ABSTRACT
BACKGROUND: Glycoprotein-2 (GP2) IgA is a predictor of disease severity in primary sclerosing cholangitis (PSC). We examined GP2's occurrence in the biliary tract, the site of inflammation. METHODS: GP2 was analyzed using ELISA, immunoblotting, mass spectrometry, and immunohistochemistry. The samples included: 20 bile and 30 serum samples from PSC patients, 23 bile and 11 serum samples from patients with gallstone disease (GD), 15 bile samples from healthy individuals undergoing liver-donation surgery (HILD), 20 extracts of gallstones (GE) obtained during cholecystectomy, and 101 blood-donor sera. RESULTS: Biliary GP2 concentrations were significantly higher in patients with PSC and GD than in HILD (p < 0.0001). Serum GP2 levels were similar in PSC and GD patients, and controls, but lower than in bile (p < 0.0001). GP2 was detected in all 20 GEs. Mass spectrometry identified GP2 in the bile of 2 randomly selected GD and 2 PSC patients, and in none of 2 HILD samples. GP2 was found in peribiliary glands in 8 out of 12 PSC patients, showing morphological changes in acinar cells, but not in GD-gallbladders. CONCLUSIONS: GP2 is present in bile of PSC and GD patients. It is synthesized in the peribiliary glands of PSC patients, supporting a pathogenic role for biliary GP2 in PSC.
Subject(s)
Bile , Cholangitis, Sclerosing , Gallstones , Humans , Cholangitis, Sclerosing/metabolism , Cholangitis, Sclerosing/pathology , Gallstones/metabolism , Gallstones/chemistry , Gallstones/pathology , Bile/chemistry , Bile/metabolism , Male , Female , Middle Aged , Adult , Aged , Young Adult , GPI-Linked ProteinsABSTRACT
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.
Subject(s)
Antigens, Bacterial , Bacterial Proteins , Epithelial Cells , Gallbladder , Gallstones , Helicobacter pylori , Animals , Gallstones/microbiology , Gallstones/pathology , Epithelial Cells/microbiology , Mice , Humans , Gallbladder/microbiology , Gallbladder/pathology , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Antigens, Bacterial/genetics , Antigens, Bacterial/metabolism , Helicobacter pylori/genetics , Helicobacter pylori/pathogenicity , Helicobacter pylori/physiology , RNA, Ribosomal, 16S/genetics , Disease Models, Animal , Permeability , Helicobacter Infections/microbiology , Helicobacter Infections/pathology , Female , Male , Mice, Inbred C57BLABSTRACT
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.
Subject(s)
Gallstones , Immunohistochemistry , Humans , Gallstones/pathology , Gallstones/metabolism , Male , Female , Middle Aged , Adult , Interleukin-6/metabolism , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/analysis , Cholecystitis/pathology , Cholecystitis/metabolism , Substance P/metabolism , Gallbladder/pathology , Gallbladder/metabolism , Receptors, Interleukin-2/metabolism , Aged , Chronic Disease , Biomarkers/metabolism , Biomarkers/analysis , Cholecystitis, Acute/pathology , Cholecystitis, Acute/metabolism , Cholecystitis, Acute/surgeryABSTRACT
The incidence of gallbladder cholesterol stones (GCS) increases rapidly among people living in high-altitude hypoxic environments compared to those in normoxic areas. Upregulation of hepatic hypoxia inducible factor 1α (Hif-1α) plays a key role in the formation of GCS. High plasma trimethylamine-N-oxide (TMAO) levels are positively correlated with the occurrence of GCS. We hypothesized that HIF-1α may upregulate TMAO levels by promoting the transcription of flavin-containing monooxygenase 3 (Fmo3), which eventually leads to GCS formation. Our study shows that in women, high plasma total cholesterol and apolipoprotein B were positively correlated with cholecystolithiasis and hypoxia. Hif-1α binds to the Fmo3 promoter and promotes Fmo3 expression. Hypoxia and lithogenic diet induce the expression of Hif-1α, Fmo3, TMAO and cholesterol tube transporters in the livers of mice, disturb the proportion of bile and plasma components, and induce the formation of GCS. In cell experiments, silencing Hif-1α downregulates the expression of Fmo3, TMAO and cholesterol tube transporters. In a mouse model of hypoxic cholecystolithiasis, silencing Hif-1α downregulates the expression of related genes, restores the proportion of bile and plasma lipid components, and reduces the formation of GCS. Our study shows that Hif-1α binds to the promoter region of Fmo3 and promotes Fmo3 transcription. Thus, it mediates the transcriptional activation of the TMA/Fmo3/TMAO pathway, upregulates the expression of ATP-binding cassettes (Abc) g5 and g8, and participates in the regulation of the occurrence of GCS in the plateau region.
Subject(s)
Cholesterol , Gallstones , Hypoxia-Inducible Factor 1, alpha Subunit , Methylamines , Oxygenases , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Animals , Humans , Female , Mice , Cholesterol/metabolism , Gallstones/metabolism , Gallstones/genetics , Gallstones/pathology , Oxygenases/metabolism , Oxygenases/genetics , Methylamines/metabolism , Male , Gallbladder/metabolism , Gallbladder/pathology , Middle Aged , Promoter Regions, Genetic , Hypoxia/metabolism , Hypoxia/genetics , Adult , Mice, Inbred C57BL , Cholecystolithiasis/metabolism , Cholecystolithiasis/geneticsABSTRACT
An 83-year-old Japanese man who underwent cholecystectomy for cholecystolithiasis 17 years ago visited our hospital owing to epigastric pain. He was initially diagnosed with choledocholithiasis and acute cholangitis following white blood cell, C-reactive protein, total bilirubin, alkaline phosphatase, and γ-glutamyltranspeptidase level elevations along with common bile duct stones on computed tomography (CT). Moreover, CT, magnetic resonance imaging, endoscopic retrograde cholangiography (ERC), and endoscopic ultrasonography (EUS) also revealed a 2-cm-diameter mass arising from the remnant cystic duct. The cytology of the bile at the time of ERC was not conclusive. However, EUS-assisted fine needle aspiration (EUS-FNA) of the mass confirmed the diagnosis of adenocarcinoma of the remnant cystic duct. The patient underwent extrahepatic bile duct resection. Cystic duct carcinoma following cholecystectomy is rare. We report a case diagnosed by EUS-FNA.
Subject(s)
Adenocarcinoma , Cholecystectomy, Laparoscopic , Gallstones , Male , Humans , Aged, 80 and over , Cystic Duct/diagnostic imaging , Cystic Duct/surgery , Cystic Duct/pathology , Cholecystectomy , Gallstones/pathology , Gallstones/surgery , Adenocarcinoma/diagnosis , Cholangiopancreatography, Endoscopic RetrogradeABSTRACT
Analysis of the chemical composition of gallstones is vital for the etiopathogenesis of gallstone diseases that can ultimately help in the prevention of its formation. In the present study, gallstones from seven different regions of India were analyzed to highlight the major difference in their composition. Also, gallstones of different pathological conditions i.e., benign (chronic cholecystitis, CC) and malignant gallbladder disease (gallbladder cancer GBC) were characterized. The type of polymorphs of cholesterol molecules was also studied to provide insight into the structure of gallstones. 1H solution state NMR spectroscopy 1D experiments were performed on a total of 94 gallstone (GS) samples collected from seven different geographical regions of India. Solid-State NMR spectroscopy 13C cross-polarization magic angle spinning (CPMAS) experiments were done on the 20 CC GS samples and 20 GBC GS samples of two regions. 1H NMR spectra from the solution state NMR of all the stones reveal that cholesterol was a major component of the maximum stones of the north India region while in south Indian regions, GS had very less cholesterol. 13C CPMAS experiments reveal that the quantity of cholesterol was significantly more in the GS of CC in the Lucknow region compared with GBC stones of Lucknow and Chandigarh. Our study also revealed that GS of the Lucknow region of both malignant and benign gallbladder diseases belong to the monohydrate crystalline form of cholesterol while GS of Chandigarh region of both malignant and benign gallbladder diseases exists in both monohydrate crystalline form with the amorphous type and anhydrous form. Gallstones have a complicated and poorly understood etiology. Therefore, it is important to understand the composition of gallstones, which can be found in various forms and clinical conditions. Variations in dietary practices, environmental conditions, and genetic factors may influence and contribute to the formation of GS. Prevention of gallstone formation may help in decreasing the cases of gallbladder cancer.
Subject(s)
Gallbladder Diseases , Gallbladder Neoplasms , Gallstones , Humans , Gallstones/pathology , Gallbladder Neoplasms/genetics , Gallbladder Diseases/complications , Cholesterol/analysis , Magnetic Resonance SpectroscopyABSTRACT
Schistosomiasis is a parasitic disease that is widely considered a neglected tropical disease. It is ranked first after malaria among all parasitic diseases. The major forms of schistosomiasis are intestinal and urogenital; however, gallbladder involvement is rare and usually accompanied by imaging findings similar to those of acute cholecystitis, such as wall thickening or pericholecystic inflammation. We encountered a patient who did not show these typical imaging findings. A man in his late 40s presented to the emergency department with a 2-month history of abdominal distention. His initial laboratory examination showed iron deficiency anemia. Computed tomography revealed a mildly distended gallbladder with septations and a small calcified gallstone. Magnetic resonance imaging was performed for better characterization, and it showed gallbladder stones with multiseptated, cystic gallbladder mural lesions and no wall thickening or pericholecystic fluid. On his second visit, the patient complained of mild epigastric pain. A provisional diagnosis of cholecystitis was considered, and laparoscopic cholecystectomy was performed. Histopathological evaluation revealed a gallbladder wall with multiple foci of chronic granulomatous inflammation. Schistosoma-like ova were observed in the mucosa and submucosa and were consistent with schistosomiasis. Periodic acid-Schiff staining of the ova was positive. The patient's postoperative course was uneventful.
Subject(s)
Cholecystitis , Gallbladder Diseases , Gallstones , Schistosomiasis , Male , Humans , Gallbladder/diagnostic imaging , Gallbladder/surgery , Gallbladder/pathology , Cholecystitis/diagnostic imaging , Cholecystitis/surgery , Gallbladder Diseases/diagnostic imaging , Gallbladder Diseases/surgery , Schistosomiasis/diagnosis , Schistosomiasis/diagnostic imaging , Inflammation/pathology , Gallstones/pathologyABSTRACT
The prevalence of cholesterol gallstone disease is increasing, primarily due to the global epidemic of obesity associated with insulin resistance, and this trend leads to a considerable healthcare, financial, and social burden worldwide. Although phospholipids play an essential role in maintaining cholesterol solubility in bile through both mixed micelles and vesicles, little attention has been paid to the impact of biliary phospholipids on the pathogenesis of cholesterol gallstone formation. A reduction or deficiency of biliary phospholipids results in a distinctly abnormal metastable physical-chemical state of bile predisposing to supersaturation with cholesterol. Changes in biliary phospholipid concentrations influence cholesterol crystallization by yielding both liquid crystalline and "anhydrous" crystalline metastable intermediates, evolving into classical parallelogram-shaped cholesterol monohydrate crystals in supersaturated bile. As a result, five distinct crystallization pathways, A-E, have been defined, mainly based on the prime habits of liquid and solid crystals in the physiological or pathophysiological cholesterol saturation of gallbladder and hepatic bile. This review concisely summarizes the chemical structures and physical-chemical properties of biliary phospholipids and their physiological functions in bile formation and cholesterol solubility in bile, as well as comprehensively discusses the latest advances in the role of biliary phospholipids in cholesterol crystallization and growth in gallstone formation, largely based on the findings from clinical and animal studies and in vitro experiments. The insights gleaned from uncovering the cholelithogenic mechanisms are expected to form a fundamental framework for investigating the hitherto elusive events in the earliest stage of cholesterol nucleation and crystallization. This may help to identify better measures for early diagnosis and prevention in susceptible subjects and effective treatment of patients with gallstones.
Subject(s)
Gallstones , Animals , Humans , Gallstones/metabolism , Gallstones/pathology , Phospholipids/chemistry , Crystallization , Bile Acids and Salts , CholesterolABSTRACT
BACKGROUND: The present study aims to evaluate the survival status of patients with gallbladder cancer (GBC) and explore the prognostic factors for the improvement and preventions. METHODS: The study consists of 176 patients with clinically diagnosed gallbladder cancer; the study was conducted between 2019 and 2021 registered at Kamala Nehru Memorial Cancer Hospital, Prayagraj, India. The survival rates were analyzed by the Kaplan-Meier method; survival rate difference was analyzed by log-rank test, prognosis factors; and hazard ratio for mortality outcomes was estimated using Cox regression method. RESULTS: The overall median survival time of patients was 5 months with the 1-year, 2-year, and 3-year survival rates of 24.4%, 8.5%, and 4.5%, respectively. The 3-year survival for patients with jaundice was 2.9%, liver infiltration (4.2%), gallstones (0.8%), and with advanced tumor grade (1.4%). Elderly GBC patients had lower survival rates (3.8%), while the 3-year overall survival for patients residing in urban areas dropped to zero. No patients in the tumor stage (T3/T4) and with distance metastasis stage survived in 3 years, while only 1.1% of patients with advanced nodal stage survived. On receiving surgery and radiation therapy, the 3-year survival rate increased to 19.5% and 35%, respectively. The results of multivariate analysis showed that urban region (HR = 1.568, p = 0.040), gallstone or not (1.571, p = 0.049), N stage (HR = 1.468, p = 0.029), and M stage (HR = 2.289, p < 0.0001) were independent risk factors for prognosis, while surgery or not (HR = 0.573, p = 0.030) was the protective factor for the prognosis of GBC. CONCLUSION: The overall survival of GBC in the Gangetic belt is poor. The geographical region of patients, gallstones, and N and M stage was the risk factors for prognosis, while surgery or not was the protective factor for the prognosis of GBC.
Subject(s)
Carcinoma , Gallbladder Neoplasms , Gallstones , Humans , Aged , Prognosis , Gallbladder Neoplasms/pathology , Gallstones/complications , Gallstones/surgery , Gallstones/pathology , Proportional Hazards Models , Carcinoma/pathology , Neoplasm Staging , Survival AnalysisABSTRACT
Women are more prone to develop either hypothyroidism or cholesterol gallstones than men. However, a male predominance in cholesterol gallstones under hypothyroidism was reported. Recently, a novel pathogenic link between thyroid hormone (TH) deficiency and cholesterol gallstones has been described in male mice. Here, we investigate if TH deficiency impacts cholesterol gallstone formation in females by the same mechanism. Three-month-old C57BL/6J mice were randomly divided into a control, a TH deficient, a lithogenic, and a lithogenic + TH deficient group and diet-treated for two, four, and six weeks. Gallstone prevalence, liver function tests, bile composition, hepatic gene expression, and gallbladder aquaporin expression and localization were investigated. Cholesterol gallstones were observed in lithogenic + TH deficient but not lithogenic only female mice. Diminished hydrophilicity of primary bile acids due to decreased gene expression of hepatic detoxification phase II enzymes was observed. A sex-specific expression and localization of hepatobiliary aquaporins involved in transcellular water and glycerol permeability was observed under TH deficient and lithogenic conditions. TH deficiency promotes cholesterol gallstone formation in female C57BL/6J mice by the same mechanism as observed in males. However, cholesterol gallstone prevalence was lower in female than male C57BL/6J mice. Interestingly, the sex-specific expression and localization of hepatobiliary aquaporins could protect female C57BL/6J mice to cholestasis and could reduce biliary water transport in male C57BL/6J mice possibly contributing to the sex-dependent cholesterol gallstone prevalence under TH deficiency.
Subject(s)
Aquaporins , Cholestasis , Gallstones , Hypothyroidism , Female , Male , Mice , Animals , Bile Acids and Salts/metabolism , Mice, Inbred C57BL , Gallstones/genetics , Gallstones/metabolism , Gallstones/pathology , Glycerol/metabolism , Cholesterol/metabolism , Liver/metabolism , Aquaporins/genetics , Aquaporins/metabolism , Cholestasis/metabolism , Cholic Acid/metabolism , Hypothyroidism/metabolism , Hydrophobic and Hydrophilic Interactions , Thyroid Hormones/metabolism , Water/metabolismABSTRACT
BACKGROUND: Common bile duct (CBD) stone is one of the most prevalent gastroenterological diseases, but the role played by biliary microbiota in the pathogenesis of CBD stones remains obscure. The aim of this study was to investigate the characteristics of the biliary tract core microbiome and its potential association with the formation of pigment stones. METHODS: Twenty-eight patients with biliary obstruction of various causes were enrolled. Thirteen had new-onset pigment CBD stone. Of the remaining 15, four had benign biliary stricture, four had gallbladder cancer, three had pancreatic cancer, 3 had distal CBD cancer, and one had hepatocellular carcinoma. Endoscopic retrograde cholangiopancreatography was used to collect bile samples for DNA extraction, 16S ribosomal RNA gene sequencing, and bile microbiota composition analysis. RESULTS: Proteobacteria (61.7%), Firmicutes (25.1%), Bacteroidetes (5%), Fusobacteria (4.6%), and Actinobacteria (2.6%) were the most dominant phyla in the bile of the 28 study subjects. A comparison between new-onset choledocholithiasis and other causes of biliary obstruction (controls) showed Enterococcus was found to be significantly abundant in the CBD stone group at the genus level (linear discriminant analysis score = 4.38; P = 0.03). However, no other significant compositional difference was observed. CONCLUSION: This study demonstrates an abundance of microbiota in bile juice and presents a biliary microbiome composition similar to that of duodenum. The study also shows Enterococcus was significantly abundant in the bile juice of patients with a brown pigment stone than in controls, which suggests Enterococcus may play an important role in the development of pigment stones.
Subject(s)
Common Bile Duct/microbiology , Gallstones/diagnosis , Microbiota , Adult , Aged , Aged, 80 and over , Cholangiopancreatography, Endoscopic Retrograde , Common Bile Duct/pathology , Discriminant Analysis , Enterococcus/genetics , Enterococcus/isolation & purification , Female , Firmicutes/genetics , Firmicutes/isolation & purification , Gallstones/pathology , Humans , Male , Middle Aged , Proteobacteria/genetics , Proteobacteria/isolation & purification , RNA, Ribosomal, 16S/analysis , RNA, Ribosomal, 16S/genetics , RNA, Ribosomal, 16S/metabolism , Young AdultABSTRACT
Chile has high incidence rates of gallbladder cancer globally, particularly among Amerindian women, who also have a high prevalence of gallstones. We examined differences in inflammatory biomarkers between Mapuche and non-Mapuche women from the Chile Biliary Longitudinal Study, a cohort of women with ultrasound-detected gallstones. We randomly selected 200 Mapuche women frequency matched to non-Mapuche women on age and statin use Inflammatory biomarkers were analyzed using a multiplex assay and linear regression to assess associations of a priori markers (CCL20, CXCL10, IL-6, and IL-8) with ethnicity. Novel biomarkers were analyzed using exploratory factor analysis (EFA) and sufficient dimension reduction (SDR) to identify correlated marker groups, followed by linear regression to examine their association with ethnicity. The mean values of IL-8 were higher in Mapuche than non-Mapuche women (P = 0.04), while CCL20, CXCL10, and IL-6 did not differ significantly by ethnicity. EFA revealed two marker groups associated with ethnicity (P = 0.03 and P < 0.001). SDR analysis confirmed correlation between the biomarkers and ethnicity. We found higher IL-8 levels among Mapuche than non-Mapuche women. Novel inflammatory biomarkers were correlated with ethnicity and should be studied further for their role in gallbladder disease. These findings may elucidate underlying ethnic disparities in gallstones and carcinogenesis among Amerindians.
Subject(s)
Chemokine CCL20/genetics , Chemokine CXCL10/genetics , Gallbladder Neoplasms/blood , Interleukin-6/genetics , Interleukin-8/genetics , Aged , Carcinogenesis/genetics , Chemokine CCL20/blood , Chemokine CXCL10/blood , Chile , Ethnicity/genetics , Female , Gallbladder/diagnostic imaging , Gallbladder/metabolism , Gallbladder/pathology , Gallbladder Neoplasms/diagnostic imaging , Gallbladder Neoplasms/genetics , Gallbladder Neoplasms/pathology , Gallstones/diagnostic imaging , Gallstones/metabolism , Gallstones/pathology , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Indians, South American/genetics , Inflammation/diagnostic imaging , Inflammation/genetics , Inflammation/pathology , Interleukin-6/blood , Interleukin-8/blood , Longitudinal Studies , Middle Aged , UltrasonographySubject(s)
Dilatation/methods , Gallstones/surgery , Sphincterotomy/methods , Age Factors , Aged , Aged, 80 and over , Ampulla of Vater/surgery , Cholangiopancreatography, Endoscopic Retrograde , Dilatation/adverse effects , Female , Gallstones/pathology , Humans , Lithotripsy/methods , Male , Retrospective Studies , Treatment OutcomeABSTRACT
INTRODUCTION: Many cases of gallbladder cancer (GBC) were made incidentally after cholecystectomy for presumed benign disease. The aim of this review is to assess the preoperative predictor factors of gallbladder cancer. METHODS: This systematic review was conducted according to PRISMA guidelines when it was applicable. We conducted bibliographic researches on October 2nd, 2019, in the following sources: The National Library of Medicine through PubMed, Cochrane database, and Google scholar. We have assessed the univariate and multivariate analysis outcomes. RESULTS: We included ten studies. Incidence of incidental GBC was 0.36%. Seven studies reported age as a significant predictive factor of iGBC. Comorbidities were the second significant predictor. One study found that iGBC group was more likely to have elevated TB, DB, PAL, and ALT. Another study reported a significantly higher rate of TB, PAL, and AST. One study concluded that elevated CA19-9 combined with CEA or CA-125 was significantly more frequent in the group with iGBC. Polyps, porcelain GB, GB wall thickness, and CBD dilation were reported to be associated with iGBC. iGBC group were more likely to have solitary and larger GS and gallbladder wall thickening, essentially focal. CONCLUSION: Incidence of iGBC was 0.365% varying between 0.19 and 1.6% of laparoscopic cholecystectomy and about 50% of GBC cases. This highlights the deficiency of preoperative diagnostic features. Despite the efforts made, the rate of this condition is still high, underlining the need of new radiological technologies.
Subject(s)
Biomarkers, Tumor/blood , Cholecystectomy, Laparoscopic , Gallbladder Neoplasms/diagnosis , Gallbladder/pathology , Gallstones/surgery , Polyps/epidemiology , Age Factors , Gallbladder/diagnostic imaging , Gallbladder/surgery , Gallbladder Neoplasms/blood , Gallbladder Neoplasms/etiology , Gallbladder Neoplasms/surgery , Gallstones/complications , Gallstones/diagnosis , Gallstones/pathology , Humans , Incidence , Incidental Findings , Polyps/pathology , Preoperative Period , Prognosis , Retrospective Studies , Risk Assessment/methods , Risk Factors , UltrasonographyABSTRACT
BACKGROUND AND AIMS: Gallstone disease (cholelithiasis) is a cholesterol-related metabolic disorders with strong familial predisposition. Mitochondrial DNA (mtDNA) variants accumulated during human evolution are associated with some metabolic disorders related to modified mitochondrial function. The mechanistic links between mtDNA variants and gallstone formation need further exploration. METHODS: In this study, we explored the possible associations of mtDNA variants with gallstone disease by comparing 104 probands and 300 controls in a Chinese population. We constructed corresponding cybrids using trans-mitochondrial technology to investigate the underlying mechanisms of these associations. Mitochondrial respiratory chain complex activity and function and cholesterol metabolism were assessed in the trans-mitochondrial cell models. RESULTS: Here, we found a significant association of mtDNA 827A>G with an increased risk of familial gallstone disease in a Chinese population (odds ratio [OR]: 4.5, 95% confidence interval [CI]: 2.1-9.4, P=1.2×10-4). Compared with 827A cybrids (haplogroups B4a and B4c), 827G cybrids (haplogroups B4b and B4d) had impaired mitochondrial respiratory chain complex activity and function and activated JNK and AMPK signaling pathways. Additionally, the 827G cybrids showed disturbances in cholesterol transport and accelerated development of gallstones. Specifically, cholesterol transport through the transporter ABCG5/8 was increased via activation of the AMPK signaling pathway in 827G cybrids. CONCLUSIONS: Our findings reveal that mtDNA 827A>G induces aberrant mitochondrial function and abnormal cholesterol transport, resulting in increased occurrence of gallstones. The results provide an important biological basis for the clinical diagnosis and prevention of gallstone disease in the future.
Subject(s)
Asian People/genetics , DNA, Mitochondrial/genetics , Gallstones/pathology , Genetic Predisposition to Disease , Mitochondria/pathology , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , Case-Control Studies , China/epidemiology , Cholesterol/metabolism , DNA, Mitochondrial/analysis , Female , Gallstones/epidemiology , Gallstones/genetics , Humans , Male , Middle Aged , Mitochondria/genetics , Risk Factors , Young AdultABSTRACT
Background: Thyroid hormone (TH) deficiency has been associated with increased cholesterol gallstone prevalence. Hypothyroidism impacts hepatic lipid homeostasis, biliary secretion, gallbladder motility, and gallstone (LITH) gene expression, all potential factors contributing to cholesterol gallstone disease (CGD). However, how TH deficiency may lead to gallstone formation is still poorly understood. Therefore, we performed molecular studies in a CGD mouse model under lithogenic conditions and modulation of TH status. Methods: Male, three-month-old C57BL/6 mice were randomly divided into a control (euthyroid) group, a hypothyroid (hypo) group, a gallstone (litho) group, and a gallstone+hypothyroid (litho+hypo) group and were treated for 2, 4, and 6 weeks (n = 8/treatment period). Gallstone prevalence, biliary composition and cholesterol crystals, hepatic expression of genes participating in cholesterol, bile acid (BA), and phosphatidylcholine synthesis (Hmgcr, Cyp7a1, Pcyt1a), and canalicular transport (Abcg5, Bsep, Abcb4) were investigated. Results: Increased cholesterol gallstone prevalence was observed in hypothyroid mice under lithogenic diet after 4 and 6 weeks of treatment (4 weeks: 25% vs. 0%; 6 weeks: 75% vs. 37.5%). Interestingly, neither the composition of the three main biliary components, cholesterol, BAs, and phosphatidylcholine, nor the hepatic expression of genes involved in synthesis and transport could explain the differences in cholesterol gallstone formation in the mice. However, TH deficiency resulted in significantly increased hydrophobicity of primary BAs in bile. Furthermore, downregulation of hepatic sulfonation enzymes Papss2 and Sult2a8 as well as diminished biliary BA sulfate concentrations in mice were observed under hypothyroid conditions all contributing to a lithogenic biliary milieu as evidenced by microscopic cholesterol crystals and macroscopic gallstone formation. Conclusions: We describe a novel pathogenic link between TH deficiency and CGD and suggest that the increased hydrophobic character of biliary BAs due to the diminished expression of hepatic detoxification enzymes promotes cholesterol crystal precipitation and enhances cholesterol gallstone formation in the bile of hypothyroid mice.
Subject(s)
Bile Acids and Salts/metabolism , Cholesterol/metabolism , Gallbladder/metabolism , Gallstones/metabolism , Hypothyroidism/metabolism , Liver/metabolism , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 5/metabolism , Animals , Bile Acids and Salts/biosynthesis , Cholelithiasis/genetics , Cholelithiasis/metabolism , Cholelithiasis/pathology , Cholesterol/biosynthesis , Cholesterol 7-alpha-Hydroxylase/genetics , Choline-Phosphate Cytidylyltransferase/genetics , Gallbladder/pathology , Gallstones/genetics , Gallstones/pathology , Hydrophobic and Hydrophilic Interactions , Hydroxymethylglutaryl CoA Reductases/genetics , Hypothyroidism/genetics , Lipoproteins/metabolism , Liver/pathology , Mice , Phosphatidylcholines/biosynthesis , Phosphatidylcholines/metabolism , ATP-Binding Cassette Sub-Family B Member 4ABSTRACT
INTRODUCTION AND OBJECTIVES: The incidence of gallstone-related disease steadily increased in the last few years. Here, we aimed to investigate the effect of tauroursodeoxycholic acid1 (TUDCA) on preventing cholesterol gallstones formation in high-fat fed (HFD) mice. MATERIAL AND METHODS: Specific pathogen-free male C57Bl/6 mice were fed a lithogenic diet2 (LD group) alone or in combination with TUDCA (5g/kg diet) for 8 weeks. Upon sacrifice, serum, gallbladder, liver and small intestine were collected and the formation of gallstones or crystals in the gallbladder was analyzed. Additionally, the intestinal microbiota, and bile acid composition, serum lipids and hepatic lipids were studied. RESULTS: Cholesterol gallstones with cholesterol crystals formed in mice of the LD-fed group (15/15, 100%). However, only cholesterol crystals were found in three mice without the presence of any gallstone in the TUDCA-treated group. Both serum and hepatic total cholesterol levels in the TUDCA group were significantly decreased compared with the LD group. Concomitantly, mRNA expression of Abcg5 and Abcg8 was significantly lower in the liver of the TUDCA group whilst mRNA transcripts for Abcb11, Acat2, and Cyp27 were significantly increased compared with the LD group. Additionally, the gallbladder cholesterol saturation index (1.06±0.15) in the TUDCA group was significantly decreased compared with the LD group. Interestingly, the ratio of Firmicutes/Bacteroides in the TUDCA group was increased 3x fold. CONCLUSIONS: TUDCA can inhibit the absorption and synthesis of lipids in the small intestine by improving the intestinal microbiota in HFD-fed mice, thus reducing gallstone formation.
Subject(s)
Cholagogues and Choleretics/therapeutic use , Gallstones/prevention & control , Gastrointestinal Microbiome/drug effects , Taurochenodeoxycholic Acid/therapeutic use , Animals , Bile Acids and Salts/metabolism , Disease Models, Animal , Gallstones/metabolism , Gallstones/pathology , Lipid Metabolism/drug effects , Liver/metabolism , Male , Mice , Mice, Inbred C57BLSubject(s)
Cholic Acids/blood , Gallbladder/abnormalities , Gallstones/genetics , Organic Anion Transporters, Sodium-Dependent/deficiency , Steroid Metabolism, Inborn Errors/genetics , Symporters/deficiency , Adolescent , Animals , Cholic Acids/metabolism , Disease Models, Animal , Female , Gallbladder/pathology , Gallstones/metabolism , Gallstones/pathology , Humans , Infant , Male , Mice , Mice, Knockout , Organic Anion Transporters, Sodium-Dependent/genetics , Polymorphism, Single Nucleotide , Retrospective Studies , Species Specificity , Steroid Metabolism, Inborn Errors/blood , Steroid Metabolism, Inborn Errors/metabolism , Steroid Metabolism, Inborn Errors/pathology , Symporters/geneticsABSTRACT
BACKGROUND: Endoscopic removal of packed, large, or impacted stones, in which a basket cannot be deployed or is unable to grasp the stone(s), is challenging and inevitably leads to repeated procedures such as stent insertion and extra- or intracorporal lithotripsy. In this study, we describe the results of an alternative stone disintegration technique in a considerable series of patients using an esophageal/pyloric balloon for stone fragmentation or making working space in the bile duct to allow the deployment of the basket, a technique we call endoscopic biliary large balloon lithotripsy. METHODS: We retrieved data from 1,429 endoscopic retrograde cholangiopancreatographies (ERCPs) from 2 prospective trials performed between 2014 and 2019. Patients with difficult bile duct stones, in which a balloon dilator up to 15 mm was used to crush or increase the working space parallel to the stones in the common or hepatic duct, were included in the study. RESULTS: From the 1,429 ERCPs, 299 had difficult stones (>1 cm, impacted or multiple stones). Large balloon lithotripsy was employed in 46 cases after endoscopic papillotomy and endoscopic biliary large balloon dilation with failed attempted balloon or basket stone(s) extraction. Failure to clear the bile duct at first ERCP occurred in 4 cases (91.3% of success). Complications were observed in 5 patients (10.8%; 1 perforation, 1 pancreatitis, and 3 bleedings), who were treated conservatively. CONCLUSIONS: Large balloon lithotripsy, in order to crush the stones or make working room for baskets or balloons in the bile duct, is an effective, safe, and low cost technique for impacted, packed, or giant bile duct stones.
Subject(s)
Catheterization/methods , Cholangiopancreatography, Endoscopic Retrograde/methods , Dilatation/methods , Gallstones/surgery , Lithotripsy/methods , Adult , Aged , Aged, 80 and over , Bile Ducts/surgery , Catheterization/adverse effects , Catheterization/instrumentation , Cholangiopancreatography, Endoscopic Retrograde/adverse effects , Cholangiopancreatography, Endoscopic Retrograde/instrumentation , Dilatation/adverse effects , Dilatation/instrumentation , Female , Gallstones/pathology , Humans , Lithotripsy/adverse effects , Lithotripsy/instrumentation , Male , Middle Aged , Postoperative Cognitive Complications/etiology , Prospective Studies , Treatment Outcome , Young AdultABSTRACT
Gallbladder stones (cholecystolithiasis) are the main risk factor for gallbladder cancer (GBC), a lethal biliary malignancy with poor survival rates worldwide. Gallbladder stones are thought to damage the gallbladder epithelium and trigger chronic inflammation. Preneoplastic lesions that arise in such an inflammatory microenvironment can eventually develop into invasive carcinoma, through mechanisms that are not fully understood. Here, we developed a novel gallbladder preneoplasia mouse model through the administration of two lithogenic diets (a low- or a high-cholesterol diet) in wild-type C57BL/6 mice over a period of 9 months. Additionally, we evaluated the chemopreventive potentials of the anti-inflammatory drug aspirin and the cholesterol absorption inhibitor ezetimibe. Both lithogenic diets induced early formation of gallbladder stones, together with extensive inflammatory changes and widespread induction of metaplasia, an epithelial adaptation to tissue injury. Dysplastic lesions were presented only in mice fed with high-cholesterol diet (62.5%) in late stages (9th month), and no invasive carcinoma was observed at any stage. The cholesterol absorption inhibitor ezetimibe inhibited gallbladder stone formation and completely prevented the onset of metaplasia and dysplasia in both lithogenic diets, whereas aspirin partially reduced metaplasia development only in the low-cholesterol diet setting. This model recapitulates several of the structural and inflammatory findings observed in human cholecystolithiasic gallbladders, making it relevant for the study of gallbladder carcinogenesis. In addition, our results suggest that the use of cholesterol absorption inhibitors and anti-inflammatory drugs can be evaluated as chemopreventive strategies to reduce the burden of GBC among high-risk populations.