallstones were linearly negative. Qg-comp showed that the PFAS mixture (OR: 0.777, 95% CI: 0.514 to 1.175) was negatively associated with gallstones, but the difference was not statistically significant, and PFDeA had the highest negative association. Moreover, smoking modified the association of perfluorononanoic acid (PFNA) with gallstones. BKMR showed that PFDeA, PFNA, and PFUA had the highest groupPIP (groupPIP = 0.93); PFDeA (condPIP = 0.82), n-perfluorooctanoic acid (n-PFOA) (condPIP = 0.68), and n-PFOS (condPIP = 0.56) also had high condPIPs. Compared with the median level, the joint association of the PFAS mixture with gallstones showed a negative trend; when the PFAS mixture level was at the 70th percentile or higher, they were negatively associated with gallstones. Meanwhile, when other PFAS were fixed at the 25th, 50th, and 75th percentiles, PFDeA had negative associations with gallstones. Our evidence emphasizes that PFAS is negatively associated with gallstones, and more studies are needed in the future to definite the associations of PFAS with gallstones and explore the underlying biological mechanisms.

Association of pro-inflammatory diet with increased risk of gallstone disease: a cross-sectional study of NHANES January 2017-March 2020.

Background and aim: Gallstone disease (GSD) is a major public health problem worldwide. The dietary inflammatory index (DII) and the energy-adjusted DII (E-DII) have been used to describe dietary inflammatory potential. The current study sought to investigate the pro-inflammatory role of diet on GSD among outpatients in the United States. Methods: Cross-sectional data from 7,334 individuals older than 20 years who participated in the National Health and Nutrition Examination Survey (NHANES) from January 2017 to March 2020 were obtained. The relationship between GSD and DII was assessed using self-reported data. An association between DII and the risk of GSD was determined using sample-weighted logistic regression and restricted cubic splines (RCS). Subgroup analyzes were conducted to assess the interaction between DII and related factors. Sensitivity analysis was further used to confirm the stability of the relationship. To control for the effect of total energy intake, E-DII was calculated and analyzed. Results: A total of 10.5% of the study participants had GSD. The DII ranged from -5.52 to 5.51, and the median DII was significantly higher for participants with GSD than those without (1.68 vs. 1.23, p < 0.001). There was a significant and stable positive relationship between DII and GSD in adjusted models (OR 1.10, 95% CI 1.00-1.20). In the fully adjusted model, subjects with DII scores in the highest tertile were more likely to have GSD than those in the lowest tertile (OR 1.52, 95% CI 1.19-1.93). An apparent dose-response association between DII and GSD was detected. The association between E-DII and GSD remained stable. Conclusion: Higher DII/E-DII scores linked to the intake of a pro-inflammatory diet were positively associated with a higher risk of GSD. These findings suggest that pro-inflammatory dietary patterns can promote the formation of gallstones.

Independent association of general and central adiposity with risk of gallstone disease: observational and genetic analyses.

Background: General obesity is a well-established risk factor for gallstone disease (GSD), but whether central obesity contributes additional independent risk remains controversial. We aimed to comprehensively clarify the effect of body fat distribution on GSD. Methods: We first investigated the observational association of central adiposity, characterized by waist-to-hip ratio (WHR), with GSD risk using data from UK Biobank (N=472,050). We then explored the genetic relationship using summary statistics from the largest genome-wide association study of GSD (ncase=43,639, ncontrol=506,798) as well as WHR, with and without adjusting for body mass index (BMI) (WHR: n=697,734; WHRadjBMI: n=694,649). Results: Observational analysis demonstrated an increased risk of GSD with one unit increase in WHR (HR=1.18, 95%CI=1.14-1.21). A positive WHR-GSD genetic correlation (rg =0.41, P=1.42×10-52) was observed, driven by yet independent of BMI (WHRadjBMI: rg =0.19, P=6.89×10-16). Cross-trait meta-analysis identified four novel pleiotropic loci underlying WHR and GSD with biological mechanisms outside of BMI. Mendelian randomization confirmed a robust WHR-GSD causal relationship (OR=1.50, 95%CI=1.35-1.65) which attenuated yet remained significant after adjusting for BMI (OR=1.17, 95%CI=1.09-1.26). Furthermore, observational analysis confirmed a positive association between general obesity and GSD, corroborated by a shared genetic basis (rg =0.40, P=2.16×10-43), multiple novel pleiotropic loci (N=11) and a causal relationship (OR=1.67, 95%CI=1.56-1.78). Conclusion: Both observational and genetic analyses consistently provide evidence on an association of central obesity with an increased risk of GSD, independent of general obesity. Our work highlights the need of considering both general and central obesity in the clinical management of GSD.

The Management of Biliary Disease in Patients with Severe Obesity Undergoing Metabolic and Bariatric Surgery-An International Expert Survey.

OBJECTIVE: This study aimed to survey international experts in metabolic and bariatric surgery (MBS) to improve and consolidate the management of biliary disease in patients with severe obesity undergoing MBS. BACKGROUND: Obesity and rapid weight loss after MBS are risk factors for the development of gallstones. Complications, such as cholecystitis, acute cholangitis, and biliary pancreatitis, are potentially life-threatening, and no guidelines for the proper management of gallstone disease exist. METHODS: An international scientific team designed an online confidential questionnaire with 26 multiple-choice questions. The survey was answered by 86 invited experts (from 38 different countries), who participated from August 1, 2023, to September 9, 2023. RESULTS: Two-thirds of experts (67.4%) perform concomitant cholecystectomy in symptomatic gallstones during MBS. Half of experts (50%) would wait 6-12 weeks between both surgeries with an interval approach. Approximately 57% of the experts prescribe ursodeoxycholic acid (UDCA) prophylactically after MBS, and most recommend a 6-month course. More than the half of the experts (59.3%/53.5%) preferred laparoscopic assisted transgastric ERCP as the approach for treating CBD stones in patients who previously had RYGB/OAGB. CONCLUSION: Concomitant cholecystectomy is preferred by the experts, although evidence in the literature reports an increased complication rate. Prophylactic UDCA should be recommended to every MBS patient, even though the current survey demonstrated that not all experts are recommending it. The preferred approach for treating common bile duct stones is a laparoscopic assisted transgastric ERCP after gastric bypass. The conflicting responses will need more scientific work and clarity in the future.

Prevalence of Thyroid Disorder in Gallstone Disease Patients: A Cross-Sectional Study.

Background Gallstone disease (GSD) is one of the most common disorders involving the biliary system. The three types of gallstones include pigment, cholesterol, and mixed stones. Studies have suggested a potential association between thyroid dysfunction and lipid pathogenesis, which influences bile composition. A higher prevalence of thyroid disorders may have an impact on the management of GSD patients. This study aimed to assess the prevalence of thyroid disorders and associated dyslipidemias among individuals diagnosed with GSD. Methodology This cross-sectional, observational study was conducted among 180 eligible patients with a mean age of 47.72 ± 15.29 years. This study included 56 (31%) male and 124 (69%) female patients admitted to the Department of General Surgery, Indira Gandhi Institute of Medical Sciences, in eastern India. A diagnosis of GSD was established based on a radiological investigation (ultrasonography) and was included in the study. A thyroid profile test, a liver function test, and a lipid profile test were done for all patients. Patients with a previous surgical history of thyroid disease and known cases of hypothyroidism taking thyroxin supplements for treatment, as well as uncontrolled diabetes mellitus and hypertension, were excluded from the study. Relevant data were collected and statistically analyzed. Results Among the 180 patients, 122 (67.77%) were euthyroid, 35 (19.44%) had subclinical hypothyroidism, 20 (11.11%) had clinical hypothyroidism, and three (1.66%) had hyperthyroidism. Out of a total of 55 hypothyroidism patients, 37 (67.27%) had dyslipidemias. Conclusions The prevalence of hypothyroidism in GSD was 30%, with a female predominance. Hypothyroidism is a specific risk factor for cholelithiasis, and all patients with GSD who have dyslipidemia should be evaluated for thyroid dysfunction.

Gut microbiota, circulating metabolites, and gallstone disease: a Mendelian randomization study.

Background: The link between Gut microbiota (GM) and Gallstone disease (GSD) is well established, but it is not clear whether there is a causal relationship between the two associations. Methods: We conducted bidirectional Mendelian randomization (MR) analyses, leveraging aggregated data from the Genome-Wide Association Study (GWAS) of GM and Circulating Metabolites. Our primary objective was to investigate the causal interplay between intestinal flora and GSD. Additionally, we performed mediational analyses, two-step MR, and multivariate MR to uncover the potential mediating effect of circulating metabolites in this relationship. Result: Our study has revealed a causal relationship between GSD and six distinct bacterial groups. Genetically predicted Class Bacilli (Odds Ratio (OR): 0.901, 95% Confidence Interval (95% CI): 0.825-0.985; p = 0.021), Order Lactobacillales (OR: 0.895, 95% CI: 0.816-0.981; p = 0.017), and Genus Coprococcus 2 (OR: 0.884, 95% CI: 0.804-0.973; p = 0.011) were inversely associated with the risk of GSD. Conversely, the Genus Clostridiumsensustricto1 (OR: 1.158, 95% CI: 1.029-1.303; p = 0.015), Genus Coprococcus3 (OR: 1.166, 95% CI: 1.024-1.327; p = 0.020), and Genus Peptococcus (OR: 1.070, 95% CI: 1.017-1.125; p = 0.009) were positively associated with the risk of GSD. Moreover, our findings suggest that the positive influence of the Genus Peptococcus on GSD may be mediated through Omega-3 polyunsaturated fatty acids (PUFA). Conclusion: This study reinforces the connection between the gut microbiome and the risk of GSD while also unveiling the mediating role of Omega-3 PUFA in the causal relationship between these factors.

Medical Therapies to Conquer Surgical Diseases: Gallstone Disease May Be the Next Frontier.

Over the past half century, diseases that were predominantly treated surgically have transitioned to less invasive medical therapies. Such diseases that are now effectively treated with medicine are (1) peptic ulcer disease (PUD), (2) coronary artery disease (CAD), and (3) gastrointestinal stromal tumors (GISTs). Likewise, gallstone disease may soon follow this trend. Currently, the gold standard treatment of symptomatic gallstones is laparoscopic cholecystectomies. Though one of the most common surgeries in the United States, certain cases of acute and gangrenous cholecystitis can be some of the most difficult surgeries to perform. Advancements in neutrophil extracellular trap (NET) inhibitor medical therapies will alter gallstone disease management and the mainstream role of surgical interventions. This focus on less invasive therapies will greatly impact the quality of patient care, financial obligations, and even resident training opportunities.

Resistance to Cholesterol Gallstone Disease: Hepatic Cholesterol Metabolism.

Cholesterol gallstone disease (CGD) is one of the most common digestive diseases, and it is closely associated with hepatic cholesterol metabolism. Cholesterol gallstones may be caused by abnormal hepatic cholesterol metabolism, such as excessive cholesterol biosynthesis within the liver, interfering with the uptake or export of cholesterol in the liver, and abnormal hepatic cholesterol esterification. In this review, we begin with a brief overview of the clinical diagnosis and treatment of gallstone disease (GSD). Then, we briefly describe the major processes of hepatic cholesterol metabolism and summarize the key molecular expression changes of hepatic cholesterol metabolism in patients with gallstones. We review and analyze the recent advances in elucidating the relationships between these key molecules and CGD, and some targets significantly impacting on CGD via hepatic cholesterol metabolism are also listed. We also provide a significant discussion on the relationship between CGD and nonalcoholic fatty liver disease (NAFLD). Finally, the new discoveries of some therapeutic strategies associated with hepatic cholesterol metabolism to prevent and treat CGD are summarized.