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Bozdag A, Yildirim M, Karaduman M, Mutlu HB, Karaduman G, Aksoy A. Detection of Gallbladder Disease Types Using a Feature Engineering-Based Developed CBIR System. Diagnostics (Basel) 2025; 15:552. [PMID: 40075799 PMCID: PMC11899127 DOI: 10.3390/diagnostics15050552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/22/2025] [Accepted: 02/23/2025] [Indexed: 03/14/2025] Open
Abstract
Background/Objectives: Early detection and diagnosis are important when treating gallbladder (GB) diseases. Poorer clinical outcomes and increased patient symptoms may result from any error or delay in diagnosis. Many signs and symptoms, especially those related to GB diseases with similar symptoms, may be unclear. Therefore, highly qualified medical professionals should interpret and understand ultrasound images. Considering that diagnosis via ultrasound imaging can be time- and labor-consuming, it may be challenging to finance and benefit from this service in remote locations. Methods: Today, artificial intelligence (AI) techniques ranging from machine learning (ML) to deep learning (DL), especially in large datasets, can help analysts using Content-Based Image Retrieval (CBIR) systems with the early diagnosis, treatment, and recognition of diseases, and then provide effective methods for a medical diagnosis. Results: The developed model is compared with two different textural and six different Convolutional Neural Network (CNN) models accepted in the literature-the developed model combines features obtained from three different pre-trained architectures for feature extraction. The cosine method was preferred as the similarity measurement metric. Conclusions: Our proposed CBIR model achieved successful results from six other different models. The AP value obtained in the proposed model is 0.94. This value shows that our CBIR-based model can be used to detect GB diseases.
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Affiliation(s)
- Ahmet Bozdag
- Department of General Surgery, School of Medicine, Firat University, Elazığ 23119, Turkey;
| | - Muhammed Yildirim
- Department of Computer Engineering, Malatya Turgut Ozal University, Malatya 44210, Turkey;
| | - Mucahit Karaduman
- Department of Software Engineering, Malatya Turgut Ozal University, Malatya 44210, Turkey;
| | - Hursit Burak Mutlu
- Department of Computer Engineering, Malatya Turgut Ozal University, Malatya 44210, Turkey;
| | - Gulsah Karaduman
- Department of Computer Engineering, Firat University, Elazığ 23119, Turkey
| | - Aziz Aksoy
- Department of Bioengineering, Malatya Turgut Ozal University, Malatya 44200, Turkey;
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Krupa L, Kalinowski P, Ligocka J, Dauer M, Jankowski K, Gozdowska J, Kruk B, Milkiewicz P, Zieniewicz K, Krawczyk M, Weber SN, Lammert F, Krawczyk M. The ABCG8 polymorphism increases the risk of gallbladder cancer in the general population and gallstones in obese patients from Poland. Eur J Clin Invest 2024; 54:e14213. [PMID: 38616505 DOI: 10.1111/eci.14213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/16/2024]
Abstract
BACKGROUND Gallstone disease (GD) is common but remains asymptomatic in most cases. However, gallstones can lead to complications like choledocholithiasis or gallbladder cancer. In this study, we analyse the common genetic risk factor for GD, the p.D19H variant in the sterol transporter ABCG8, in Polish patients with gallstones and gallbladder cancer. METHODS Three adult cohorts were prospectively recruited: 65 patients with gallbladder cancer, 170 obese individuals scheduled for bariatric surgery and 72 patients who underwent endoscopic retrograde cholangiopancreatography due to recurrent choledocholithiasis. The control cohort consisted of 172 gallstone-free adults. The ABCG8 p.D19H (rs11887534) polymorphism was genotyped using TaqMan assays. RESULTS The minor allele frequency (MAF) of the ABCG8 p.D19H polymorphism was significantly (p = .02) higher among cases with either gallstones or gallbladder cancer (MAF = 8.4%) as compared to controls (MAF = 4.0%). The highest frequency of the risk allele was detected in patients with gallbladder cancer (18.5%) and obese patients with GD (17.5%), followed by individuals with choledocholithiasis (13.9%). Notably, the p.19H variant was associated with an increased risk of developing gallbladder cancer (OR 2.76, 95% CI 1.16-6.54, p = .01) and an increased risk of GD in obese individuals scheduled for bariatric surgery (OR = 2.70, 95% CI 1.05-6.49, p = .03), but did not significantly affect the risk of choledocholithiasis. CONCLUSIONS The ABCG8 p.D19H common risk variant increases the risk of developing gallbladder cancer in Central Europeans and enhances the risk of gallstones in the obese. Carriers of the p.D19H variant might benefit from personalized preventive strategies, particularly regarding gallbladder cancer.
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Affiliation(s)
- Lukasz Krupa
- Department of Gastroenterology and Hepatology with Internal Disease Unit, Teaching Hospital No 1 in Rzeszów, Rzeszów, Poland
- Medical Department, University of Rzeszów, Rzeszów, Poland
| | - Piotr Kalinowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Joanna Ligocka
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Marc Dauer
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Krzysztof Jankowski
- Department of Internal Medicine and Cardiology, Medical University of Warsaw, Warsaw, Poland
- Department of Social Medicine and Public Health, Medical University of Warsaw, Warsaw, Poland
| | - Jolanta Gozdowska
- Department of Transplantation Medicine and Nephrology, Medical University of Warsaw, Warsaw, Poland
| | - Beata Kruk
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Milkiewicz
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
- Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Marek Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Susanne N Weber
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | | | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
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Ali M, Usman A, Usman J, Abid M, Najeeb W, Imran M, Fakih N. Significance of family history of cholelithiasis in a Pakistani population: A single center, descriptive cross-sectional study. Medicine (Baltimore) 2024; 103:e38925. [PMID: 38996112 PMCID: PMC11245235 DOI: 10.1097/md.0000000000038925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/21/2024] [Indexed: 07/14/2024] Open
Abstract
Linkage studies have indicated a potential genetic predisposition to cholelithiasis. This study aims to determine the frequency of positive family history of gallstone disease in patients presenting with gallstones in a Pakistani population. A descriptive, cross-sectional study was conducted at the surgical department of the University of Lahore Teaching Hospital from June 30, 2023 to August 30, 2023. A total of 102 radiologically confirmed cholelithiasis patients were enrolled. Out of 102 participants, 75.5% (n = 77) were females, with a mean age at presentation of 42.1 ± 12.1 years. The study found that 32.4% (n = 33) of participants had a single family member with gallstones, 3.9% (n = 4) had 2 family members affected, and 1% (n = 1) had 3 family members affected. The attributable risk of genetics from our study was 37.2%. Additionally, there was no significant association between positive family history and earlier onset of disease. A significant percentage of Pakistani population may have gallstone disease due to genetic factors.
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Affiliation(s)
- Mansab Ali
- Department of General Surgery, The University of Lahore Teaching Hospital, Lahore, Pakistan
| | - Amir Usman
- Department of General Surgery, The University of Lahore Teaching Hospital, Lahore, Pakistan
| | - Javeria Usman
- Department of General Surgery, The University of Lahore Teaching Hospital, Lahore, Pakistan
| | - Muhammad Abid
- Department of General Surgery, The University of Lahore Teaching Hospital, Lahore, Pakistan
| | - Wafa Najeeb
- Department of Gynecology and Obstetrics, The University of Lahore Teaching Hospital, Lahore, Pakistan
| | - Muhammad Imran
- Faculty of Medicine, University College of Medicine and Dentistry, The University of Lahore, Lahore, Pakistan
| | - Nour Fakih
- Department of Natural Sciences, Lebanese American University, Beirut, Lebanon
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Liu Z, Liu S, Song P, Jiao Y. Mendelian randomization study on the causal relationship between food and cholelithiasis. Front Nutr 2024; 11:1276497. [PMID: 38501068 PMCID: PMC10944874 DOI: 10.3389/fnut.2024.1276497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 02/21/2024] [Indexed: 03/20/2024] Open
Abstract
Background Cholelithiasis, commonly referred to as gallstones, is a prevalent medical condition influenced by a combination of genetic factors, lifestyle choices, and dietary habits. Specific food items have been associated with an increased susceptibility to cholelithiasis, whereas others seem to offer a protective effect against its development. Methods In this study, we conducted a Mendelian randomization (MR) analysis using a large-scale genetic dataset comprising individuals with European ancestry to explore the potential causal relationship between diet and cholelithiasis. The analysis incorporated 17 food-related variables, which were considered as potential factors influencing the occurrence of this condition. Results Our findings indicate that a higher consumption of cooked vegetables, dried fruit, and oily fish is associated with a reduced risk of cholelithiasis. Conversely, a higher consumption of lamb is associated with an increased risk of developing the condition. Importantly, these associations proved robust to sensitivity and heterogeneity tests, and the pleiotropic test results further supported the hypothesis of a causal relationship between diet and cholelithiasis. Conclusion Through our study, we provide compelling evidence for the existence of a causal relationship between diet and cholelithiasis. Adopting a dietary pattern enriched with cooked vegetables, dried fruit, and oily fish, while minimizing lamb intake, may contribute to the prevention of cholelithiasis. Recognizing diet as a modifiable risk factor in the prevention and management of this condition is of paramount importance, and our study offers valuable insights in this regard.
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Affiliation(s)
- Zhicheng Liu
- Department of Gastric and Intestinal, General Surgery Center, First Hospital of Jilin University, Changchun, China
| | - Shun Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, China
| | - Peizhe Song
- Department of Gastric and Intestinal, General Surgery Center, First Hospital of Jilin University, Changchun, China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, China
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Su Y, Lin S, Chen Y. Causal effects from nonalcoholic fatty liver disease on cholelithiasis: A mendelian randomization study. Health Sci Rep 2024; 7:e1987. [PMID: 38505680 PMCID: PMC10948589 DOI: 10.1002/hsr2.1987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 02/18/2024] [Accepted: 03/03/2024] [Indexed: 03/21/2024] Open
Abstract
Background and Aims Both nonalcoholic fatty liver disease (NAFLD) and cholelithiasis are highly prevalent hepatobiliary diseases with risk of progression into severe outcomes. Considering the close relationship between liver and gallbladder in anatomy and physiology, a potential causal relationship between NAFLD and cholelithiasis has been speculated. Methods Mendelian randomization (MR) was employed using genome-wide association study (GWAS) summary statistics in Million Veteran Program (MVP) for NAFLD, and statistics in UK biobank for cholelithiasis. Results Our results demonstrate that NAFLD has a causal effect on cholelithiasis risk (OR, 1.003; 95%CI, 1.000-1.006; p = 0.03). We also performed the sensitivity analysis and heterogeneity test to ensure the accuracy of outcome and avoid the reverse causality. Conclusion NAFLD should be regarded as a potential pathogenic factor in pathogenesis study of cholelithiasis, and be considered in assessment and treatment of cholelithiasis.
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Affiliation(s)
- Yin‐Shi Su
- Department of GastroenterologyHuadong Hospital Affiliated to Fudan UniversityShanghaiChina
| | - Shuang‐Zhe Lin
- Department of GastroenterologyXin Hua Hospital affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yuan‐Wen Chen
- Department of GastroenterologyHuadong Hospital Affiliated to Fudan UniversityShanghaiChina
- Department of GerontologyHuadong Hospital Affiliated to Fudan UniversityShanghaiChina
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Alzain AA, Mukhtar RM. Application of computational approaches for the drug discovery of cholesterol gallstone disease: identification of new farnesoid X receptor modulators as a case study. GALLSTONE FORMATION, DIAGNOSIS, TREATMENT AND PREVENTION 2024:223-243. [DOI: 10.1016/b978-0-443-16098-1.00003-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Zhang L, Zhang W, He L, Cui H, Wang Y, Wu X, Zhao X, Yan P, Yang C, Xiao C, Tang M, Chen L, Xiao C, Zou Y, Liu Y, Yang Y, Zhang L, Yao Y, Li J, Liu Z, Yang C, Jiang X, Zhang B. Impact of gallstone disease on the risk of stroke and coronary artery disease: evidence from prospective observational studies and genetic analyses. BMC Med 2023; 21:353. [PMID: 37705021 PMCID: PMC10500913 DOI: 10.1186/s12916-023-03072-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 09/06/2023] [Indexed: 09/15/2023] Open
Abstract
BACKGROUND Despite epidemiological evidence associating gallstone disease (GSD) with cardiovascular disease (CVD), a dilemma remains on the role of cholecystectomy in modifying the risk of CVD. We aimed to characterize the phenotypic and genetic relationships between GSD and two CVD events - stroke and coronary artery disease (CAD). METHODS We first performed a meta-analysis of cohort studies to quantify an overall phenotypic association between GSD and CVD. We then investigated the genetic relationship leveraging the largest genome-wide genetic summary statistics. We finally examined the phenotypic association using the comprehensive data from UK Biobank (UKB). RESULTS An overall significant effect of GSD on CVD was found in meta-analysis (relative risk [RR] = 1.26, 95% confidence interval [CI] = 1.19-1.34). Genetically, a positive shared genetic basis was observed for GSD with stroke ([Formula: see text]=0.16, P = 6.00 × 10-4) and CAD ([Formula: see text]=0.27, P = 2.27 × 10-15), corroborated by local signals. The shared genetic architecture was largely explained by the multiple pleiotropic loci identified in cross-phenotype association study and the shared gene-tissue pairs detected by transcriptome-wide association study, but not a causal relationship (GSD to CVD) examined through Mendelian randomization (MR) (GSD-stroke: odds ratio [OR] = 1.00, 95%CI = 0.97-1.03; GSD-CAD: OR = 1.01, 95%CI = 0.98-1.04). After a careful adjustment of confounders or considering lag time using UKB data, no significant phenotypic effect of GSD on CVD was detected (GSD-stroke: hazard ratio [HR] = 0.95, 95%CI = 0.83-1.09; GSD-CAD: HR = 0.98, 95%CI = 0.91-1.06), further supporting MR findings. CONCLUSIONS Our work demonstrates a phenotypic and genetic relationship between GSD and CVD, highlighting a shared biological mechanism rather than a direct causal effect. These findings may provide insight into clinical and public health applications.
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Affiliation(s)
- Li Zhang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Wenqiang Zhang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Lin He
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Huijie Cui
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Yutong Wang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Xueyao Wu
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Xunying Zhao
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Peijing Yan
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Chao Yang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Changfeng Xiao
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Mingshuang Tang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Lin Chen
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Chenghan Xiao
- Department of Maternal, Child and Adolescent Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Yanqiu Zou
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Yunjie Liu
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Yanfang Yang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Ling Zhang
- Department of Iatrical Polymer Material and Artificial Apparatus, School of Polymer Science and Engineering, Sichuan University, Chengdu, China
| | - Yuqin Yao
- Department of Occupational and Environmental Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Jiayuan Li
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Zhenmi Liu
- Department of Maternal, Child and Adolescent Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Chunxia Yang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China
| | - Xia Jiang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China.
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
| | - Ben Zhang
- Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, and West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 16, Section 3, South Renmin Road, Wuhou District, Chengdu, 610041, China.
- Department of Occupational and Environmental Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
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Xia Y, Xu Y, Liu Q, Zhang J, Zhang Z, Jia Q, Tang Q, Jing X, Li J, Chen J, Xiong Y, Li Y, He J. Glutaredoxin 1 regulates cholesterol metabolism and gallstone formation by influencing protein S-glutathionylation. Metabolism 2023:155610. [PMID: 37277061 DOI: 10.1016/j.metabol.2023.155610] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/23/2023] [Accepted: 05/30/2023] [Indexed: 06/07/2023]
Abstract
OBJECTIVE Cholesterol gallstone disease (CGD) is closely related to cholesterol metabolic disorder. Glutaredoxin-1 (Glrx1) and Glrx1-related protein S-glutathionylation are increasingly being observed to drive various physiological and pathological processes, especially in metabolic diseases such as diabetes, obesity and fatty liver. However, Glrx1 has been minimally explored in cholesterol metabolism and gallstone disease. METHODS We first investigated whether Glrx1 plays a role in gallstone formation in lithogenic diet-fed mice using immunoblotting and quantitative real-time PCR. Then a whole-body Glrx1-deficient (Glrx1-/-) mice and hepatic-specific Glrx1-overexpressing (AAV8-TBG-Glrx1) mice were generated, in which we analyzed the effects of Glrx1 on lipid metabolism upon LGD feeding. Quantitative proteomic analysis and immunoprecipitation (IP) of glutathionylated proteins were performed. RESULTS We found that protein S-glutathionylation was markedly decreased and the deglutathionylating enzyme Glrx1 was greatly increased in the liver of lithogenic diet-fed mice. Glrx1-/- mice were protected from gallstone disease induced by a lithogenic diet because their biliary cholesterol and cholesterol saturation index (CSI) were reduced. Conversely, AAV8-TBG-Glrx1 mice showed greater gallstone progression with increased cholesterol secretion and CSI. Further studies showed that Glrx1-overexpressing greatly induced bile acid levels and/or composition to increase intestinal cholesterol absorption by upregulating Cyp8b1. In addition, liquid chromatography-mass spectrometry and IP analysis revealed that Glrx1 also affected the function of asialoglycoprotein receptor 1 (ASGR1) by mediating its deglutathionylation, thereby altering the expression of LXRα and controlling cholesterol secretion. CONCLUSION Our findings present novel roles of Glrx1 and Glrx1-regulated protein S-glutathionylation in gallstone formation through the targeting of cholesterol metabolism. Our data advises Glrx1 significantly increased gallstone formation by simultaneously increase bile-acid-dependent cholesterol absorption and ASGR1- LXRα-dependent cholesterol efflux. Our work suggests the potential effects of inhibiting Glrx1 activity to treat cholelithiasis.
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Affiliation(s)
- Yan Xia
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Ying Xu
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qinhui Liu
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jinhang Zhang
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zijing Zhang
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qingyi Jia
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qin Tang
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiandan Jing
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiahui Li
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiahao Chen
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yimin Xiong
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yanping Li
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Jinhan He
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Chang Y, Lin HM, Chi KY, Lin WY, Chou TC. Association between statin use and risk of gallstone disease and cholecystectomy: a meta-analysis of 590,086 patients. PeerJ 2023; 11:e15149. [PMID: 37051411 PMCID: PMC10084820 DOI: 10.7717/peerj.15149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 03/09/2023] [Indexed: 04/14/2023] Open
Abstract
Background Statins have been reported to reduce the risk of gallstone disease. However, the impacts of different durations of statin use on gallstone disease have not been clarified. The aim of this study is toperform a systematic review with meta-analysis to update and to elucidate the association between statin use and the risk of gallstone disease and cholecystectomy. Methods Medline, Embase and Cochrane Library were searched from the inception until August 2022 for relevant articles investigating the difference in the risk of gallstone disease between statin users and non-users (PROSPERO, ID: CRD42020182445). Meta-analyses were conducted using odds ratios (ORs) with corresponding 95% confidence intervals (CIs) to compare the risk of gallstone disease and cholecystectomy between statin user and nonusers. Results Eight studies enrolling 590,086 patients were included. Overall, the use of statins was associated with a marginally significant lower risk of gallstone disease than nonusers (OR, 0.91; 95% CI [0.82-1.00]). Further subgroup analysis showed that short-term users, medium-term users, and long-term users were associated with a significantly higher risk (OR, 1.18; 95% CI [1.11-1.25]), comparable risk (OR, 0.93; 95% CI [0.83-1.04]), and significantly lower risk of gallstone diseases (OR, 0.78; 95% CI [0.68-0.90]) respectively, compared to nonusers. Conclusions Patients with medium-term or long-term use of statins without discontinuation are at a lower risk of gallstone disease or cholecystectomy.
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Affiliation(s)
- Yu Chang
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hong-Min Lin
- Department of Family Medicine, Chi-Mei Medical Center, Tainan, Taiwan
| | - Kuan-Yu Chi
- Department of Education, Center for Evidence-Based Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Wan-Ying Lin
- Department of Family Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Tsung-Ching Chou
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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10
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MacCormick A, Jenkins P, Gafoor N, Chan D. Percutaneous transcystic removal of gallbladder and common bile duct stones: a narrative review. Acta Radiol 2022; 63:571-576. [PMID: 33845612 DOI: 10.1177/02841851211006915] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The incidence of gallstone-related complications is rising, thus leading to increases in waiting list times for elective laparoscopic cholecystectomy (LC). Percutaneous cholecystostomy (PC) provides immediate biliary drainage and may be used as an emergency option in a critically unwell patient as a bridge to surgery, or as the management option of a patient who is not fit for surgery. However, a significant number of these patients may be readmitted after PC with recurrent acute cholecystitis or pancreatitis, leading to significant morbidity and mortality. The aim of the present review was to analyze the available literature surrounding the use of the transcystic approach, including the extraction and balloon expulsion method, in the management of patients with gallbladder stones and/or common bile duct (CBD) stones. The full text of 18 articles were reviewed, of which four were included in this review. Results showed an overall success rate of CBD stone extraction in 118 of 139 patients (84.9%), gallbladder stone extraction in 97 of 114 (85.0%), and CBD stone expulsion in 27 of 29 (93.1%). Percutaneous CBD and gallbladder stone extraction may be a safe management option for elderly or co-morbid patients who are not appropriate for surgical intervention. However, the evidence base surrounding this is very limited; therefore, further research is required in order to evaluate this in more detail.
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Affiliation(s)
- Andrew MacCormick
- Department of Interventional Radiology, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Paul Jenkins
- Department of Interventional Radiology, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Nelofer Gafoor
- Department of Interventional Radiology, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - David Chan
- Department of Upper GI Surgery, University Hospitals Plymouth NHS Trust, Plymouth, UK
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11
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Nogoy DM, Padmanaban V, Balazero LL, Rosado J, Sifri ZC. Predictors of Difficult Laparoscopic Cholecystectomy on Humanitarian Missions to Peru Difficult LC in Surgical Missions. J Surg Res 2021; 267:102-108. [PMID: 34157489 DOI: 10.1016/j.jss.2021.04.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 04/07/2021] [Accepted: 04/10/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Laparoscopic cholecystectomy (LC) is the gold standard treatment of gallstone disease. On short-term surgical missions (STSMs), it is unclear what factors can predict safety of LC. This study evaluates patient risk factors of difficult LC in Northern Peru, towards optimizing outcomes. MATERIALS AND METHODS A retrospective review was performed of patients who underwent LC during short-term surgical missions to Peru from 2016-2019 under the International Surgical Health Initiative (ISHI). Difficult and routine LC groups were compared for: age, weight, gender, symptom duration, pain on presentation, history of abdominal or pelvic surgery, diabetes and hypertension. RESULTS 68 of 194 patients underwent LC; 42 patients (62%) were classified as difficult with OR (operating room) time > 70 min (90%), 2 cases converted to open (5%) and 2 aborted cases (5%). Higher weight class was found to correlate with difficult LC. CONCLUSION Increased patient weight was correlated to longer operative time during STSMs. Patients undergoing LC must be selected carefully to mitigate risks of difficult operations on STSMs.
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Affiliation(s)
- Danielle M Nogoy
- Department of Surgery, Rutgers New Jersey Medical School, Newark, New Jersey.
| | - Vennila Padmanaban
- Department of Surgery, Rutgers New Jersey Medical School, Newark, New Jersey
| | | | - Jesus Rosado
- Department of Surgery, Rutgers New Jersey Medical School, Newark, New Jersey
| | - Ziad C Sifri
- Department of Surgery, Rutgers New Jersey Medical School, Newark, New Jersey
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12
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Fan N, Meng K, Zhang Y, Hu Y, Li D, Gao Q, Wang J, Li Y, Wu S, Cui Y. The effect of ursodeoxycholic acid on the relative expression of the lipid metabolism genes in mouse cholesterol gallstone models. Lipids Health Dis 2020; 19:158. [PMID: 32615989 PMCID: PMC7333299 DOI: 10.1186/s12944-020-01334-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 06/23/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Many studies indicate that gallstone formation has genetic components. The abnormal expression of lipid-related genes could be the basis for particular forms of cholesterol gallstone disease. The aim of this study was to obtain insight into lipid metabolism disorder during cholesterol gallstone formation and to evaluate the effect of ursodeoxycholic acid (UDCA) on the improvement of bile lithogenicity and its potential influence on the transcription of lipid-related genes. METHODS Gallstone-susceptible mouse models were induced by feeding with a lithogenic diet (LD) for 8 weeks. Bile and liver tissues were obtained from these mouse models after 0, 4 and 8 weeks. Bile lipids were measured enzymatically, and the cholesterol saturation index (CSI) was calculated to evaluate the bile lithogenicity by using Carey's critical tables. Real-time polymerase chain reaction (RT-PCR) was used to detect the mRNA expression levels of farnesoid X receptor (FXR), liver X receptor (LXR), adenosine triphosphate-binding cassette subfamily G member 5/8 (ABCG5/8), cholesterol 7-α hydroxylase (CYP7A1), oxysterol 7-α hydroxylase (CYP7B1), sterol 27-α hydroxylase (CYP27A1), peroxisome proliferator-activated receptor alpha (PPAR-α) and adenosine triphosphate-binding cassette subfamily B member 11 (ABCB11). RESULTS The rate of gallstone formation was 100% in the 4-week group but only 30% in the UDCA-treated group. The UDCA-treated group had a significantly lower CSI compared with other groups. Of special note, the data on the effects of UDCA showed higher expression levels of ABCG8, ABCB11 and CYP27A1, as well as lower expression levels of LXR and PPAR-α, compared to the model control group. CONCLUSIONS UDCA exhibits tremendously potent activity in restraining lipid accumulation, thus reversing the lithogenic effect and protecting hepatocytes from serious pathological damage. The abnormal expression of ABCG8, CYP7A1, CYP27A1, LXR and PPAR-α might lead to high lithogenicity of bile. These results are helpful in exploring new lipid metabolism pathways and potential targets for the treatment of cholesterol stones and for providing some basis for the study of the pathogenesis and genetic characteristics of cholelithiasis. Research on the mechanism of UDCA in improving lipid metabolism and bile lithogenicity may be helpful for clinical treatment and for reducing the incidence of gallstones.
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Affiliation(s)
- Ning Fan
- Beichen Chinese Medicine Hospital Affiliated to Tianjin University of Traditional Chinese Medicine, 436 Jingjin Road, Beichen District, Tianjin, 300400, China
| | - Ke Meng
- Department of Obstetrics and Gynecology, General Hospital of Tianjin Medical University, 154 AnShan Road, HePing District, Tianjin, 300052, China
| | - Yuqing Zhang
- Department of Surgery, Tianjin Nankai Hospital, Nankai Clinical School of Medicine, Tianjin Medical University, 122 Sanwei Road Nankai District, Tianjin, 300100, China
| | - Yong Hu
- Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China
| | - Donghua Li
- Institute of Acute Abdomen in Integrative Medicine, Tianjin Nankai Hospital, Nankai Clinical School of Medicine, Tianjin Medical University, 122 Sanwei Road Nankai District, Tianjin, 300100, China
| | - Qiaoying Gao
- Institute of Acute Abdomen in Integrative Medicine, Tianjin Nankai Hospital, Nankai Clinical School of Medicine, Tianjin Medical University, 122 Sanwei Road Nankai District, Tianjin, 300100, China
| | - Jianhua Wang
- Beichen Chinese Medicine Hospital Affiliated to Tianjin University of Traditional Chinese Medicine, 436 Jingjin Road, Beichen District, Tianjin, 300400, China
| | - Yanning Li
- Beichen Chinese Medicine Hospital Affiliated to Tianjin University of Traditional Chinese Medicine, 436 Jingjin Road, Beichen District, Tianjin, 300400, China
| | - Shangwei Wu
- Institute of Acute Abdomen in Integrative Medicine, Tianjin Nankai Hospital, Nankai Clinical School of Medicine, Tianjin Medical University, 122 Sanwei Road Nankai District, Tianjin, 300100, China
| | - Yunfeng Cui
- Department of Surgery, Tianjin Nankai Hospital, Nankai Clinical School of Medicine, Tianjin Medical University, 122 Sanwei Road Nankai District, Tianjin, 300100, China.
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13
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Transcriptomic profiles reveal differences in zinc metabolism, inflammation, and tight junction proteins in duodenum from cholesterol gallstone subjects. Sci Rep 2020; 10:7448. [PMID: 32366946 PMCID: PMC7198580 DOI: 10.1038/s41598-020-64137-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 04/13/2020] [Indexed: 02/08/2023] Open
Abstract
Cholesterol Gallstone Disease (GSD) is a common multifactorial disorder characterized by crystallization and aggregation of biliary cholesterol in the gallbladder. The global prevalence of GSD is ~10–20% in the adult population but rises to 28% in Chile (17% among men and 30% among women). The small intestine may play a role in GSD pathogenesis, but the molecular mechanisms have not been clarified. Our aim was to identify the role of the small intestine in GSD pathogenesis. Duodenal biopsy samples were obtained from patients with GSD and healthy volunteers. GSD status was defined by abdominal ultrasonography. We performed a transcriptome study in a discovery cohort using Illumina HiSeq. 2500, and qPCR, immunohistochemistry and immunofluorescence were used to validate differentially expressed genes among additional case-control cohorts. 548 differentially expressed genes between GSD and control subjects were identified. Enriched biological processes related to cellular response to zinc, and immune and antimicrobial responses were observed in GSD patients. We validated lower transcript levels of metallothionein, NPC1L1 and tight junction genes and higher transcript levels of genes involved in immune and antimicrobial pathways in GSD patients. Interestingly, serum zinc and phytosterol to cholesterol precursor ratios were lower in GSD patients. A significant association was observed between serum zinc and phytosterol levels. Our results support a model where proximal small intestine plays a key role in GSD pathogenesis. Zinc supplementation, modulation of proximal microbiota and/or intestinal barrier may be novel targets for strategies to prevent GSD.
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14
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Feng X, Zhu C, Lee S, Gao J, Zhu P, Yamauchi J, Pan C, Singh S, Qu S, Miller R, Monga SP, Peng Y, Dong HH. Depletion of hepatic forkhead box O1 does not affect cholelithiasis in male and female mice. J Biol Chem 2020; 295:7003-7017. [PMID: 32273342 DOI: 10.1074/jbc.ra119.012272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 04/07/2020] [Indexed: 11/06/2022] Open
Abstract
Cholelithiasis is one of the most prevalent gastroenterological diseases and is characterized by the formation of gallstones in the gallbladder. Both clinical and preclinical data indicate that obesity, along with comorbidity insulin resistance, is a predisposing factor for cholelithiasis. Forkhead box O1 (FoxO1) is a key transcription factor that integrates insulin signaling with hepatic metabolism and becomes deregulated in the insulin-resistant liver, contributing to dyslipidemia in obesity. To gain mechanistic insights into how insulin resistance is linked to cholelithiasis, here we determined FoxO1's role in bile acid homeostasis and its contribution to cholelithiasis. We hypothesized that hepatic FoxO1 deregulation links insulin resistance to impaired bile acid metabolism and cholelithiasis. To address this hypothesis, we used the FoxO1LoxP/LoxP-Albumin-Cre system to generate liver-specific FoxO1-knockout mice. FoxO1-knockout mice and age- and sex-matched WT littermates were fed a lithogenic diet, and bile acid metabolism and gallstone formation were assessed in these animals. We showed that FoxO1 affected bile acid homeostasis by regulating hepatic expression of key enzymes in bile acid synthesis and in biliary cholesterol and phospholipid secretion. Furthermore, FoxO1 inhibited hepatic expression of the bile acid receptor farnesoid X receptor and thereby counteracted hepatic farnesoid X receptor signaling. Nonetheless, hepatic FoxO1 depletion neither affected the onset of gallstone disease nor impacted the disease progression, as FoxO1-knockout and control mice of both sexes had similar gallstone weights and incidence rates. These results argue against the notion that FoxO1 is a link between insulin resistance and cholelithiasis.
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Affiliation(s)
- Xiaoyun Feng
- Division of Endocrinology and Diabetes, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.,Department of Endocrinology & Metabolism, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China
| | - Cuiling Zhu
- Division of Endocrinology and Diabetes, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.,Department of Endocrinology & Metabolism, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Sojin Lee
- Division of Endocrinology and Diabetes, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Jingyang Gao
- Division of Endocrinology and Diabetes, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.,Department of Endocrinology & Metabolism, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Ping Zhu
- Division of Endocrinology and Diabetes, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.,Department of Endocrinology and Metabolism, Guangzhou Red Cross Hospital, Medical College of Jinan University, Guangzhou 510220, China
| | - Jun Yamauchi
- Division of Endocrinology and Diabetes, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Chenglin Pan
- Division of Endocrinology and Diabetes, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.,Department of Pediatrics, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Sucha Singh
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.,Pittsburgh Liver Research Center, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Shen Qu
- Department of Endocrinology & Metabolism, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Rita Miller
- Division of Endocrinology and Diabetes, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.,Pittsburgh Liver Research Center, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Yongde Peng
- Department of Endocrinology & Metabolism, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China
| | - H Henry Dong
- Division of Endocrinology and Diabetes, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224 .,Pittsburgh Liver Research Center, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
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15
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Kuan LL, Oyebola T, Mavilakandy A, Dennison AR, Garcea G. Retrospective Analysis of Outcomes Following Percutaneous Cholecystostomy for Acute Cholecystitis. World J Surg 2020; 44:2557-2561. [DOI: 10.1007/s00268-020-05491-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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16
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Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry. Sci Rep 2019; 9:772. [PMID: 30692554 PMCID: PMC6349870 DOI: 10.1038/s41598-018-35852-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 10/28/2018] [Indexed: 01/12/2023] Open
Abstract
Latin Americans and Chilean Amerindians have the highest prevalence of gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however, they only explain a small portion of the genetic component of the disease. Here, we performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Chilean Latinos with Mapuche Native American ancestry. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Top-10 candidate variants surpassing the suggestive cutoff of P < 1 × 10−5 in the discovery cohort were genotyped in an independent replication sample composed of 1,643 individuals. Variants with positive replication were further examined in two European GSD populations and a Chilean GBC cohort. We consistently replicated the association of ABCG8 gene with GSD (rs11887534, P = 3.24 × 10−8, OR = 1.74) and identified TRAF3 (rs12882491, P = 1.11 × 10−7, OR = 1.40) as a novel candidate gene for the disease in admixed Chilean Latinos. ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 was significantly decreased in gallbladder (P = 0.015) and duodenal mucosa (P = 0.001) of GSD individuals compared to healthy controls, where according to GTEx data in the small intestine, the presence of the risk allele contributes to the observed effect. We conclude that ABCG8 and TRAF3 genes are associated with GSD and GBC in admixed Latinos and that decreased TRAF3 levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.
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17
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Di Ciaula A, Garruti G, Frühbeck G, De Angelis M, de Bari O, Wang DQH, Lammert F, Portincasa P. The Role of Diet in the Pathogenesis of Cholesterol Gallstones. Curr Med Chem 2019; 26:3620-3638. [PMID: 28554328 PMCID: PMC8118138 DOI: 10.2174/0929867324666170530080636] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 03/03/2017] [Accepted: 03/16/2017] [Indexed: 02/06/2023]
Abstract
Cholesterol gallstone disease is a major health problem in Westernized countries and depends on a complex interplay between genetic factors, lifestyle and diet, acting on specific pathogenic mechanisms. Overweigh, obesity, dyslipidemia, insulin resistance and altered cholesterol homeostasis have been linked to increased gallstone occurrence, and several studies point to a number of specific nutrients as risk- or protective factors with respect to gallstone formation in humans. There is a rising interest in the identification of common and modifiable dietetic factors that put the patients at risk of gallstones or that are able to prevent gallstone formation and growth. In particular, dietary models characterized by increased energy intake with highly refined sugars and sweet foods, high fructose intake, low fiber contents, high fat, consumption of fast food and low vitamin C intake increase the risk of gallstone formation. On the other hand, high intake of monounsaturated fats and fiber, olive oil and fish (ω-3 fatty acids) consumption, vegetable protein intake, fruit, coffee, moderate alcohol consumption and vitamin C supplementation exert a protective role. The effect of some confounding factors (e.g., physical activity) cannot be ruled out, but general recommendations about the multiple beneficial effects of diet on cholesterol gallstones must be kept in mind, in particular in groups at high risk of gallstone formation.
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Affiliation(s)
| | - Gabriella Garruti
- Department of Emergency and Organ Transplants, Section of Endocrinology, Andrology and Metabolic Diseases, University of Bari Medical School, Bari, Italy
| | - Gema Frühbeck
- Dept Endocrinology and Nutrition, University of Navarra Medical School, Pamplona, Spain
| | - Maria De Angelis
- Department of Soil, Plant and Food Science, Department of Biomedical Sciences and Human Oncology
| | - Ornella de Bari
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology
| | - David Q.-H. Wang
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
| | - Frank Lammert
- Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg, Germany
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology
- Address correspondence to this author at the University of Bari Medical School, Clinica Medica “A. Murri”; Department of Biosciences and Human Oncology (DIMO), Policlinico Hospital - 70124 Bari, Italy; Tel: +39-080-5478227; Fax: +39-080-5478232;
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18
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Wang HH, Portincasa P, Liu M, Tso P, Wang DQH. Similarities and differences between biliary sludge and microlithiasis: Their clinical and pathophysiological significances. LIVER RESEARCH 2018; 2:186-199. [PMID: 34367716 PMCID: PMC8341470 DOI: 10.1016/j.livres.2018.10.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The terms biliary sludge and cholesterol microlithiasis (hereafter referred to as microlithiasis) were originated from different diagnostic techniques and may represent different stages of cholesterol gallstone disease. Although the pathogenesis of biliary sludge and microlithiasis may be similar, microlithiasis could be preceded by biliary sludge, followed by persistent precipitation and aggregation of solid cholesterol crystals, and eventually, gallstone formation. Many clinical conditions are clearly associated with the formation of biliary sludge and microlithiasis, including total parenteral nutrition, rapid weight loss, pregnancy, organ transplantation, administration of certain medications, and a variety of acute and chronic illnesses. Numerous studies have demonstrated complete resolution of biliary sludge in approximately 40% of patients, a cyclic pattern of disappearing and reappearing in about 40%, and progression to gallstones in nearly 20%. Although only a minority of patients with ultrasonographic demonstration of biliary sludge develop gallstones, it is still a matter of controversy whether microlithiasis could eventually evolve to cholesterol gallstones. Biliary sludge and microlithiasis are asymptomatic in the vast majority of patients; however, they can cause biliary colic, acute cholecystitis, and acute pancreatitis. Biliary sludge and microlithiasis are most often diagnosed ultrasonographically and bile microscopy is considered the gold standard for their diagnosis. Specific measures to prevent the development of biliary sludge are not practical or cost-effective in the general population. Laparoscopic cholecystectomy offers the most definitive therapy on biliary sludge. Endoscopic sphincterotomy or surgical intervention is effective for microlithiasis-induced pancreatitis. Ursodeoxycholic acid can effectively prevent the recurrence of solid cholesterol crystals and significantly reduce the risk of recurrent pancreatitis.
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Affiliation(s)
- Helen H. Wang
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica “A. Murri”, University of Bari “Aldo Moro” Medical School, Bari, Italy
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - David Q.-H. Wang
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA,Corresponding author. Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA., (D.Q.-H. Wang)
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19
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Abstract
Gallstone disease is caused by multiple pathogenic factors and is common worldwide. Most studies have focused on the significance of the biliary microbiome in gallstone pathogenesis. Areas covered: In this study, the epidemiology of gallstone diseases and the existence, composition, origin, and mechanisms of the biliary microbiota were reviewed. Mechanisms involved in promoting the formation of different types of gallstones were also emphasized. The antibiotic susceptibility of the biliary microbiota is briefly discussed because it may guide clinical strategies. Expert commentary: The biliary microbiome facilitates the formation of brown pigment stones. Although glycoprotein (mucin) may be pivotal for many promoting substances to coagulate and integrate relevant components, new mechanisms involving prostaglandins, oxysterols, oxygen free radicals, and lipopolysaccharides have been discovered. Furthermore, specific bacterial species such as Helicobacter and Salmonella are involved in the pathogenesis of cholesterol gallstones. Recently, metabolomics of the biliary microbiome has been used to determine the detailed mechanisms that promote gallstone formation. Previously, the bacterial effects involved in the pathogenesis of brown pigment stones have not been analyzed in detail. Whether the administration of antibiotics is related to prophylaxis for gallstone formation and gallstone-associated infections remains unclear.
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Affiliation(s)
- Yining Wang
- a Department of Gastroenterology , The First Affiliated Hospital of Nanchang University , Nanchang, Jiangxi , China.,b Joint Programme of Nanchang University and Queen Mary University of London , Nanchang , China
| | - Miao Qi
- a Department of Gastroenterology , The First Affiliated Hospital of Nanchang University , Nanchang, Jiangxi , China.,b Joint Programme of Nanchang University and Queen Mary University of London , Nanchang , China
| | - Cheng Qin
- a Department of Gastroenterology , The First Affiliated Hospital of Nanchang University , Nanchang, Jiangxi , China.,b Joint Programme of Nanchang University and Queen Mary University of London , Nanchang , China
| | - Junbo Hong
- a Department of Gastroenterology , The First Affiliated Hospital of Nanchang University , Nanchang, Jiangxi , China
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20
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Chang HY, Wang CJ, Liu B, Wang YZ, Wang WJ, Wang W, Li D, Li YL. Ursodeoxycholic acid combined with percutaneous transhepatic balloon dilation for management of gallstones after elimination of common bile duct stones. World J Gastroenterol 2018; 24:4489-4498. [PMID: 30356997 PMCID: PMC6196333 DOI: 10.3748/wjg.v24.i39.4489] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 08/29/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effectiveness and safety of combined ursodeoxycholic acid and percutaneous transhepatic balloon dilation for management of gallstones after expulsion of common bile duct (CBD) stones.
METHODS From April 2014 to May 2016, 15 consecutive patients (6 men and 9 women) aged 45-86 (mean, 69.07 ± 9.91) years suffering from CBD stones associated with gallstones were evaluated. Good gallbladder contraction function was confirmed by type B ultrasonography. Dilation of the CBD and cystic duct was detected. Percutaneous transhepatic balloon dilation of the papilla was performed, ursodeoxycholic acid was administered, and all patients had a high-fat diet. All subjects underwent repeated cholangiography, and percutaneous transhepatic removal was carried out in patients with secondary CBD stones originating from the gallbladder.
RESULTS All patients underwent percutaneous transhepatic balloon dilation with a primary success rate of 100%. The combined therapy was successful in 86.7% of patients with concomitant CBD stones and gallstones. No remaining stones were detected in the gallbladder. Transient adverse events include abdominal pain (n = 1), abdominal distension (n = 1), and fever (n = 1). Complications were treated successfully via nonsurgical management without long-term complications. No procedure-related mortality occurred.
CONCLUSION For patients with concomitant CBD stones and gallstones, after percutaneous transhepatic removal of primary CBD stones, oral ursodeoxycholic acid and a high-fat diet followed by percutaneous transhepatic removal of secondary CBD stones appear to be a feasible and effective option for management of gallstones.
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Affiliation(s)
- Hai-Yang Chang
- Department of Intervention Medicine, the Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Interventional Oncology Institute, Shandong University, Jinan 250033, Shandong Province, China
| | - Chang-Jun Wang
- Department of Radiology, Jiyang People’s Hospital, Jinan 251400, Shandong Province, China
| | - Bin Liu
- Department of Intervention Medicine, the Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Interventional Oncology Institute, Shandong University, Jinan 250033, Shandong Province, China
| | - Yong-Zheng Wang
- Department of Intervention Medicine, the Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Interventional Oncology Institute, Shandong University, Jinan 250033, Shandong Province, China
| | - Wu-Jie Wang
- Department of Intervention Medicine, the Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Interventional Oncology Institute, Shandong University, Jinan 250033, Shandong Province, China
| | - Wei Wang
- Department of Intervention Medicine, the Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Interventional Oncology Institute, Shandong University, Jinan 250033, Shandong Province, China
| | - Dong Li
- Department of Intervention Medicine, the Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Interventional Oncology Institute, Shandong University, Jinan 250033, Shandong Province, China
| | - Yu-Liang Li
- Department of Intervention Medicine, the Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Interventional Oncology Institute, Shandong University, Jinan 250033, Shandong Province, China
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Liu B, Wu DS, Cao PK, Wang YZ, Wang WJ, Wang W, Chang HY, Li D, Li X, Hertzanu Y, Li YL. Percutaneous transhepatic extraction and balloon dilation for simultaneous gallbladder stones and common bile duct stones: A novel technique. World J Gastroenterol 2018; 24:3799-3805. [PMID: 30197485 PMCID: PMC6127656 DOI: 10.3748/wjg.v24.i33.3799] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/09/2018] [Accepted: 07/21/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the clinical efficacy and safety of an innovative percutaneous transhepatic extraction and balloon dilation (PTEBD) technique for clearance of gallbladder stones in patients with concomitant stones in the common bile duct (CBD).
METHODS The data from 17 consecutive patients who underwent PTEBD for clearance of gallbladder stones were retrospectively analyzed. After removal of the CBD stones by percutaneous transhepatic balloon dilation (PTBD), the gallbladder stones were extracted to the CBD and pushed into the duodenum with a balloon after dilation of the sphincter of Oddi. Large stones were fragmented using a metallic basket. The patients were monitored for immediate adverse events including hemorrhage, perforation, pancreatitis, and cholangitis. During the two-year follow-up, they were monitored for stone recurrence, reflux cholangitis, and other long-term adverse events.
RESULTS Gallbladder stones were successfully removed in 16 (94.1%) patients. PTEBD was repeated in one patient. The mean hospitalization duration was 15.9 ± 2.2 d. Biliary duct infection and hemorrhage occurred in one (5.9%) patient. No severe adverse events, including pancreatitis or perforation of the gastrointestinal or biliary tract occurred. Neither gallbladder stone recurrence nor refluxing cholangitis had occurred two years after the procedure.
CONCLUSION Sequential PTBD and PTEBD are safe and effective for patients with simultaneous gallbladder and CBD stones. These techniques provide a new therapeutic approach for certain subgroups of patients in whom endoscopic retrograde cholangiopancreatography/endoscopic sphincterotomy or surgery is not appropriate.
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Affiliation(s)
- Bin Liu
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Interventional Oncology Institute of Shandong University, Jinan 250033, Shandong Province, China
| | - De-Shun Wu
- Department of General Surgery, Jiyang County People’s Hospital, Jinan 251400, Shandong Province, China
| | - Pi-Kun Cao
- School of Medicine, Shandong University, Jinan 250014, Shandong Province, China
| | - Yong-Zheng Wang
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Interventional Oncology Institute of Shandong University, Jinan 250033, Shandong Province, China
| | - Wu-Jie Wang
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Interventional Oncology Institute of Shandong University, Jinan 250033, Shandong Province, China
| | - Wei Wang
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Interventional Oncology Institute of Shandong University, Jinan 250033, Shandong Province, China
| | - Hai-Yang Chang
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Interventional Oncology Institute of Shandong University, Jinan 250033, Shandong Province, China
| | - Dong Li
- School of Medicine, Shandong University, Jinan 250014, Shandong Province, China
| | - Xiao Li
- School of Medicine, Shandong University, Jinan 250014, Shandong Province, China
| | - Yancu Hertzanu
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Department of Radiology, Ben-Gurion University, Negev 88874, Israel
| | - Yu-Liang Li
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
- Interventional Oncology Institute of Shandong University, Jinan 250033, Shandong Province, China
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Wang W, Wang C, Qi H, Wang Y, Li Y. Percutaneous transcystic balloon dilation for common bile duct stone removal in high-surgical-risk patients with acute cholecystitis and co-existing choledocholithiasis. HPB (Oxford) 2018; 20:327-331. [PMID: 29146469 DOI: 10.1016/j.hpb.2017.10.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 10/04/2017] [Accepted: 10/07/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Percutaneous procedures to treat common bile duct (CBD) stones typically require access via intrahepatic bile ducts. This study aimed to describe the outcomes of a percutaneous transcystic approach that expelled the CBD stones into the duodenum after percutaneous transcystic balloon dilation of the ampulla (PTCBDA) for high-risk patients who present with acute cholecystitis and CBD stones. METHODS Patients diagnosed with acute cholecystitis and CBD stones who were deemed too high-risk for surgery or general anesthesia and were treated with PTCBDA and CBD stone removal between March 2010 and November 2015 were included for further analysis. Patients underwent emergency percutaneous transhepatic gallbladder drainage under ultrasound. Staged PTCBDA and CBD stone expulsion were performed. Outcomes evaluated included the success rate, causes of failure, and complications. RESULTS Eighteen patients met the inclusion criteria. CBD stones were successfully expelled in 16 patients. A second procedure was performed in one patient because of residual stones. The procedure failed in two patients because their stones were large. One patient developed bile peritonitis and underwent percutaneous catheter drainage. DISCUSSION Percutaneous transcystic anterograde expulsion of CBD stones may be a feasible and effective method for treating high-risk surgical patients with acute cholecystitis and co-existing CBD stones.
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Affiliation(s)
- Wujie Wang
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan City, Shandong Province, China
| | - Changjun Wang
- Department of Radiology, Jiyang People's Hospital, Jiyang County, Jinan City, Shandong Province, China
| | - Hongjun Qi
- Department of General Surgery, Dezhou Municipal Hospital, Dezhou City, Shandong Province, China
| | - Yongzheng Wang
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan City, Shandong Province, China
| | - Yuliang Li
- Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan City, Shandong Province, China.
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Abstract
Gallstone disease is one of the most common public health problems in the United States. Approximately 10%-20% of the national adult populations currently carry gallstones, and gallstone prevalence is rising. In addition, nearly 750,000 cholecystectomies are performed annually in the United States; direct and indirect costs of gallbladder surgery are estimated to be $6.5 billion. Cholelithiasis is also strongly associated with gallbladder, pancreatic, and colorectal cancer occurrence. Moreover, the National Institutes of Health estimates that almost 3,000 deaths (0.12% of all deaths) per year are attributed to complications of cholelithiasis and gallbladder disease. Although extensive research has tried to identify risk factors for cholelithiasis, several studies indicate that definitive findings still remain elusive. In this review, predisposing factors for cholelithiasis are identified, the pathophysiology of gallstone disease is described, and nonsurgical preventive options are discussed. Understanding the risk factors for cholelithiasis may not only be useful in assisting nurses to provide resources and education for patients who are diagnosed with gallstones, but also in developing novel preventive measures for the disease.
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Wang HH, Li T, Portincasa P, Ford DA, Neuschwander-Tetri BA, Tso P, Wang DQH. New insights into the role of Lith genes in the formation of cholesterol-supersaturated bile. LIVER RESEARCH 2017; 1:42-53. [PMID: 34367715 PMCID: PMC8341472 DOI: 10.1016/j.livres.2017.05.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Cholesterol gallstone formation represents a failure of biliary cholesterol homeostasis in which the physical-chemical balance of cholesterol solubility in bile is disturbed. Lithogenic bile is mainly caused by persistent hepatic hypersecretion of biliary cholesterol and sustained cholesterol-supersaturated bile is an essential prerequisite for the precipitation of solid cholesterol monohydrate crystals and the formation of cholesterol gallstones. The metabolic determinants of the supply of hepatic cholesterol molecules that are recruited for biliary secretion are dependent upon the input-output balance of cholesterol and its catabolism in the liver. The sources of cholesterol for hepatic secretion into bile have been extensively investigated; however, to what extent each cholesterol source contributes to hepatic secretion is still unclear both under normal physiological conditions and in the lithogenic state. Although it has been long known that biliary lithogenicity is initiated by hepatic cholesterol hypersecretion, the genetic mechanisms that cause supersaturated bile have not been defined yet. Identification of the Lith genes that determine hepatic cholesterol hypersecretion should provide novel insights into the primary genetic and pathophysiological defects for gallstone formation. In this review article, we focus mainly on the pathogenesis of the formation of supersaturated bile and gallstones from the viewpoint of genetics and pathophysiology. A better understanding of the molecular genetics and pathophysiology of the formation of cholesterol-supersaturated bile will undoubtedly facilitate the development of novel, effective, and noninvasive therapies for patients with gallstones, which would reduce the morbidity, mortality, and costs of health care associated with gallstones, a very prevalent liver disease worldwide.
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Affiliation(s)
- Helen H. Wang
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Tiangang Li
- Department of Pharmacology, Toxicology and Therapeutics, Kansas University Medical Center, Kansas City, KS, USA
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”Medical School, Bari, Italy
| | - David A. Ford
- Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Brent A. Neuschwander-Tetri
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - David Q.-H. Wang
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO, USA
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Tonkikh YL, Tsukanov VV, Kasparov EV, Bronnikova EP, Vasyutin AV. [Change in the ratio of blood saturated to unsaturated fatty acids is a universal marker of lipid metabolic disorder in patients with cholelithiasis]. TERAPEVT ARKH 2017; 89:66-69. [PMID: 28281518 DOI: 10.17116/terarkh201789266-69] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
AIM To study the spectrum of serum fatty acids (SSFA) and the composition of blood lipids in cholelithiasis (CL) in various ethnic groups of East Siberia. SUBJECTS AND METHODS A clinical and epidemiological study was conducted, during which ultrasonography and oral cholecystography were used to examine 991 Khakases and 934 Europoids in Khakassia and 652 Evenks and 996 Europoids in Evenkia. Biochemical tests were performed to determine serum lipids in 20% of the random sample. Gas liquid chromatography was applied to investigate ASSFA in 220 patients in Khakassia and 157 people in Evenkia. RESULTS The manifestations of hyperlipidemia were detected in the Europoids with CL in Evenkia and Khakassia. These changes were less pronounced in the Evenks with CL and absent in the Khakases with CL. In all populations, the blood levels of saturated FAs and ratios of saturated to unsaturated FAs were considerably higher in the patients with CL than in the healthy individuals. CONCLUSION The higher levels of saturated FAs and the lower proportion of serum unsaturated FAs are a universal marker of lipid metabolic disturbances in patients with CL in genetically different populations.
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Affiliation(s)
- Yu L Tonkikh
- Research Institute of Medical Problems of the North, Krasnoyarsk, Russia
| | - V V Tsukanov
- Research Institute of Medical Problems of the North, Krasnoyarsk, Russia
| | - E V Kasparov
- Research Institute of Medical Problems of the North, Krasnoyarsk, Russia
| | - E P Bronnikova
- Research Institute of Medical Problems of the North, Krasnoyarsk, Russia
| | - A V Vasyutin
- Research Institute of Medical Problems of the North, Krasnoyarsk, Russia
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Biétry FA, Reich O, Schwenkglenks M, Meier CR. Statin use and risk of cholecystectomy – A case-control analysis using Swiss claims data. Expert Opin Drug Saf 2016; 15:1577-1582. [DOI: 10.1080/14740338.2016.1240782] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Martin D, Schmidt R, Mortensen EM, Mansi I. Association of Statin Therapy and Risks of Cholelithiasis, Biliary Tract Diseases, and Gallbladder Procedures: Retrospective Cohort Analysis of a US Population. Ann Pharmacother 2015; 50:161-71. [PMID: 26706861 DOI: 10.1177/1060028015622649] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Gallstone disease is a leading cause of morbidity in Western countries and carries a high economic burden. Statin medications decrease hepatic cholesterol biosynthesis and may, therefore, lower the risk of cholesterol cholelithiasis by reducing the cholesterol concentration in the bile. Population-based evidence, however, is sparse. OBJECTIVE To assess the risk of gallbladder diseases among statin users compared with nonusers in an American patient cohort. METHODS We performed a retrospective cohort study of patients enrolled in the San Antonio Tricare health system using data between October 2003 and March 2012. We defined 2 groups: statin users (use for 90 days or greater) and nonusers (no prior statin). A propensity score based on 82 variables was generated to match statin users and nonusers 1:1. Outcomes included incidence of cholelithiasis, biliary tract diseases, and gallbladder procedures. RESULTS A total of 43 438 patients were identified; 13 626 (31.4%) were statin users, and 29 812 (68.6%) were nonusers. We matched 6342 pairs of statin users and nonusers based on propensity score. The odds ratios (ORs) in statin users in comparison to nonusers were similar for cholelithiasis (OR = 0.86; 95% CI = 0.73, 1.02), biliary tract disease (OR = 0.85; 95% CI = 0.67-1.08), and gall bladder procedures (OR = 0.85; 95% CI = 0.69, 1.04). CONCLUSIONS Statin use was not significantly associated with either an increased or decreased risk of cholelithiasis or gallbladder disease.
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Affiliation(s)
- Donald Martin
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Robert Schmidt
- University of Texas Southwestern Medical Center, Dallas, TX, USA VA North Texas Health Care System, Dallas, TX, USA
| | - Eric M Mortensen
- University of Texas Southwestern Medical Center, Dallas, TX, USA VA North Texas Health Care System, Dallas, TX, USA
| | - Ishak Mansi
- University of Texas Southwestern Medical Center, Dallas, TX, USA VA North Texas Health Care System, Dallas, TX, USA
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Abstract
Background Acute bacterial cholangitis for the most part owing to common bile duct stones is common in gastroenterology practice and represents a potentially life-threatening condition often characterized by fever, abdominal pain, and jaundice (Charcot's triad) as well as confusion and septic shock (Reynolds' pentad). Methods This review is based on a systematic literature review in PubMed with the search items ‘cholangitis’, ‘choledocholithiasis’, ‘gallstone disease’, ‘biliary infection’, and ‘biliary sepsis’. Results Although most patients respond to empiric broad-spectrum antibiotic treatment, timely endoscopic biliary drainage depending on the severity of the disease is required to eliminate the underlying obstruction. Specific recommendations have been derived from the Tokyo guideline working group consensus 2006 and its update in 2013, albeit poorly evidence-based, providing a comprehensive overview of diagnosis, classification, risk stratification, and treatment algorithms in acute bacterial cholangitis. Conclusion Prompt clinical recognition and accurate diagnostic workup including adequate laboratory assessment and (aetiology-oriented) imaging are critical steps in the management of cholangitis. Treatment is directed at the two major interrelated pathophysiologic components, i.e. bacterial infection (immediate antimicrobial therapy) and bile duct obstruction (biliary drainage). As for the latter, transpapillary endoscopic drainage by stent or nasobiliary drain and/or same-session bile duct clearance, depending on individual disease severity, represent first-line treatment approaches.
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Affiliation(s)
- Vincent Zimmer
- Department of Medicine II, Saarland University Medical Center, Homburg/Saar, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg/Saar, Germany
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The APOB gene polymorphism in the pathogenesis of gallstone disease in pre- and postmenopausal women. MENOPAUSE REVIEW 2015; 14:35-40. [PMID: 26327886 PMCID: PMC4440195 DOI: 10.5114/pm.2015.49169] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 10/12/2014] [Accepted: 12/02/2014] [Indexed: 01/07/2023]
Abstract
Aim of the study The decrease in estrogen levels in the postmenopausal period changes the lipid profile by the expression of hepatic genes related to metabolism of cholesterol and bile acid synthesis that could be important in the pathogenesis of cholelithiasis. The aim of the study was to determine the APOB gene 7673C>T and 12669G>A polymorphisms in the pathogenesis of gallstones and analysis of the composition of gallstones in pre- and postmenopausal women. Material and methods The study group consisted of 94 women qualified to the laparoscopic cholecystectomy while the control group consisted of 81 women in whom gallstones and other changes in the bile ducts were excluded. Gallstones composition analysis was performed using commercially available assays. The prevalence of the APOB gene polymorphisms was determined using the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Results When assessing the composition of gallstones in pre- and postmenopausal women, we observed differences in the studied parameters. Analysis of genetic variants of APOB gene 7673C>T and 12669G>A polymorphisms showed no significant statistical differences between studied groups and controls. Conclusions Analysis of 7673C>T and 12669G>A polymorphisms showed no relationship between specific genetic variants and the risk of gallstones in pre- and postmenopausal women, pointing to the fact that the investigated polymorphisms are not relevant as prognostic factors in gallstone disease in the Caucasian population. Because of the possible contribution of a variety of factors in gallstones pathogenesis the studies are required to take account of additional environmental factors, what may indicate different occurrence between investigated polymorphisms, gallstone disease development and gallstones composition in Caucasians.
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Zimmer V, Lammert F. Role of genetics in diagnosis and therapy of acquired liver disease. Mol Aspects Med 2014; 37:15-34. [DOI: 10.1016/j.mam.2013.10.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 10/07/2013] [Accepted: 10/15/2013] [Indexed: 02/08/2023]
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Karlsen TH, Vesterhus M, Boberg KM. Review article: controversies in the management of primary biliary cirrhosis and primary sclerosing cholangitis. Aliment Pharmacol Ther 2014; 39:282-301. [PMID: 24372568 DOI: 10.1111/apt.12581] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 10/09/2013] [Accepted: 11/18/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND Despite considerable advances over the last two decades in the molecular understanding of cholestasis and cholestatic liver disease, little improvement has been made in diagnostic tools and therapeutic strategies. AIMS To critically review controversial aspects of the scientific basis for common clinical practice in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and to discuss key ongoing challenges to improve patient management. METHODS We performed a literature search using PubMed and by examining the reference lists of relevant review articles related to the clinical management of PBC and PSC. Articles were considered on the background of the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) practice guidelines and clinical experience of the authors. RESULTS Ongoing challenges in PBC mainly pertain to the improvement of medical therapy, particularly for patients with a suboptimal response to ursodeoxycholic acid. In PSC, development of medical therapies and sensitive screening protocols for cholangiocarcinoma represent areas of intense research. To rationally improve patient management, a better understanding of pathogenesis, including complications like pruritis and fatigue, is needed and there is a need to identify biomarker end-points for treatment effect and prognosis. Timing of liver transplantation and determining optimal regimens of immunosuppression post-liver transplantation will also benefit from better appreciation of pre-transplant disease mechanisms. CONCLUSION Controversies in the management of PBC and PSC relate to topics where evidence for current practice is weak and further research is needed.
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Affiliation(s)
- T H Karlsen
- Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway
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Guarino MPL, Cocca S, Altomare A, Emerenziani S, Cicala M. Ursodeoxycholic acid therapy in gallbladder disease, a story not yet completed. World J Gastroenterol 2013; 19:5029-5034. [PMID: 23964136 PMCID: PMC3746374 DOI: 10.3748/wjg.v19.i31.5029] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 07/12/2013] [Accepted: 07/19/2013] [Indexed: 02/06/2023] Open
Abstract
Gallstone disease represents an important issue in the healthcare system. The principal non-invasive non-surgical medical treatment for cholesterol gallstones is still represented by oral litholysis with bile acids. The first successful and documented dissolution of cholesterol gallstones was achieved in 1972. Since then a large number of investigators all over the world, have been dedicated in biochemical and clinical studies on ursodeoxycholic acid (UDCA), demonstrating its extreme versatility. This editorial is aimed to provide a brief review of recent developments in UDCA use, current indications for its use and, the more recent advances in understanding its effects in terms of an anti-inflammatory drug.
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Abstract
PURPOSE OF REVIEW The global burden of gallstones is increasing. Although the gallbladder is the most common site for gallstone formation, 10-25% of patients display concurrent gallbladder and bile duct stones. Secondary stones are differentiated from primary stones that develop de novo in the biliary tree. Overall, the natural history of bile duct stones is less well defined and their diagnosis and treatment are more complex as compared to gallbladder stones. RECENT FINDINGS Elevated liver function tests are not always reflective of bile duct stones, and noninvasive diagnosis by endoscopic ultrasound or MRI should be pursued in ambiguous cases. For treatment, recent studies report endoscopic dilation to result in similar clearance but lower complication and recurrence rates as with sphincterotomy. Pharmacological adjuvants such as ursodeoxycholic acid with sphincterotomy and stenting have been suggested for elderly patients. Indication and timing of cholecystectcomy after endoscopic treatment of bile duct stones is critical, and early cholecystectomy within 3-7 days prevents recurrent biliary events. SUMMARY In this review we address the pathophysiology of bile duct stones and present the latest developments in the diagnosis and treatment of this challenging condition, with a consideration of stone recurrence.
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Shih SC, Yang HW, Chang TY, Wang HY, Hu KC, Chang CW, Chang CW, Hung CY, Lin M, Chan HW, Lin WS, Chang SC, Lee YJ. Gender-specific association of the interleukin 18 gene with symptomatic gallstone disease. J Gastroenterol Hepatol 2013; 28:744-9. [PMID: 23302036 DOI: 10.1111/jgh.12117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/21/2012] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIM Symptomatic gallstone disease (SGSD) induced several inflammatory responses and affected extrahepatic bile ducts. Although the pathology and environmental risk factors of gallstone disease are well documented, immune or inflammatory responses in SGSD development are still inconclusive. Interleukin 18 (IL18) is a pro-inflammatory cytokine that plays an important role in immune, infectious, and inflammatory diseases because of the induction of interferon-γ. In this study, we investigated whether polymorphisms of the IL18 gene were associated with SGSD susceptibility. METHODS Genomic DNA was isolated from the whole blood samples of 445 patients with SGSD and 1121 gallstone-free controls. The IL18 rs549908T>G, rs5744247C>G, rs187238G>C, rs1946518T>G, and rs360719A>G polymorphisms were genotyped using predeveloped TaqMan allelic discrimination assay. RESULTS We found IL18 rs5744247G allele conferred protection against SGSD in female patients (odds ratio = 0.75, corrected P-value = 0.015). Haplotype analysis revealed that TGGTA protected females from SGSD development (odds ratio = 0.75, corrected P-value = 0.02). CONCLUSIONS Based on our findings, IL18 rs5744247C>G polymorphism could be a potential genetic marker to predict SGSD susceptibility in Han Chinese women.
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Affiliation(s)
- Shou-Chuan Shih
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
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Krawczyk M, Miquel JF, Stokes CS, Zuniga S, Hampe J, Mittal B, Lammert F. Genetics of biliary lithiasis from an ethnic perspective. Clin Res Hepatol Gastroenterol 2013; 37:119-25. [PMID: 23340007 DOI: 10.1016/j.clinre.2012.09.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Accepted: 09/25/2012] [Indexed: 02/04/2023]
Abstract
Gallstone disease represents one of the most common gastroenterological disorders worldwide. Gallstones affect over 15% of adults in Europe and 25-30% of Hispanic populations in Central and South America. The heritability of gallstones varies considerably according to ethnicity, with Native Americans and Hispanics with Amerindian admixture being the most susceptible populations. Genetic factors have been shown to account for 25-30% of total gallstone risk in Europe, however, in Hispanic populations, this risk percentage may increase to 45-65%. Recent genome-wide association and candidate gene studies have identified common polymorphisms in enterohepatic transporters (ABCG5/8, SLC10A2) and the Gilbert syndrome UGT1A1 variant as genetic determinants of gallstone formation. Together, these polymorphisms cover a significant proportion of the previously predicted genetic background of gallstones in European populations. New lithogenic genes need to be discovered in future studies in high-risk populations. In this review, we address the latest developments in the genetic analysis of gallstones and discuss the ethnic background of this condition in European, Central and South American and Asian populations.
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Affiliation(s)
- Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Kirrberger Str. 100, 66421 Homburg, Germany
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von Schönfels W, Buch S, Wölk M, Aselmann H, Egberts JH, Schreiber S, Krawczak M, Becker T, Hampe J, Schafmayer C. Recurrence of gallstones after cholecystectomy is associated with ABCG5/8 genotype. J Gastroenterol 2013; 48:391-6. [PMID: 22869156 DOI: 10.1007/s00535-012-0639-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 07/05/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Gallstone disease is a frequent and economically highly relevant disorder, with cholecystectomy representing one of the most frequently performed operations world-wide. Gallstone recurrence after cholecystectomy is associated with complications such as biliary sepsis and pancreatitis. As yet, variant ABCG8-D19H is the most widely recognized genetic risk factor for gallstone disease. The aim of the study is to investigate whether ABCG8-D19H is associated with gallstone recurrence after cholecystectomy. METHODS Two thousand three hundred and eight patients from an earlier study of gallstone risk factors were re-contacted by mail, leading to 1,915 patients with available clinical and genetic information. Symptomatic gallstone recurrence was established if it occurred more than six months after surgery. Median follow-up time after cholecystectomy was eight years. RESULTS Gallstones recurred in 37 patients (1.9%). ABCG-D19H was found to be significantly associated with gallstone recurrence (p = 0.034). The allelic odds ratio was 1.97 (95% CI 1.12-∞). In a multivariate logistic regression analysis adjusted for age, sex, BMI and type of surgery, ABCG8-D19H remained a significant predictor, both in the total cohort (p = 0.024) and in the subgroup for whom information on type and scheduling of surgery was available (N = 1,650, p = 0.020). CONCLUSIONS ABCG8-D19H is a predictor of gallstone recurrence, a major long term postoperative biliary complication. Moreover, the observed association also reemphasizes the importance of the sterolin transporter for stone formation.
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Affiliation(s)
- Witigo von Schönfels
- Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Arnold-Heller-Str. 6, 24105, Kiel, Germany
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Strnad P, von Figura G, Gruss R, Jareis KM, Stiehl A, Kulaksiz H. Oblique bile duct predisposes to the recurrence of bile duct stones. PLoS One 2013; 8:e54601. [PMID: 23365676 PMCID: PMC3554756 DOI: 10.1371/journal.pone.0054601] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Accepted: 12/13/2012] [Indexed: 12/17/2022] Open
Abstract
Background and Study Aims Bile stones represent a highly prevalent condition and abnormalities of the biliary tree predispose to stone recurrence due to development of biliary stasis. In our study, we assessed the importance of an altered bile duct course for stone formation. Patients and Methods 1,307 patients with choledocholithiasis in the absence of any associated hepatobiliary disease who underwent endoscopic retrograde cholangiopancreatography (ERCP) between 2002 and 2009 were analysed. The angle enclosed between the horizontal portion of the common bile duct (CBD) and the horizontal plane was measured (angle α). Oblique common bile duct (OCBD) was defined as a CBD with angle α<45°. Results 103 patients (7.9%) were found to harbour OCBD and these were compared to 104 randomly selected control subjects. Compared to controls, OCBD patients were (i) significantly older (72±13 vs. 67±13, p<0.00001); (ii) more frequently underwent a cholecystectomy (p = 0.02) and biliary surgery (p = 0.003) prior to the diagnosis and (iii) more often developed chronic pancreatitis (p = 0.04) as well as biliary fistulae (p = 0.03). Prior to and after ERCP, OCBD subjects displayed significantly elevated cholestatic parameters and angle α negatively correlated with common bile duct diameter (r = -0.29, p = 0.003). OCBD subjects more often required multiple back-to-back ERCP sessions to remove bile stones (p = 0.005) as well as more ERCPs later on due to recurrent stone formation (p<0.05). Conclusion OCBD defines a novel variant of the biliary tree, which is associated with chronic cholestasis, hampers an efficient stone removal and predisposes to recurrence of bile duct stones.
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Affiliation(s)
- Pavel Strnad
- Department of Internal Medicine I, University Medical Centre Ulm, Ulm, Germany
- Department of Internal Medicine III and IZKF, University Hospital Aachen, Aachen, Germany
- * E-mail: (HK); (PS)
| | - Guido von Figura
- Department of Internal Medicine I, University Medical Centre Ulm, Ulm, Germany
| | - Regina Gruss
- Department of Internal Medicine I, University Medical Centre Ulm, Ulm, Germany
| | - Katja-Marlen Jareis
- Department of Internal Medicine I, University Medical Centre Ulm, Ulm, Germany
| | - Adolf Stiehl
- Department of Internal Medicine I, Division of Gastroenterology, University Medical Centre Heidelberg, Heidelberg, Germany
| | - Hasan Kulaksiz
- Department of Internal Medicine I, University Medical Centre Ulm, Ulm, Germany
- Department of Internal Medicine II, Hospital Waldshut-Tiengen, Waldshut-Tiengen, Germany
- * E-mail: (HK); (PS)
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Di Ciaula A, Wang DQH, Bonfrate L, Portincasa P. Current views on genetics and epigenetics of cholesterol gallstone disease. CHOLESTEROL 2013; 2013:298421. [PMID: 23691293 PMCID: PMC3649201 DOI: 10.1155/2013/298421] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Revised: 03/06/2013] [Accepted: 03/20/2013] [Indexed: 02/07/2023]
Abstract
Cholesterol gallstone disease, one of the commonest digestive diseases in western countries, is induced by an imbalance in cholesterol metabolism, which involves intestinal absorption, hepatic biosynthesis, and biliary output of cholesterol, and its conversion to bile acids. Several components of the metabolic syndrome (e.g., obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia) are also well-known risk factors for gallstones, suggesting the existence of interplay between common pathophysiological pathways influenced by insulin resistance, genetic, epigenetic, and environmental factors. Cholesterol gallstones may be enhanced, at least in part, by the abnormal expression of a set of the genes that affect cholesterol homeostasis and lead to insulin resistance. Additionally, epigenetic mechanisms (mainly DNA methylation, histone acetylation/deacetylation, and noncoding microRNAs) may modify gene expression in the absence of an altered DNA sequence, in response to different lithogenic environmental stimuli, such as diet, lifestyle, pollutants, also occurring in utero before birth. In this review, we will comment on various steps of the pathogenesis of cholesterol gallstones and interaction between environmental and genetic factors. The epigenomic approach may offer new options for therapy of gallstones and better possibilities for primary prevention in subjects at risk.
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Affiliation(s)
- Agostino Di Ciaula
- 1Division of Internal Medicine Hospital of Bisceglie, 76011 Bisceglie, Italy
| | - David Q.-H. Wang
- 2Saint Louis University School of Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Edward Doisy Research Center, St. Louis, MO 63104, USA
| | - Leonilde Bonfrate
- 3Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University “Aldo Moro“ of Bari Medical School, 70124 Bari, Italy
| | - Piero Portincasa
- 3Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University “Aldo Moro“ of Bari Medical School, 70124 Bari, Italy
- 4European Society for Clinical Investigation (ESCI), 3584 CJ Utrecht, The Netherlands
- *Piero Portincasa:
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Stein A, Hermoni D, Elis A, Konikoff FM. Effect of ezetimibe on the prevalence of cholelithiasis. World J Gastroenterol 2012; 18:5789-92. [PMID: 23155321 PMCID: PMC3484349 DOI: 10.3748/wjg.v18.i40.5789] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Revised: 02/12/2012] [Accepted: 05/12/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the prevalence of cholelithiasis among patients treated with ezetimibe.
METHODS: A retrospective, case-control study based on computerized medical records from patients of the Clalit Health Services, Sharon-Shomron region, from 2000 to 2009. Patients 20-85 years of age, who had been treated with ezetimibe and statins or statins only for at least 6 mo, and who had an abdominal ultrasound were included in the study. Collected data included age, gender, ezetimibe treatment duration, presence of hypothyroidism or diabetes, and existence of cholelithiasis as determined by ultrasound. Excluded were subjects after gallbladder resection, with hemolysis, myeloproliferative or inflammatory bowel diseases, and those treated with ursodeoxycholic acid and fibrates. Patients treated with statins and ezetimibe (study group) were compared to patients treated with statins only (control group).
RESULTS: The study group included 25 patients and the control group 168. All patients in the study were treated with statins. The study group included 13 males (52%) and 12 females (48%), the control group 76 males (45%) and 92 (55%) females (P = 0.544). The groups did not differ in age (mean age: 68 ± 8 years, range 53-85 years vs mean age: 71 ± 8 years, range 51-85 years; P = 0.153) or in the rate of diabetic and hypothyroid patients [11 (44%) vs 57 (33%), P = 0.347 in the study group and 5 (20%) vs 23 (14%), P = 0.449 in the control group, respectively]. Patients in the study group were treated with ezetimibe for an average of 798 ± 379 d. Cholelithiasis was found in 4 (16%) patients in the study group and in 33 (20%) patients in the control group (P = 0.666).
CONCLUSION: Ezetimibe does not appear to influence the prevalence of gallstones.
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Su Y, Dai Y, Lin Y, Gao X, Han Y, Zhao B. Serum organochlorine pesticide residues and risk of gallstone disease: a case-control study in Xiamen. Ann Epidemiol 2012; 22:592-7. [PMID: 22695391 DOI: 10.1016/j.annepidem.2012.05.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Revised: 05/08/2012] [Accepted: 05/08/2012] [Indexed: 01/06/2023]
Abstract
PURPOSE To investigate the association between serum organochlorine pesticide residues and risk of gallstone disease. METHODS A 1:1, pair-matched, case-control study was designed. Data from 150 patients with gallstones diagnosed by abdominal ultrasonography at a single hospital from June 2009 to June 2010 were collected. A total of 150 patients without gallstones during the same period at the same hospital were recruited as the control group. Capillary gas chromatography was employed to measure the serum concentrations of dichlorodiphenyltrichloroethane (DDT) and hexachlorocyclohexane (HCH) residues. Multiple-factor conditional logistic regression analysis was conducted to estimate the relative risk of gallstones in relation to organochlorine pesticide residues in serum. RESULTS The percentages of p,p'-DDD and o,p'-DDT in serum of patients were significantly higher than those in serum of controls. The p,p'-DDE, α-HCH, and δ-HCH residues in serum of patients were also significantly increased compared with those in serum of controls. Multiple-factor conditional logistic regression analysis showed that high levels of p,p'-DDE and p,p'-DDT residues were risk factors for gallstone disease. CONCLUSIONS A high level of organochlorine pesticide residues in serum is a potential risk factor for gallstone disease, which suggests that environmental exposure to organochlorine pesticides should be evaluated with respect to gallstone formation.
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Affiliation(s)
- Yanhua Su
- School of Public Health, Xiamen University, Fujian, China
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Krawczyk M, Lütjohann D, Schirin-Sokhan R, Villarroel L, Nervi F, Pimentel F, Lammert F, Miquel JF. Phytosterol and cholesterol precursor levels indicate increased cholesterol excretion and biosynthesis in gallstone disease. Hepatology 2012; 55:1507-17. [PMID: 22213168 DOI: 10.1002/hep.25563] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Accepted: 12/06/2011] [Indexed: 01/10/2023]
Abstract
UNLABELLED In hepatocytes and enterocytes sterol uptake and secretion is mediated by Niemann-Pick C1-like 1 (NPC1L1) and ATP-binding cassette (ABC)G5/8 proteins, respectively. Whereas serum levels of phytosterols represent surrogate markers for intestinal cholesterol absorption, cholesterol precursors reflect cholesterol biosynthesis. Here we compare serum and biliary sterol levels in ethnically different populations of patients with gallstone disease (GSD) and stone-free controls to identify differences in cholesterol transport and synthesis between these groups. In this case-control study four cohorts were analyzed: 112 German patients with GSD and 152 controls; two distinct Chilean ethnic groups: Hispanics (100 GSD, 100 controls), and Amerindians (20 GSD, 20 controls); additionally an 8-year follow-up of 70 Hispanics was performed. Serum sterols were measured by gas chromatography / mass spectrometry. Gallbladder bile sterol levels were analyzed in cholesterol GSD and controls. Common ABCG5/8 variants were genotyped. Comparison of serum sterols showed lower levels of phytosterols and higher levels of cholesterol precursors in GSD patients than in controls. The ratios of phytosterols to cholesterol precursors were lower in GSD patients, whereas biliary phytosterol and cholesterol concentrations were elevated as compared with controls. In the follow-up study, serum phytosterol levels were significantly lower even before GSD was detectable by ultrasound. An ethnic gradient in the ratios of phytosterols to cholesterol precursors was apparent (Germans > Hispanics > Amerindians). ABCG5/8 variants did not fully explain the sterol metabolic trait of GSD in any of the cohorts. CONCLUSION Individuals predisposed to GSD display increased biliary output of cholesterol in the setting of relatively low intestinal cholesterol absorption, indicating enhanced whole-body sterol clearance. This metabolic trait precedes gallstone formation and is a feature of ethnic groups at higher risk of cholesterol GSD.
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Affiliation(s)
- Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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Non-orthopaedic causes of shoulder pain: what the shoulder expert must remember. Musculoskelet Surg 2012; 96 Suppl 1:S63-8. [PMID: 22528847 DOI: 10.1007/s12306-012-0192-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Accepted: 02/26/2012] [Indexed: 12/14/2022]
Abstract
Aim of this review is to underline some specific patterns of shoulder pain that are not related to musculoskeletal diseases but are manifestations of gastrointestinal, neurological, cardiological or rheumatological diseases. The most important pathologies (like gallstones, myocardial ischaemia and Parsonage-Turner syndrome...) that can manifest with shoulder pain will be presented by specialty doctors and elements for differential diagnosis will be discussed. Orthopaedic shoulder surgeons should always suspect other causes of pain, different from those related to bone, tendons and joint. If there is something unfair, patients should be referred to family doctor for further investigations in order to exclude major systemic diseases.
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Portincasa P, Ciaula AD, Bonfrate L, Wang DQ. Therapy of gallstone disease: What it was, what it is, what it will be. World J Gastrointest Pharmacol Ther 2012; 3:7-20. [PMID: 22577615 PMCID: PMC3348960 DOI: 10.4292/wjgpt.v3.i2.7] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Revised: 09/21/2011] [Accepted: 09/28/2011] [Indexed: 02/06/2023] Open
Abstract
Cholesterol gallstone disease is a common clinical condition influenced by genetic factors, increasing age, female gender, and metabolic factors. Although laparoscopic cholecystectomy is currently considered the gold standard in treating patients with symptomatic gallstones, new perspectives regarding medical therapy of cholelithiasis are currently under discussion, also taking into account the pathogenesis of gallstones, the natural history of the disease and the analysis of the overall costs of therapy. A careful selection of patients may lead to successful non-surgical therapy in symptomatic subjects with a functioning gallbladder harboring small radiolucent stones. The classical oral litholysis by ursodeoxycholic acid has been recently paralleled by new experimental observations, suggesting that cholesterol-lowering agents which inhibit cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe), or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis, might be proposed as additional approaches for treating cholesterol gallstones. In this review we discuss old, recent and future perspectives on medical treatment of cholesterol cholelithiasis.
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Affiliation(s)
- Piero Portincasa
- Piero Portincasa, Leonilde Bonfrate, Department of Biomedical Sciences and Human Oncology, Clinica Medica "A. Murri", University of Bari Medical School, Piazza Giulio Cesare 11, Policlinico, 70124 Bari, Italy
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Chiu HF, Chen CC, Kuo HW, Lee IM, Wu TN, Yang CY. Statin use and the risk of gallstone disease: a population-based case-control study. Expert Opin Drug Saf 2012; 11:369-74. [PMID: 22243480 DOI: 10.1517/14740338.2012.653560] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The aim of this study was to investigate whether the use of statins was associated with a decreased risk of gallstone disease. METHODS We conducted a population-based case-control study in Taiwan. Cases consisted of all patients who were aged 50 years and older and had a first-time diagnosis of gallstone disease or cholecystectomy for the period between 2005 and 2009. The controls were matched to cases by age, sex and index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using multiple logistic regression. RESULTS We examined 1014 gallstone disease cases and 1014 controls. The unadjusted ORs for any statin prescription was 1.06 (95% CI 0.86 to 1.29), and the adjusted OR was 1.14 (95% CI 0.90 to 1.43). Compared with no use of statins, the adjusted ORs were 1.05 (95% CI 0.72 to 1.54) for the group having been prescribed statins with cumulative defined daily doses (DDDs) below 41.53, 1.12 (95% CI 0.84 to 1.50) for the group with cumulative dose between 41.54 and 334.81 DDD, and 1.30 (95% CI 0.86 to 1.95) for the group with cumulative statin use of 334.81 DDDs or more. CONCLUSIONS This study does not provide support for a beneficial association between usage of statin and gallstone disease.
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Affiliation(s)
- Hui-Fen Chiu
- Kaohsiung Medical University, Institute of Pharmacology, College of Medicine, Kaohsiung, Taiwan
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Cui Y, Li Z, Zhao E, Cui N. Risk factors in patients with hereditary gallstones in Chinese pedigrees. Med Princ Pract 2012; 21:467-71. [PMID: 22473058 DOI: 10.1159/000337437] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Accepted: 02/23/2012] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE We aimed to define the risk factors and to evaluate the impact of family background on the prevalence of gallstones in China. SUBJECTS AND METHODS Thirty-eight gallstone pedigrees were collected and a case-control study was conducted. This study consisted of 272 first-degree relatives and 201 non-first-degree relatives of index patients. The participants completed a questionnaire and underwent physical and ultrasonographic examinations. The risk factors examined included age, sex, body mass index (BMI), smoking status, alcohol consumption, pregnancy, fat content in dietary meat, history of gastrointestinal surgery, hypertension, hyperlipidemia, fatty liver, coronary heart disease and diabetes. RESULTS The prevalence of gallstones in first-degree and non-first-degree relatives of index patients was 38.2 and 10.9%, respectively. Age, pregnancy and BMI significantly differed between cases and controls (p < 0.05). The relative risks were: consumption of meat with a high fat content 1.4 (95% CI 1.1-1.8); hyperlipidemia 2.4 (95% CI 1.3-4.6); diabetes 1.9 (95% CI 1.1-3.2); fatty liver 4.9 (95% CI 1.0-24); coronary heart disease 2.5 (95% CI 1.7-3.9). CONCLUSION Data showed that age, overweight, more consumption of high-fat food, high frequency of pregnancy, fatty liver, hyperlipidemia, coronary heart disease and diabetes could increase the risk of gallstones in the first-degree relatives of index patients.
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Affiliation(s)
- Yunfeng Cui
- Department of Surgery, Tianjin Nankai Hospital, Nankai Clinical School of Medicine, Tianjin Medical University, Tianjin, China
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Tönjes A, Wittenburg H, Halbritter J, Renner O, Harsch S, Stange EF, Lammert F, Stumvoll M, Kovacs P. Effects of SLC10A2 variant rs9514089 on gallstone risk and serum cholesterol levels- meta-analysis of three independent cohorts. BMC MEDICAL GENETICS 2011; 12:149. [PMID: 22093174 PMCID: PMC3261098 DOI: 10.1186/1471-2350-12-149] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Accepted: 11/17/2011] [Indexed: 01/23/2023]
Abstract
Background Recently, a single nucleotide polymorphism (SNP) rs9514089 in SLC10A2 (apical sodium-dependent bile acid transporter gene) has been identified as a susceptibility variant for cholelithiasis in humans. Methods Here we assessed the effects of rs9514089 on gallstone risk and related phenotypes of the metabolic syndrome in the self-contained population of Sorbs (183 cases with gallstones/826 controls). Furthermore, we performed a meta-analysis for effects of rs9514089 on susceptibility for cholelithiasis in three independent cohorts (Stuttgart: 56 cases/71 controls, Aachen: 184 cases/184 controls and Sorbs). Results There was no significant association of rs9514089 with gallstone risk, serum lipid parameters and BMI in the Sorbs and in the meta-analysis of all three cohorts (p > 0.05). There was an effect trend in the subgroup of lean subjects but based on different effect directions in the three cohorts there was no significant association in the meta-analysis. Conclusions We were not able to replicate the effect of rs9514089 on gallstone risk in the Sorbs. Further analyses in larger cohorts are required to finally assess the role of genetic variants in SLC10A2 in human gallstone development and lipid metabolism.
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Affiliation(s)
- Anke Tönjes
- Department of Medicine, Division of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
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Molecular Mechanisms Underlying the Link between Nuclear Receptor Function and Cholesterol Gallstone Formation. J Lipids 2011; 2012:547643. [PMID: 22132343 PMCID: PMC3206498 DOI: 10.1155/2012/547643] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2011] [Accepted: 08/10/2011] [Indexed: 12/23/2022] Open
Abstract
Cholesterol gallstone disease is highly prevalent in western countries, particularly in women and some specific ethnic groups. The formation of water-insoluble cholesterol crystals is due to a misbalance between the three major lipids present in the bile: cholesterol, bile salts, and phospholipids. Many proteins implicated in biliary lipid secretion in the liver are regulated by several transcription factors, including nuclear receptors LXR and FXR. Human and murine genetic, physiological, pathophysiological, and pharmacological evidence is consistent with the relevance of these nuclear receptors in gallstone formation. In addition, there is emerging data that also suggests a role for estrogen receptor ESR1 in abnormal cholesterol metabolism leading to gallstone disease. A better comprehension of the role of nuclear receptor function in gallstone formation may help to design new and more effective therapeutic strategies for this highly prevalent disease condition.
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Balboa E, Morales G, Aylwin P, Carrasco G, Amigo L, Castro J, Rigotti A, Zanlungo S. Niemann-Pick C2 protein expression regulates lithogenic diet-induced gallstone formation and dietary cholesterol metabolism in mice. Lipids 2011; 47:13-25. [PMID: 22038687 DOI: 10.1007/s11745-011-3625-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Accepted: 10/11/2011] [Indexed: 12/21/2022]
Abstract
Niemann-Pick C2 protein (NPC2) is a lysosomal soluble protein that is highly expressed in the liver; it binds to cholesterol and is involved in intracellular cholesterol trafficking, allowing the exit of lysosomal cholesterol obtained via the lipoprotein endocytic pathway. Thus, this protein may play an important role in controlling hepatic cholesterol transport and metabolism. The aim of this work was to study the relevance of NPC2 protein expression in hepatic cholesterol metabolism, biliary lipid secretion and gallstone formation by comparing NPC2 hypomorph [NPC2 (h/h)] and wild-type mice fed control, 2% cholesterol, and lithogenic diets. NPC2 (h/h) mice exhibited resistance to a diet-induced increase in plasma cholesterol levels. When consuming the chow diet, we observed increased biliary cholesterol and phospholipid secretions in NPC2 (h/h) mice. When fed the 2% cholesterol diet, NPC2 (h/h) mice exhibited low and high gallbladder bile cholesterol and phospholipid concentrations, respectively. NPC2 (h/h) mice fed with the lithogenic diet showed reduced biliary cholesterol secretion, gallbladder bile cholesterol saturation, and cholesterol crystal and gallstone formation. This work indicates that hepatic NPC2 expression is an important factor in the regulation of diet-derived cholesterol metabolism and disposal as well as in diet-induced cholesterol gallstone formation in mice.
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Affiliation(s)
- Elisa Balboa
- Departmento de Gastroenterología, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, Casilla 114-D, Santiago, Chile
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