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Shapiro SB, Yin H, Yu OHY, Azoulay L. Dipeptidyl Peptidase-4 Inhibitors and the Risk of Gallbladder and Bile Duct Disease Among Patients with Type 2 Diabetes: A Population-Based Cohort Study. Drug Saf 2024; 47:759-769. [PMID: 38720114 DOI: 10.1007/s40264-024-01434-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2024] [Indexed: 07/30/2024]
Abstract
INTRODUCTION The use of dipeptidyl peptidase-4 (DPP-4) inhibitors may be associated with an increased risk of gallbladder and bile duct disease among patients with type 2 diabetes. METHODS We conducted a population-based cohort study using an active comparator, new-user design. We used data from the United Kingdom Clinical Practice Research Datalink to identify patients newly treated with either a DPP-4 inhibitor or sodium-glucose cotransporter-2 (SGLT-2) inhibitor between January 2013 and December 2020. We fitted Cox proportional hazards models with propensity score fine stratification weighting to estimate the hazard ratio (HR) and its 95% confidence interval (CI) for incident gallbladder and bile duct disease associated with DPP-4 inhibitors compared to SGLT-2 inhibitors. RESULTS DPP-4 inhibitors were associated with a 46% increased risk of gallbladder and bile duct disease (4.3 vs. 3.0 events per 1000 person-years, HR 1.46, 95% CI 1.17-1.83). At 6 months and 1 year, 745 and 948 patients, respectively, would need to be treated with DPP-4 inhibitors for one patient to experience a gallbladder or bile duct disease. CONCLUSIONS In this population-based cohort study, the use of DPP-4 inhibitors, when compared with SGLT-2 inhibitors, was associated with a moderately increased risk of gallbladder and bile duct disease among patients with type 2 diabetes. This outcome was still quite rare with a high number needed to harm at 6 months and 1 year.
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Affiliation(s)
- Samantha B Shapiro
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Cote Sainte-Catherine, H425.1, Montreal, H3T 1E2, Canada
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, H3A 1G1, Canada
| | - Hui Yin
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Cote Sainte-Catherine, H425.1, Montreal, H3T 1E2, Canada
| | - Oriana H Y Yu
- Division of Endocrinology, Jewish General Hospital, Montreal, H3T 1E2, Canada
| | - Laurent Azoulay
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Cote Sainte-Catherine, H425.1, Montreal, H3T 1E2, Canada.
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, H3A 1G1, Canada.
- Gerald Bronfman Department of Oncology, McGill University, Montreal, H4A 3T2, Canada.
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Han X, Wang J, Wu Y, Gu H, Zhao N, Liao X, Jiang M. Predictive value of bile acids as metabolite biomarkers for gallstone disease: A systematic review and meta-analysis. PLoS One 2024; 19:e0305170. [PMID: 39052638 PMCID: PMC11271903 DOI: 10.1371/journal.pone.0305170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 05/26/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND The profiles of bile acids (BAs) in patients with gallstone disease (GSD) have been found to be altered markedly though in an inconsistent pattern. This study aims to characterize the variation of the BA profiles in GSD patients, thereby to discover the potential metabolite biomarkers for earlier detection of GSD. METHODS Literature search of eight electronic database in both English and Chinese was completed on May 11, 2023. The qualitative and quantitative reviews were performed to summarize the changes of BA profiles in GSD patients compared with healthy subjects. The concentrations of BAs were adopted as the primary outcomes and the weighted mean differences (WMDs) and 95% confidence interval (CI) were generated by random-effects meta-analysis models. RESULTS A total of 30 studies were enrolled which included 2313 participants and reported the 39 BAs or their ratios. Qualitative review demonstrated serum Taurocholic Acid (TCA), Glycochenodeoxycholic acid (GCDCA), Glycocholic acid (GCA), Taurochenodeoxycholic acid (TCDCA), Glycodeoxycholic acid (GDCA) and Deoxycholic acid (DCA) were significantly increased in GSD patients compared with healthy subjects. Meta analysis was performed in 16 studies and showed that serum Total BAs (TBA) (WMD = 1.36μmol/L, 95%CI = 0.33; 2.4) was elevated however bile TBA (WMD = -36.96mmol/L, 95%CI = -52.32; -21.6) was declined in GSD patients. GCA (WMD = 0.83μmol/L, 95%CI = 0.06; 1.6) and TCA (WMD = 0.51μmol/L; 95%CI = 0.18; 0.85) were both increased in serum sample; TCDCA (WMD = 2.64mmol/L, 95%CI = 0.16; 5.12) was rising, however GCDCA (WMD = -13.82mmol/L, 95%CI = -21.86; -5.78) was falling in bile sample of GSD patients. The level of serum DCA in the GSD patients was found to be increased by using chromatography, yet decreased by chromatography mass spectrometry. CONCLUSION The profiles of BAs demonstrated distinctive changes in GSD patients compared with healthy control subjects. Serum GCA, TCA and GCDCA, as the typically variant BAs, presented as a potential marker for earlier diagnosis of GSD, which could facilitate early prophylactic intervention. Yet, further validation of these biomarkers by longitudinal studies is still warranted in the future. PROSPERO registration number CRD42022339649.
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Affiliation(s)
- Xu Han
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Juan Wang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yingnan Wu
- Department of Traditional Chinese Medicine, Inner Mongolia People’s Hospital, Hohhot, China
| | - Hao Gu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ning Zhao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xing Liao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Miao Jiang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
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Han F, Zhao T, Zhang Y, Yun Y, Xu Y, Guo S, Zhong Y, Xie X, Shen J. Discovery and exploration of novel somatostatin receptor subtype 5 (SSTR5) antagonists for the treatment of cholesterol gallstones. Eur J Med Chem 2024; 264:116017. [PMID: 38070432 DOI: 10.1016/j.ejmech.2023.116017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 12/30/2023]
Abstract
The shortage of cholesterol gallstones treatment intensifies the need to discover of effective small molecule drugs. Clinical follow-up and studies have found that activation of somatostatin receptor subtype 5 (SSTR5) reduce gallbladder contraction and thus increase the risk of cholesterol gallstones, implying that antagonizing SSTR5 may promote gallbladder emptying and reduce the formation of gallstones. Herein, we discovered novel SSTR5 antagonists and firstly investigated its effects on cholesterol gallstone. From loperamide, a reported seed structure with micromole activity, we identified optimal compound 23 as an SSTR5 antagonist exhibiting single-digit nanomolar potency, low hERG inhibition and oral availability. Further in vivo evaluation revealed that 23 significantly promoted gallbladder emptying. Moreover, in a mouse cholesterol gallstone model, 23 (3 mg/kg) effectively reduced the cholesterol gallstones formation, showing better efficacy than the clinical first-line drug UDCA (60 mg/kg), providing a new insight into the development of anti-gallstone drugs.
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Affiliation(s)
- Fanghui Han
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Tingting Zhao
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China
| | - Yanglong Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Ying Yun
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
| | - Yuanyuan Xu
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China
| | - Shimeng Guo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yongqing Zhong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmacy, Nanchang University, Nanchang, 330000, Jiangxi Province, China
| | - Xin Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
| | - Jianhua Shen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China.
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Fujita N, Yasuda I, Endo I, Isayama H, Iwashita T, Ueki T, Uemura K, Umezawa A, Katanuma A, Katayose Y, Suzuki Y, Shoda J, Tsuyuguchi T, Wakai T, Inui K, Unno M, Takeyama Y, Itoi T, Koike K, Mochida S. Evidence-based clinical practice guidelines for cholelithiasis 2021. J Gastroenterol 2023; 58:801-833. [PMID: 37452855 PMCID: PMC10423145 DOI: 10.1007/s00535-023-02014-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/21/2023] [Indexed: 07/18/2023]
Abstract
The Japanese Society of Gastroenterology first published evidence-based clinical practice guidelines for cholelithiasis in 2010, followed by a revision in 2016. Currently, the revised third edition was published to reflect recent evidence on the diagnosis, treatment, and prognosis of cholelithiasis conforming to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Following this revision, the present English version of the guidelines was updated and published herein. The clinical questions (CQ) in the previous version were reviewed and rearranged into three newly divided categories: background questions (BQ) dealing with basic background knowledge, CQ, and future research questions (FRQ), which refer to issues that require further accumulation of evidence. Finally, 52 questions (29 BQs, 19 CQs, and 4 FRQs) were adopted to cover the epidemiology, pathogenesis, diagnosis, treatment, complications, and prognosis. Based on a literature search using MEDLINE, Cochrane Library, and Igaku Chuo Zasshi databases for the period between 1983 and August 2019, along with a manual search of new information reported over the past 5 years, the level of evidence was evaluated for each CQ. The strengths of recommendations were determined using the Delphi method by the committee members considering the body of evidence, including benefits and harms, patient preference, and cost-benefit balance. A comprehensive flowchart was prepared for the diagnosis and treatment of gallbladder stones, common bile duct stones, and intrahepatic stones, respectively. The current revised guidelines are expected to be of great assistance to gastroenterologists and general physicians in making decisions on contemporary clinical management for cholelithiasis patients.
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Affiliation(s)
- Naotaka Fujita
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.
- Miyagi Medical Check-up Plaza, 1-6-9 Oroshi-machi, Wakabayashi-ku, Sendai, Miyagi, 984-0015, Japan.
| | - Ichiro Yasuda
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Itaru Endo
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroyuki Isayama
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takuji Iwashita
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Toshiharu Ueki
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kenichiro Uemura
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Akiko Umezawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Akio Katanuma
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yu Katayose
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yutaka Suzuki
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Junichi Shoda
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Toshio Tsuyuguchi
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Toshifumi Wakai
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuo Inui
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Michiaki Unno
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshifumi Takeyama
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takao Itoi
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Satoshi Mochida
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Cholelithiasis'', The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
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5
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Yang M, Xia B, Lu Y, He Q, Lin Y, Yue P, Bai B, Dong C, Meng W, Qi J, Yuan J. Association Between Regular Use of Gastric Acid Suppressants and Subsequent Risk of Cholelithiasis: A Prospective Cohort Study of 0.47 Million Participants. Front Pharmacol 2022; 12:813587. [PMID: 35153765 PMCID: PMC8831324 DOI: 10.3389/fphar.2021.813587] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/28/2021] [Indexed: 12/17/2022] Open
Abstract
Background: Gastric acid suppressants have a major impact on gut microbiome which in turn, may increase the risk of cholelithiasis, but epidemiological evidence remains unclear. We undertook this research to evaluate the association between regular use of proton pump inhibitors (PPIs) and H2-receptor antagonists (H2RAs) with risk of cholelithiasis. Methods: Prospective cohort study included 477,293 UK residents aged 37–73 years from the UK Biobank. We included the participants reported PPI or H2RA use, and were free of cholelithiasis or cancer. We evaluated hazard ratios (HRs) of regular use of PPIs or H2RAs and risk of cholelithiasis adjusting for demographic factors, lifestyle habits, the presence of comorbidities, use of other medications, and clinical indications. Results: We identified 12,870 cases of cholelithiasis over a median follow-up of 8.1 years. Regular use of PPIs (HR 1.22 95% CI 1.16–1.29) or H2RAs (HR 1.16, 95% CI 1.05–1.28) was associated with an increased risk of cholelithiasis after confounding adjustment. There were no major differences among individual PPIs/H2RAs. The absolute risk of PPI-associated cholelithiasis was increased with the baseline predicted risk evaluated by known environmental and genetic risk factors (Risk differences in the lowest vs. the highest quartile: 1.37 vs. 4.29 per 1,000 person-years). Conclusion: Regular use of PPIs and H2RAs was associated with increased risk of cholelithiasis. Future prospective studies are required to confirm whether the observed associations are casual.
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Affiliation(s)
- Man Yang
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Guangdong Provincial Key Laboratory of Gastrointestinal Cancers, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Bin Xia
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- Big Data Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yawen Lu
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Qiangsheng He
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- Big Data Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yanyan Lin
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Ping Yue
- The Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Bing Bai
- The Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Chunlu Dong
- The Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Wenbo Meng
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- *Correspondence: Wenbo Meng, ; Jian Qi, ; Jinqiu Yuan,
| | - Jian Qi
- Guangdong Provincial Key Laboratory of Gastrointestinal Cancers, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- *Correspondence: Wenbo Meng, ; Jian Qi, ; Jinqiu Yuan,
| | - Jinqiu Yuan
- Guangdong Provincial Key Laboratory of Gastrointestinal Cancers, Center for Digestive Disease, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- Big Data Centre, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
- *Correspondence: Wenbo Meng, ; Jian Qi, ; Jinqiu Yuan,
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Yu L, Zhou Y, Wang L, Zhou X, Sun J, Xiao J, Xu X, Larsson SC, Yuan S, Li X. GDF-15 as a Therapeutic Target of Diabetic Complications Increases the Risk of Gallstone Disease: Mendelian Randomization and Polygenic Risk Score Analysis. Front Genet 2022; 13:814457. [PMID: 35769993 PMCID: PMC9234303 DOI: 10.3389/fgene.2022.814457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 05/02/2022] [Indexed: 11/24/2022] Open
Abstract
Growth differentiation factor 15 (GDF-15) levels have been revealed as a robust biomarker for metformin use. We conducted Mendelian randomization (MR) analysis to explore the association between GDF-15 and gallstone disease to inform potential therapeutic effects targeting GDF-15. Four genetic variants associated with GDF-15 levels at p < 5 × 10-8 were selected as instrumental variables from a genome-wide association meta-analysis including 21,758 individuals. Two-sample MR analysis was conducted using summary-level data from UK Biobank (10,520 gallstone cases and 350,674 controls) and FinnGen consortium (19,023 gallstone cases and 195,144 controls). Polygenic risk score analysis using individual-level data in UK biobank was performed to complement the MR findings by examining the non-linearity of the association. Diabetic complications were taken as positive controls to validate the therapeutic effect of targeting GDF-15. Linear and nonlinear associations between genetically predicted GDF-15 levels and gallstones were estimated with stratification by the diabetic status. In the two-sample MR analysis, the odds ratio (OR) of gallstones was 1.09 (95% confidence interval (CI), 1.03-1.15; p = 0.001) for one standard deviation increase in genetically predicted GDF-15 levels in the meta-analysis of two datasets. Polygenic risk score analysis found this association to be U-shaped (p = 0.037). The observed association was predominantly seen in nondiabetic population (OR = 1.11, 95% CI: 1.01-1.21; p = 0.003). An inverse association between genetically predicted GDF-15 levels and diabetic complications (OR = 0.77, 95% CI: 0.62-0.96; p = 0.023) was observed, validating the potential therapeutic effects of targeting GDF-15 levels. This MR study indicates that the increased risk of gallstone disease should be taken into account when considering GDF-15 as a therapeutic target for diabetic complications.
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Affiliation(s)
- Lili Yu
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yajing Zhou
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lijuan Wang
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xuan Zhou
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Sun
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiarui Xiao
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaolin Xu
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Susanna C Larsson
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.,Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Shuai Yuan
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Xue Li
- Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom
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7
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Park SK, Jung JY, Oh CM, Kim MH, Ha E, Lee DY, Kim JW, Kang HY, Ryoo JH. The Level of Urine Dipstick Proteinuria and Its Relation to the Risk of Incident Cholelithiasis. J Epidemiol 2020; 31:59-64. [PMID: 31956168 PMCID: PMC7738639 DOI: 10.2188/jea.je20190223] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background Previous studies have suggested the potential association between renal diseases and gallstone. The extent of proteinuria is recognized as a marker for the severity of chronic kidney disease. However, little data is available to identify the risk of incident gallstone according to the level of proteinuria. Methods Using a data of 207,356 Koreans registered in National Health Insurance Database, we evaluated the risk of gallstone according to the levels of urine dipstick proteinuria through an average follow-up of 4.36 years. Study subjects were divided into 3 groups by urine dipstick proteinuria (negative: 0, mild: 1+ and heavy: 2+ or greater). Multivariate Cox-proportional hazard model was used to assess the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident cholelithiasis according to urine dipstick proteinuria. Results The group with higher urine dipstick proteinuria had worse metabolic, renal, and hepatic profiles than those without proteinuria, which were similarly observed in the group with incident cholelithiasis. The heavy proteinuria group had the greatest incidence of cholelithiasis (2.39%), followed by mild (1.54%) and negative proteinuria groups (1.39%). Analysis for multivariate Cox-proportional hazard model indicated that the heavy proteinuria group had higher risk of cholelithiasis than other groups (negative: reference, mild proteinuria: HR 0.97 [95% CI, 0.74–1.26], and heavy proteinuria: HR 1.46 [95% CI, 1.09–1.96]). Conclusion Urine dipstick proteinuria of 2+ or greater was significantly associated with increased risk for incident gallstone.
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Affiliation(s)
- Sung Keun Park
- Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine
| | - Ju Young Jung
- Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine
| | - Chang-Mo Oh
- Departments of Preventive Medicine, School of Medicine, Kyung Hee University
| | - Min-Ho Kim
- Ewha Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital
| | - Eunhee Ha
- Department of Occupational and Environment Medicine, College of Medicine, Ewha Womans University
| | - Dong-Young Lee
- Department of Internal Medicine, Veterans Healthcare Service Medical Center
| | - Jung-Wook Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyung Hee University School of Medicine
| | - Hee Yong Kang
- Department of Anesthesiology and Pain Medicine, Kyung Hee University Hospital
| | - Jae-Hong Ryoo
- Departments of Occupational and Environmental Medicine, School of Medicine, Kyung Hee University
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9
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Di Ciaula A, Wang DQH, Portincasa P. Cholesterol cholelithiasis: part of a systemic metabolic disease, prone to primary prevention. Expert Rev Gastroenterol Hepatol 2019; 13:157-171. [PMID: 30791781 DOI: 10.1080/17474124.2019.1549988] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cholesterol gallstone disease have relationships with various conditions linked with insulin resistance, but also with heart disease, atherosclerosis, and cancer. These associations derive from mechanisms active at a local (i.e. gallbladder, bile) and a systemic level and are involved in inflammation, hormones, nuclear receptors, signaling molecules, epigenetic modulation of gene expression, and gut microbiota. Despite advanced knowledge of these pathways, the available therapeutic options for symptomatic gallstone patients remain limited. Therapy includes oral litholysis by the bile acid ursodeoxycholic acid (UDCA) in a small subgroup of patients at high risk of postdissolution recurrence, or laparoscopic cholecystectomy, which is the therapeutic radical gold standard treatment. Cholecystectomy, however, may not be a neutral event, and potentially generates health problems, including the metabolic syndrome. Areas covered: Several studies on risk factors and pathogenesis of cholesterol gallstone disease, acting at a systemic level have been reviewed through a PubMed search. Authors have focused on primary prevention and novel potential therapeutic strategies. Expert commentary: The ultimate goal appears to target the manageable systemic mechanisms responsible for gallstone occurrence, pointing to primary prevention measures. Changes must target lifestyles, as well as experimenting innovative pharmacological tools in subgroups of patients at high risk of developing gallstones.
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Affiliation(s)
- Agostino Di Ciaula
- a Division of Internal Medicine , Hospital of Bisceglie , Bisceglie , Italy
| | - David Q-H Wang
- b Department of Medicine, Division of Gastroenterology and Liver Diseases , Marion Bessin Liver Research Center, Albert Einstein College of Medicine , Bronx , NY , USA
| | - Piero Portincasa
- c Department of Biomedical Sciences and Human Oncology, Clinica Medica "A. Murri" , University of Bari Medical School , Bari , Italy
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Portincasa P, van Erpecum KJ, Di Ciaula A, Wang DQH. The physical presence of gallstone modulates ex vivo cholesterol crystallization pathways of human bile. Gastroenterol Rep (Oxf) 2019; 7:32-41. [PMID: 30792864 PMCID: PMC6375352 DOI: 10.1093/gastro/goy044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 08/15/2018] [Accepted: 08/28/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Cholesterol crystallization is an essential step toward gallstone formation. Although model bile studies showed that competition occurs between the gallstone surface and the surrounding aqueous phase for cholesterol molecules available for crystallization, this has not been investigated in human bile. METHODS Fresh gallbladder bile was obtained during laparoscopic cholecystectomy from 13 patients with cholesterol (n = 10) or pigment (n = 3) stones. Small cholesterol gallstones were collected from another two patients. Both native and ultrafiltered bile with or without added gallstones was analysed by polarized light microscopy for the presence of arc-like and needle-like anhydrous cholesterol crystals and classic cholesterol monohydrate crystals. Weight of the added stones was evaluated before and after 21 days of bile incubation. RESULTS In unfiltered bile, the presence of stones was associated with a trend towards less anhydrous cholesterol crystals, but significantly more aggregated cholesterol monohydrate crystals. In ultrafiltered bile, the presence of stones tended to inhibit the formation of arc-like or needle-like crystals and was associated with significantly greater amounts of both plate-like and aggregated cholesterol monohydrate crystals. After 21 days of the incubation, stone weight was decreased in both unfiltered (-4.5 ± 1.6%, P = 0.046) and ultrafiltered bile (-6.5 ± 1.5%, P = 0.002). Bile from pigment-stone patients was clear in the absence of stones, but showed early appearance of plate-like and aggregated cholesterol monohydrate crystals in all samples to which cholesterol gallstones were added. CONCLUSIONS The physical presence of cholesterol gallstones in both native and filtered bile greatly influences cholesterol crystallization pathways. Whereas cholesterol monohydrate crystals increase, anhydrous cholesterol crystals tend to be inhibited. Detachment of solid cholesterol crystals from the gallstone surface may explain these findings.
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Affiliation(s)
- Piero Portincasa
- Division of Internal Medicine, Department of Biomedical Sciences and Human Oncology, University Medical School, Bari, Italy
- Corresponding author. Division of Internal Medicine, Clinica Medica ‘A. Murri’, Department of Biomedical Sciences and Human Oncology, University Medical School, Policlinico, Piazza Giulio Cesare 11, Bari, 70124, Italy. Tel: +39-80-5478892; Fax: +39-80-5478232;
| | - Karel J van Erpecum
- Department of Gastroenterology, University Medical Center, Utrecht, The Netherlands
| | - Agostino Di Ciaula
- Division of Internal Medicine, Hospital of Bisceglie, ASL BAT, Bisceglie, Italy
| | - 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
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11
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Sawas T, Bazerbachi F, Haffar S, Cho WK, Levy MJ, Martin JA, Petersen BT, Topazian MD, Chandrasekhara V, Abu Dayyeh BK. End-stage renal disease is associated with increased post endoscopic retrograde cholangiopancreatography adverse events in hospitalized patients. World J Gastroenterol 2018; 24:4691-4697. [PMID: 30416316 PMCID: PMC6224476 DOI: 10.3748/wjg.v24.i41.4691] [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: 08/08/2018] [Revised: 10/04/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To determine if end-stage renal disease (ESRD) is a risk factor for post endoscopic retrograde cholangiopancreatography (ERCP) adverse events (AEs).
METHODS We performed a retrospective cohort study using the Nationwide Inpatient Sample (NIS) 2011-2013. We identified adult patients who underwent ERCP using the International Classification of Diseases 9th Revision (ICD-9-CM). Included patients were divided into three groups: ESRD, chronic kidney disease (CKD), and control. The primary outcome was post-ERCP AEs including pancreatitis, bleeding, and perforation determined based on specific ICD-9-CM codes. Secondary outcomes were length of hospital stay, in-hospital mortality, and admission cost. AEs and mortality were compared using multivariate logistic regression analysis.
RESULTS There were 492175 discharges that underwent ERCP during the 3 years. The ESRD and CKD groups contained 7347 and 39403 hospitalizations respectively, whereas the control group had 445424 hospitalizations. Post-ERCP pancreatitis (PEP) was significantly higher in the ESRD group (8.3%) compared to the control group (4.6%) with adjusted odd ratio (aOR) = 1.7 (95%CI: 1.4-2.1, aP < 0.001). ESRD was associated with significantly higher ERCP-related bleeding (5.1%) compared to the control group 1.5% (aOR = 1.86, 95%CI: 1.4-2.4, aP < 0.001). ESRD had increased hospital mortality 7.1% vs 1.15% in the control OR = 6.6 (95%CI: 5.3-8.2, aP < 0.001), longer hospital stay with adjusted mean difference (aMD) = 5.9 d (95%CI: 5.0-6.7 d, aP < 0.001) and higher hospitalization charges aMD = $+82064 (95%CI: $68221-$95906, aP < 0.001).
CONCLUSION ESRD is a risk factor for post-ERCP AEs and is associated with higher hospital mortality. Careful selection and close monitoring is warranted to improve outcomes.
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Affiliation(s)
- Tarek Sawas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | - Fateh Bazerbachi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | - Samir Haffar
- Department of Gastroenterology, Digestive Center for Diagnosis and Treatment, Damascus 00000, Syrian Arab Republic
| | - Won K Cho
- Division of Gastroenterology and Hepatology, Georgetown University Medstar Washington Hospital Center, Washington, DC 20010, United States
| | - Michael J Levy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | - John A Martin
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | - Bret T Petersen
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | - Mark D Topazian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | - Vinay Chandrasekhara
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
| | - Barham K Abu Dayyeh
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
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12
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Nexøe-Larsen CC, Sørensen PH, Hausner H, Agersnap M, Baekdal M, Brønden A, Gustafsson LN, Sonne DP, Vedtofte L, Vilsbøll T, Knop FK. Effects of liraglutide on gallbladder emptying: A randomized, placebo-controlled trial in adults with overweight or obesity. Diabetes Obes Metab 2018; 20:2557-2564. [PMID: 29892986 PMCID: PMC6220792 DOI: 10.1111/dom.13420] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 06/01/2018] [Accepted: 06/09/2018] [Indexed: 02/06/2023]
Abstract
AIMS Treatment with liraglutide 3.0 mg has been associated with gallbladder-related adverse events. To conduct a single-centre, double-blind, 12-week trial comparing the effect of 0.6 mg liraglutide and steady-state liraglutide 3.0 mg with placebo on gallbladder emptying in adults with body mass index (BMI) ≥27 kg/m2 and without diabetes. METHODS Participants were randomized 1:1 to once-daily subcutaneous liraglutide (n = 26) or placebo (n = 26), starting at 0.6 mg with 0.6-mg weekly increments to 3.0 mg, with nutritional and physical activity counselling. A 600-kcal (23.7 g fat) liquid meal test was performed at baseline, after the first dose and after 12 weeks. The primary endpoint was the 12-week maximum postprandial gallbladder ejection fraction (GBEFmax ), measured over 240 minutes after starting the meal. RESULTS Baseline characteristics were similar between groups (mean ± SD overall age 47.6 ± 10.0 years, BMI 32.6 ±3.4 kg/m2 , 50% women). Mean 12-week GBEFmax (treatment difference -3.7%, 95% confidence interval [CI] -13.1, 5.7) and area under the GBEF curve in the first 60 minutes (-390% × min, 95% CI -919, 140) did not differ for liraglutide 3.0 mg (n = 23) vs placebo (n = 24). The median (range) time to GBEFmax was 151 (11-240) minutes with liraglutide 3.0 mg and 77 (22-212) minutes with placebo. Similar findings were noted after the first 0.6-mg liraglutide dose. Gastrointestinal disorders, notably nausea and constipation, were the most frequently reported adverse events. CONCLUSIONS Treatment with liraglutide did not affect the GBEFmax but appeared to prolong the time to GBEFmax .
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Affiliation(s)
- Christina C Nexøe-Larsen
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Pernille H Sørensen
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Helene Hausner
- Department of Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark
| | - Mikkel Agersnap
- Department of Medicine and Science, Novo Nordisk A/S, Søborg, Denmark
| | - Mille Baekdal
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Andreas Brønden
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | | | - David P Sonne
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Louise Vedtofte
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
| | - Tina Vilsbøll
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Abstract
PURPOSE OF REVIEW Gallstone disease is a major epidemiologic and economic burden worldwide, and the most frequent form is cholesterol gallstone disease. RECENT FINDINGS Major pathogenetic factors for cholesterol gallstones include a genetic background, hepatic hypersecretion of cholesterol, and supersaturated bile which give life to precipitating cholesterol crystals that accumulate and grow in a sluggish gallbladder. Additional factors include mucin and inflammatory changes in the gallbladder, slow intestinal motility, increased intestinal absorption of cholesterol, and altered gut microbiota. Mechanisms of disease are linked with insulin resistance, obesity, the metabolic syndrome, and type 2 diabetes. The role of nuclear receptors, signaling pathways, gut microbiota, and epigenome are being actively investigated. SUMMARY Ongoing research on cholesterol gallstone disease is intensively investigating several pathogenic mechanisms, associated metabolic disorders, new therapeutic approaches, and novel strategies for primary prevention, including lifestyles.
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Affiliation(s)
| | - 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
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, Bari, Italy
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Abstract
The high prevalence of cholesterol gallstones, the availability of new information about pathogenesis, and the relevant health costs due to the management of cholelithiasis in both children and adults contribute to a growing interest in this disease. From an epidemiologic point of view, the risk of gallstones has been associated with higher risk of incident ischemic heart disease, total mortality, and disease-specific mortality (including cancer) independently from the presence of traditional risk factors such as body weight, lifestyle, diabetes, and dyslipidemia. This evidence points to the existence of complex pathogenic pathways linking the occurrence of gallstones to altered systemic homeostasis involving multiple organs and dynamics. In fact, the formation of gallstones is secondary to local factors strictly dependent on the gallbladder (that is, impaired smooth muscle function, wall inflammation, and intraluminal mucin accumulation) and bile (that is, supersaturation in cholesterol and precipitation of solid crystals) but also to "extra-gallbladder" features such as gene polymorphism, epigenetic factors, expression and activity of nuclear receptors, hormonal factors (in particular, insulin resistance), multi-level alterations in cholesterol metabolism, altered intestinal motility, and variations in gut microbiota. Of note, the majority of these factors are potentially manageable. Thus, cholelithiasis appears as the expression of systemic unbalances that, besides the classic therapeutic approaches to patients with clinical evidence of symptomatic disease or complications (surgery and, in a small subgroup of subjects, oral litholysis with bile acids), could be managed with tools oriented to primary prevention (changes in diet and lifestyle and pharmacologic prevention in subgroups at high risk), and there could be relevant implications in reducing both prevalence and health costs.
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Affiliation(s)
- Agostino Di Ciaula
- Division of Internal Medicine - Hospital of Bisceglie, ASL BAT, Bisceglie, Italy
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Bari, Italy
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15
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Liu FC, Ting PC, Lin JR, Yu HP. Immunosuppressants and new onset gallstone disease in patients having undergone renal transplantation. Ther Clin Risk Manag 2017; 13:1391-1398. [PMID: 29075123 PMCID: PMC5648321 DOI: 10.2147/tcrm.s144975] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND There are very few reports describing the development of gallstone disease after renal transplantation (GSDART) in Asia. The aim of this population-based study was to explore the prevalence, predictive factors, and outcomes of newly developed GSDART. The relationship between immunosuppressant and GSDART was also explored. PATIENTS AND METHODS Renal transplantation (RT) recipients were identified from the National Health Insurance Research Database of Taiwan during January 1998-December 2012. In total, 2,630 adult patients, who had neither been diagnosed with gallstone disease (GSD) nor undergone cholecystectomy, were included in this study. These patients underwent follow-up till the diagnosis of GSDART was established. Risk factors and post-RT immunosuppressant treatments were investigated and analyzed using Cox regression analysis. The cumulative mortality in patients with and without GSDART was also evaluated. RESULTS The final dataset comprised 143 patients who developed GSDART and 2,487 patients who had not been diagnosed with GSDART during the follow-up period. The prevalence of GSDART was 5.4%. On performing univariate analysis, age (p=0.0276) and certain immunosuppressant administrations were identified as significant risk factors for GSDART. After adjusting for age, multivariable analysis showed that everolimus (adjusted hazard ratio 0.287, p=0.0013) was independently associated with the development of GSDART. The overall mortality rate (6.99%, p=0.0341) was significantly decreased in the GSDART group. CONCLUSION Increased age was the most consistent risk factor for GSD, and everolimus-based immunotherapy indicated a decreased incidence of GSDART in RT recipients. The long-term mortality rate was significantly decreased in patients with GSDART.
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Affiliation(s)
- Fu-Chao Liu
- Department of Anesthesiology, Chang Gung Memorial Hospital.,College of Medicine, Chang Gung University
| | - Pei-Chi Ting
- Department of Anesthesiology, Chang Gung Memorial Hospital.,College of Medicine, Chang Gung University
| | - Jr-Rung Lin
- Clinical Informatics and Medical Statistics Research Center and Graduate Institute of Clinical Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China
| | - Huang-Ping Yu
- Department of Anesthesiology, Chang Gung Memorial Hospital.,College of Medicine, Chang Gung University
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16
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Sauerbruch T. EASL Recognition Award Recipient 2017: Prof. Gustav Paumgartner. J Hepatol 2017; 66:875-877. [PMID: 28417885 DOI: 10.1016/j.jhep.2016.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 12/14/2016] [Indexed: 12/04/2022]
Affiliation(s)
- Tilman Sauerbruch
- Department of Medicine, University of Bonn, Sigmund-Freud-Straße 25, Bonn 53105, Germany.
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17
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Sanal B, Korkmaz M, Zeren S, Can F, Elmali F, Bayhan Z. Does gallbladder angle affect gallstone formation? Pan Afr Med J 2016; 24:165. [PMID: 27795762 PMCID: PMC5072821 DOI: 10.11604/pamj.2016.24.165.7768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 06/21/2016] [Indexed: 01/05/2023] Open
Abstract
INTRODUCTION Morphology of gallbladder varies considerably from person to person. We believe that one of the morphological variations of gallbladder is the "gallbladder angle". Gallbladder varies also in "angle", which, to the best of our knowledge, has never been investigated before. The purpose of this study was to investigate the impact of gallbladder angle on gallstone formation. METHODS in this study, 1075 abdominal computed tomography (CT) images were retrospectively examined. Patients with completely normal gallbladders were selected. Among these patients, those with both abdominal ultrasound and blood tests were identified in the hospital records and included in the study. Based on the findings of the ultrasound scans, patients were divided into two groups as patients with gallstones and patients without gallstones. Following the measurement of gallbladder angles on the CT images, the groups were statistically evaluated. RESULTS The gallbladder angle was smaller in patients with gallstones (49 ± 21 degrees and 53 ± 19 degrees) and the gallbladder with larger angle was 1.015 (1/0.985) times lower the risk of gallstone formation. However, these were not statistically significant (p>0,05). CONCLUSION A more vertically positioned gallbladder does not affect gallstone formation. However, a smaller gallbladder angle may facilitate gallstone formation in patients with the risk factors. Gallstones perhaps more easily and earlier develop in gallbladders with a smaller angle.
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Affiliation(s)
- Bekir Sanal
- Department of Radiology, Dumlupinar University Faculty of Medicine, 43100, Kutahya, Turkey
| | - Mehmet Korkmaz
- Department of Radiology, Dumlupinar University Faculty of Medicine, 43100, Kutahya, Turkey
| | - Sezgin Zeren
- Department of General Surgery, Dumlupinar University Faculty of Medicine, 43100, Kutahya, Turkey
| | - Fatma Can
- Department of Radiology, Dumlupinar University Faculty of Medicine, 43100, Kutahya, Turkey
| | - Ferhan Elmali
- Department of Biostatistics and Bioinformatics, Erciyes University Faculty of Medicine, 38100, Kayseri, Turkey
| | - Zulfu Bayhan
- Department of General Surgery, Dumlupinar University Faculty of Medicine, 43100, Kutahya, Turkey
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Tharp KM, Khalifeh-Soltani A, Park HM, Yurek DA, Falcon A, Wong L, Feng R, Atabai K, Stahl A. Prevention of gallbladder hypomotility via FATP2 inhibition protects from lithogenic diet-induced cholelithiasis. Am J Physiol Gastrointest Liver Physiol 2016; 310:G855-64. [PMID: 27033116 PMCID: PMC4888547 DOI: 10.1152/ajpgi.00316.2015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 03/28/2016] [Indexed: 01/31/2023]
Abstract
Gallstone disease is a widespread disorder costing billions for annual treatment in the United States. The primary mechanisms underlying gallstone formation are biliary cholesterol supersaturation and gallbladder hypomotility. The relative contribution of these two processes has been difficult to dissect, as experimental lithogenic diets cause both bile supersaturation and alterations in gallbladder motility. Importantly, there is no mechanistic explanation for obesity as a major risk factor for cholelithiasis. We discovered that lithogenic diets induce ectopic triacylglycerol (TAG) accumulation, a major feature of obesity and a known muscle contraction impairing condition. We hypothesized that prevention of TAG accumulation in gallbladder walls may prevent gallbladder contractile dysfunction without impacting biliary cholesterol saturation. We utilized adeno-associated virus-mediated knock down of the long-chain fatty acid transporter 2 (FATP2; Slc27A2), which is highly expressed by gallbladder epithelial cells, to downregulate lithogenic diet-associated TAG accumulation. FATP2-knockdown significantly reduced gallbladder TAG, but did not affect key bile composition parameters. Importantly, measurements with force displacement transducers showed that contractile strength in FATP2-knockdown gallbladders was significantly greater than in control gallbladders following lithogenic diet administration, and the magnitude of this effect was sufficient to prevent the formation of gallstones. FATP2-driven fatty acid uptake and the subsequent TAG accumulation in gallbladder tissue plays a pivotal role in cholelithiasis, and prevention of this process can protect from gallstone formation, even in the context of supersaturated bile cholesterol levels, thus pointing to new treatment approaches and targets.
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Affiliation(s)
- Kevin M. Tharp
- 1Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
| | - Amin Khalifeh-Soltani
- 2Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California; and
| | - Hyo Min Park
- 1Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
| | | | - Alaric Falcon
- 1Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
| | - Louis Wong
- 1Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
| | - Rouying Feng
- 1Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
| | - Kamran Atabai
- 2Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California; and
| | - Andreas Stahl
- Program for Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California;
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19
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Yoon H, Kwon CI, Jeong S, Lee TH, Han JH, Song TJ, Hwang JC, Kim DJ. Clinical Significance of Biliary Dilatation and Cholelithiasis after Subtotal Gastrectomy. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2016; 66:33-40. [PMID: 26194127 DOI: 10.4166/kjg.2015.66.1.33] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND/AIMS The well-organized study to support that increased cholelithiasis and bile duct dilatation can occur after gastrectomy has not been reported. The aim of this study was to determine the incidence of cholelithiasis and the degree of common bile duct (CBD) dilatation in patients undergoing subtotal gastrectomy, compared to those undergoing endoscopic treatment for gastric cancer. METHODS Patients who diagnosed with gastric cancer and received treatment at six academic referral centers were investigated for the incidence and time of cholelithiasis and the degree of CBD dilatation after treatment by analysis of 5-year follow-up CTs. The operation group underwent subtotal gastrectomy without vagotomy, while in the control group endoscopic treatment was administered for gastric cancer. RESULTS A total of 802 patients were enrolled in 5-year analysis (735 patients in the operation group and 67 patients in the control group). Cholelithiasis occurred in 47 patients (6.39%) in the operation group and 3 patients (4.48%) in the control group (p=0.7909). The incidences of cholelithiasis were 4.28% in Billoth-I and 7.89% in Billoth-II (p=0.0487). The diameter of proximal CBD and distal CBD increased by 1.11 mm and 1.41 mm, respectively, in the operation group, compared to 0.4 mm and 0.38 mm, respectively, in the control group (p0.05). Patients with increased CBD dilatation more than 5 mm showed statistically significant increases in alkaline phosphatase and gamma-glutamyltransferase. CONCLUSIONS The incidence of cholelithiasis was not increased due to subtotal gastrectomy without vagotomy, but the incidence was higher after Billoth-II compared to Billoth-I. In addition, significant change in the CBD diameter was observed after subtotal gastrectomy.
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Affiliation(s)
- Harry Yoon
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Chang Il Kwon
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Seok Jeong
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Tae Hoon Lee
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Joung Ho Han
- Division of Gastroenterology, Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Tae Jun Song
- Division of Gastroenterology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Ilsan, Korea
| | - Jae Chul Hwang
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Dae Jung Kim
- Department of Radiology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
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Chen Y, Kong J, Wu S. Cholesterol gallstone disease: focusing on the role of gallbladder. J Transl Med 2015; 95:124-31. [PMID: 25502177 DOI: 10.1038/labinvest.2014.140] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Revised: 10/11/2014] [Accepted: 10/15/2014] [Indexed: 02/06/2023] Open
Abstract
Gallstone disease (GSD) is one of the most common biliary tract diseases worldwide in which both genetic and environmental factors have roles in its pathogenesis. Biliary cholesterol supersaturation from metabolic defects in the liver is traditionally seen as the main pathogenic factor. Recently, there have been renewed investigative interests in the downstream events that occur in gallbladder lithogenesis. This article focuses on the role of the gallbladder in the pathogenesis of cholesterol GSD (CGD). Various conditions affecting the crystallization process are discussed, such as gallbladder motility, concentrating function, lipid transport, and an imbalance between pro-nucleating and nucleation inhibiting proteins.
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Affiliation(s)
- Yongsheng Chen
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jing Kong
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shuodong Wu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
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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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Corradini SG, Ferri F, Mordenti M, Iuliano L, Siciliano M, Burza MA, Sordi B, Caciotti B, Pacini M, Poli E, Santis AD, Roda A, Colliva C, Simoni P, Attili AF. Beneficial effect of sulphate-bicarbonate-calcium water on gallstone risk and weight control. World J Gastroenterol 2012; 18:930-7. [PMID: 22408352 PMCID: PMC3297052 DOI: 10.3748/wjg.v18.i9.930] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Revised: 09/09/2011] [Accepted: 12/31/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of drinking sulphate-bicarbonate-calcium thermal water (TW) on risk factors for atherosclerosis and cholesterol gallstone disease.
METHODS: Postmenopausal women with functional dyspepsia and/or constipation underwent a 12 d cycle of thermal (n = 20) or tap (n = 20) water controlled drinking. Gallbladder fasting volume at ultrasound, blood vitamin E, oxysterols (7-β-hydroxycholesterol and 7-ketocholesterol), bile acid (BA), triglycerides, total/low density lipoprotein and high density lipoprotein cholesterol were measured at baseline and at the end of the study. Food consumption, stool frequency and body weight were recorded daily.
RESULTS: Blood lipids, oxysterols and vitamin E were not affected by either thermal or tap water consumption. Fasting gallbladder volume was significantly (P < 0.005) smaller at the end of the study than at baseline in the TW (15.7 ± 1.1 mL vs 20.1 ± 1.7 mL) but not in the tap water group (19.0 ± 1.4 mL vs 19.4 ± 1.5 mL). Total serum BA concentration was significantly (P < 0.05) higher at the end of the study than at baseline in the TW (5.83 ± 1.24 μmol vs 4.25 ± 1.00 μmol) but not in the tap water group (3.41 ± 0.46 μmol vs 2.91 ± 0.56 μmol). The increased BA concentration after TW consumption was mainly accounted for by glycochenodeoxycholic acid. The number of pasta (P < 0.001), meat (P < 0.001) and vegetable (P < 0.005) portions consumed during the study and of bowel movements per day (P < 0.05) were significantly higher in the TW than in the tap water group. Body weight did not change at the end of the study as compared to baseline in both groups.
CONCLUSION: Sulphate-bicarbonate-calcium water consumption has a positive effect on lithogenic risk and intestinal transit and allows maintenance of a stable body weight despite a high food intake.
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Nihei N, Sekime A, Kanai S, Takiguchi S, Funakoshi A. Administration of ursodeoxycholate failed to prevent sludge and/or gallstone formation in cholecystokinin-1(A) receptor-deficient mice. Biomed Res 2011; 32:401-6. [DOI: 10.2220/biomedres.32.401] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Abstract
BACKGROUND AND AIM The incidence of gallbladder stones is higher in women during pregnancy than in men. Progesterone can inhibit gallbladder motility and facilitate gallstone formation. However, the ionic mechanisms have not been fully illuminated. This study sought to investigate the effects of progesterone on L-type calcium currents and voltage-dependent potassium currents in gallbladder smooth muscle cells. METHODS Gallbladder smooth muscle cells were isolated by enzymatic digestion from adult guinea pigs. Ionic currents were recorded by the whole-cell patch clamp method. RESULTS Progesterone inhibited L-type calcium currents in a concentration-dependent manner. The characteristic of current-voltage curve was not significantly altered. The amplitude of calcium currents was gradually suppressed, reached a steady-state level within 4-6 min, and restored partly after washout. In the presence of protein kinase A (PKA) inhibitor, Rp-cAMP, the inhibitory effect induced by progesterone was apparently attenuated, whereas forskolin, a direct activator of adenylate cyclase, could suppress L-type calcium channel. However, progesterone did not significantly affect voltage-dependent potassium currents. CONCLUSIONS Progesterone inhibits L-type calcium channel by cAMP/PKA pathway in gallbladder smooth muscle cells. This may be an important mechanism for the gallbladder hypomotility induced by progesterone.
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Affiliation(s)
- Zhixuan Wu
- Department of Gastroenterology, The Second Affiliated Hospital, Chonqing Medical Universtity, Chonqing, China
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Abstract
Cholesterol gallstone formation is a complex process and involves phase separation of cholesterol crystals from supersaturated bile. In most cases, cholesterol hypersecretion is considered the primary event in gallstone formation. The sterol is transported through the hepatocytic canalicular membrane by ABCG5-G8. Expression of this transport protein is regulated by transcription factor Liver X Receptor-alpha, which may be responsible for biliary hypersecretion. Hydrophobic bile salt pool, bile concentration, excess pronucleating mucin, and impaired gallbladder and intestinal motility are secondary phenomena in most cases but nevertheless may contribute to gallstone formation.
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Affiliation(s)
- Niels Gerard Venneman
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
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Di Ciaula A, Wang DQH, Wang HH, Bonfrate L, Portincasa P. Targets for current pharmacologic therapy in cholesterol gallstone disease. Gastroenterol Clin North Am 2010; 39:245-64, viii-ix. [PMID: 20478485 PMCID: PMC2915454 DOI: 10.1016/j.gtc.2010.02.005] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gallstone disease is a frequent condition throughout the world and, cholesterol stones are the most frequent form in Western countries. The standard treatment of symptomatic gallstone subjects is laparoscopic cholecystectomy. The selection of patients amenable for nonsurgical, medical therapy is of key importance; a careful analysis should consider the natural history of the disease and the overall costs of therapy. Only patients with mild symptoms and small, uncalcified cholesterol gallstones in a functioning gallbladder with a patent cystic duct are considered for oral litholysis by hydrophilic ursodeoxycholic acid, in the hope of achieving cholesterol desaturation of bile and progressive stone dissolution. Recent studies have raised the possibility that cholesterol-lowering agents that inhibit hepatic cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe), or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis, may offer, alone or in combination, additional medical therapeutic tools for treating cholesterol gallstones. Recent perspectives on medical treatment of cholesterol gallstone disease are discussed in this article.
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Affiliation(s)
- Agostino Di Ciaula
- Division of Internal Medicine, Hospital of Bisceglie, via Bovio 279 - 70052 - Bisceglie (Bari), Italy, +39-80-3363271, +39-80-3363232 (fax)
| | - David Q.-H. Wang
- Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School and Harvard Digestive Diseases Center, 330 Brookline Avenue, DA 601, Boston, MA 02215, (617) 667-0561, (617) 975-5071 (fax)
| | - Helen H. Wang
- Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, DA 601, Boston, MA 02215, (617) 667-5156, (617) 975-5071 (fax)
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Internal and Public Medicine, University of Bari Medical School, Piazza Giulio Cesare 11, Policlinico, 70124 Bari, Italy. +39-80-5478227, +39-80-5478232 (fax)
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Internal Medicine and Public Medicine, University Medical School, Bari, Italy
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Abstract
A review is presented of Gustav Paumgartner's five decades of research and practice in hepatology focusing on biliary physiology and disease. It begins with studies of the excretory function of the liver including hepatic uptake of indocyanine green, bilirubin, and bile acids. The implications of these studies for diagnosis and understanding of liver diseases are pointed out. From there, the path of scientific research leads to investigations of hepatobiliary bile acid transport and the major mechanisms of bile formation. The therapeutic effects of the hydrophilic bile acid, ursodeoxycholic acid, have greatly stimulated these studies. Although ursodeoxycholic acid therapy for dissolution of cholesterol gallstones and some other nonsurgical treatments of gallstones were largely superseded by surgical techniques, ursodeoxycholic acid is currently considered the mainstay of therapy of some chronic cholestatic liver diseases, such as primary biliary cirrhosis. The major mechanisms of action of ursodeoxycholic acid therapy in cholestatic liver diseases are discussed. An attempt is made to illustrate how scientific research can lead to advances in medical practice that help patients.
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Affiliation(s)
- Gustav Paumgartner
- Department of Medicine II, Klinikum Grosshadern, University of Munich, Munich, Germany.
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Bektas A, Belet U, Kelkitli E, Bakir T, Acikgoz A, Akpolat T. Ultrasonic Gallbladder Function in Chronic Kidney Disease: Does Predialysis, Hemodialysis, or CAPD Affect it? Ren Fail 2009; 27:677-81. [PMID: 16350817 DOI: 10.1080/08860220500234949] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND There are contradictory reports about the prevalence of cholelithiasis in chronic kidney disease (CKD). The pathogenesis of gallstones is associated with the lithogenic changes of bile composition, increased tendency to nucleation, and decreased gallbladder motility. The studies related to these factors can predict the development of cholelithiasis. The aim of this study was to evaluate the ultrasonic gallbladder function in CKD and to compare it in predialysis (PreD), hemodialysis (HD), and continuous ambulatory peritoneal dialysis (CAPD) patients. METHODS Age, gender, and body mass index matched 49 CKD patients (14 PreD, 19 HD, 16 CAPD), and 17 control individuals were included in the study. Diabetic and cirrhotic patients were not included. Ultrasonic gallbladder volume was evaluated in pre- and postprandial period, and ejection fraction was calculated. We also measured several biochemical parameters (cholesterol, triglyceride, blood urea nitrogen (BUN), creatinine, calcium, Phosphorus, parathormone, albumin, total protein) in blood. RESULTS Preprandial gallbladder volume in PreD, HD, CAPD, and control groups were 26.7 +/-13.6, 20.8+/-10.4, 23.2+/-14.7, and 26.4+/-14.8 mL, respectively (p > 0.05). Ejection fractions were 54.1 +/- 22.9%, 54.9 +/- 23.9%, 48.6 +/- 15.9%, and 51.8 +/- 19.2% in PreD, HD, CAPD, and control groups, respectively (p > 0.05). Serum triglyceride was higher in PreD patients than control group (207 +/- 144 vs. 110 +/-48 mg/dL) (p<0.05). Serum BUN, Cre, P, and PTH levels were higher in CKD groups than the control group, whereas serum total protein and albumin levels were higher in the control group (p<0.05). Serum Ca was lower in PreD and HD patients than in the controls (p<0.05). CONCLUSIONS In conclusion, CKD and renal replacement therapy (HD and CAPD) do not affect gallbladder functions, but more studies are needed to evaluate prevalence of gallstones, gallbladder motility, and the composition of bile in CKD.
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Affiliation(s)
- Ahmet Bektas
- Department of Gastroenterology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.
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Abstract
Function tests in gastroenterology and hepatology aim to provide criteria for diagnosis of specific disorders and for prediction of patient responses to therapy. This review focuses on the utility of function tests in the management of gallstone disease and functional biliary disorders. In gallstone disease, function tests may be considered in the selection of candidates for nonsurgical therapy of gallbladder stones only. In cases of suspected functional biliary disorders, experts have advocated the use of classical noninvasive tests such as hepatobiliary scintigraphy. However, unequivocal evidence for their utility in diagnosis or patient selection for invasive treatment is yet to be provided. Recently, more advanced noninvasive tests such as real-time ultrasonography or secretin-stimulated magnetic resonance cholangiopancreaticography have been described. Controlled trials using these novel techniques may provide a rationale for the use of function tests in clinical management of calculous and acalculous biliary diseases, but are currently not available.
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Affiliation(s)
- Marc Dauer
- Department of Medicine II, Saarland University Hospital, Saarland University, Kirrberger Str., 66421 Homburg/Saar, Germany.
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Lai SW, Liao KF, Lai HC, Chou CY, Cheng KC, Lai YM. The prevalence of gallbladder stones is higher among patients with chronic kidney disease in Taiwan. Medicine (Baltimore) 2009; 88:46-51. [PMID: 19352299 DOI: 10.1097/md.0b013e318194183f] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
The pathogenesis of gallstone disease is multifactorial. Few studies have focused on gallbladder stones in the chronic kidney disease population in Taiwan. We conducted the current study to determine the prevalence of gallbladder stones in populations with and without chronic kidney disease.This was a hospital-based, cross-sectional study. We retrospectively analyzed the patients receiving periodic health examinations at 1 medical center in Taiwan from 2001 to 2004. In all, 4773 patients were enrolled in the study. Chronic kidney disease was defined as a glomerular filtration rate less than 60 mL/min per 1.73 m by the Modification of Diet in Renal Disease formula. Odds ratio (OR) and 95% confidence intervals (CI) were expressed using a multivariate logistic regression analysis.We studied 2686 men (56.3%) and 2087 women (43.7%). The mean age was 49.1 +/- 12.2 years (range, 20-87 yr). The prevalence of gallbladder stones was 13.1% in the group of patients with chronic kidney disease and 4.9% in the group of patients without chronic kidney disease (p < 0.001). After controlling for the other covariates, multivariate logistic regression analysis showed that increasing age (aged 40-64 yr vs. 20-39 yr, OR = 3.06, 95% CI = 1.81-5.15; and > or =65 yr vs. 20-39 yr, OR = 6.13, 95% CI = 3.42-10.98), chronic kidney disease (OR = 1.58, 95% CI = 1.01-2.47), body mass index > or =27 kg/m (OR = 1.39, 95% CI = 1.02-1.91), metabolic syndrome (OR = 1.45, 95% CI = 1.08-1.94), and cirrhosis (OR = 4.23, 95% CI = 1.25-14.29) were significantly related to gallbladder stone disease.The prevalence of gallbladder stones in patients with chronic kidney disease is significantly higher than in those without chronic kidney disease. Our findings suggest that increasing age, chronic kidney disease, body mass index > or =27 kg/m, metabolic syndrome, and cirrhosis are the related factors for gallbladder stone formation.
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Affiliation(s)
- Shih-Wei Lai
- From the Department of Family Medicine (SWL, KCC, YML) and Department of Internal Medicine (KFL, HCL, CYC), China Medical University Hospital, Taichung, Taiwan
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Pamuk GE, Umit H, Harmandar F, Yeşil N. Patients with iron deficiency anemia have an increased prevalence of gallstones. Ann Hematol 2008; 88:17-20. [PMID: 18679684 DOI: 10.1007/s00277-008-0557-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2008] [Accepted: 07/08/2008] [Indexed: 10/21/2022]
Abstract
We determined the frequency of gallstones (GS) in iron deficiency anemia (IDA) patients and evaluated factors that could affect GS formation-like lipid levels and gallbladder (GB) motilities of the patients. One hundred and eleven IDA patients (88 females, 23 males; median age, 42) and 81 healthy controls (68 females, 13 males; median age, 42) were included into our study. The clinical findings of all IDA patients were recorded down; biochemical values and body mass index (BMI) were determined; and abdominal ultrasonography was performed. In addition, GB emptying was monitored by ultrasound at 30-min intervals for 2 h after a mixed meal in randomly chosen, age-matched 25 IDA patients and 26 controls. Fasting volume (FV), residual volume (RV), and ejection fraction (EF) for all GBs were determined. The frequency of GS plus cholecystectomy was significantly higher in IDA patients (15 cases, 13.5%) than in the control group (five cases, 6.2%, p = 0.048). IDA patients with GS plus cholecystectomy were older than those without GS plus cholecystectomy (p < 0.001). FV and EF did not differ between IDA and control groups (p > 0.05). On the other hand, RV was significantly higher in IDA group than in controls (p = 0.035). The frequency of GS in IDA patients was significantly higher than in controls. The increased prevalence of GS in IDA might be explained with impaired GB motility.
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Affiliation(s)
- Gülsüm Emel Pamuk
- Division of Hematology, Trakya University Medical Faculty, Edirne, Turkey.
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Abstract
BACKGROUND AND OBJECTIVES The mechanisms that trigger gallbladder evacuation dysfunction, the key risk factor for gallstone formation, have not yet been fully elucidated. The sphincter of Oddi (SO) plays important roles in the regulation of gallbladder evacuation and maintenance of normal hydraulic pressure of the biliary tract. The aim of our study was to investigate the effects of hypercholesterolemia on the motility function of SO and the underlying mechanisms of SO dysfunction (SOD). METHODS Forty New Zealand white rabbits were divided randomly into the control group fed with standard chow and the experimental (Ch) group fed with a high-cholesterol diet for 8 weeks. Changes in the maximal gallbladder emptying rate, gallbladder evacuation with cholecystokinin-octapeptide (CCK-8) stimulation and SO functions of both groups were measured in vivo; B ultrasound examination was used for dynamic observation of peristaltic movements in vivo; SO pressure was measured using manometry; morphological characteristics were observed by electronic microscope; laser scanning confocal fluorescence microscopy was used to identify changes in [Ca]i and Ca oscillation in primary SO smooth muscle cells (SMCs). RESULTS Gallbladder cholestasis was observed during early stages of gallstone formation in Ch rabbits. CCK-8 could not improve the gallbladder cholestatic state in Ch group. Passive dilation of SO significantly improved the cholestatic state in Ch rabbits (P<0.05), although the maximal gallbladder emptying rate was still lower than that of the control group. Manometry data indicted a significant increase in the base pressure of the SO low-pressure ampulla segment and high-pressure segment (P<0.05) in Ch group. laser scanning confocal fluorescence microscopy assay data indicated that [Ca]i in SO cells of Ch group significantly increased and were in a state of overload (P<0.05); Ca oscillation signals in SO cells of Ch group were also abnormal. CONCLUSION Hypercholesterolemia initially induced SOD, leading to increased gallbladder evacuation resistance and cholestasis. We suggested that [Ca]i overload and/or Ca oscillation abnormality potentially play important roles in the pathogenesis of SOD.
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Klass DM, Lauer N, Hay B, Kratzer W, Fuchs M. Arg64 variant of the beta3-adrenergic receptor is associated with gallstone formation. Am J Gastroenterol 2007; 102:2482-7. [PMID: 17640319 DOI: 10.1111/j.1572-0241.2007.01430.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The beta3-adrenergic receptor (ADRB3) is a transmembrane receptor highly expressed in adipose tissue and thought to be involved in the regulation of lipolysis. ADRB3 is also highly expressed in gallbladder tissue where it may be involved in gallbladder contraction. Because polymorphisms of ADRB3 are present in populations with a high prevalence of gallstones (e.g., Pima-Indians, obese subjects), we hypothesized that known polymorphisms for ADRB3 (Trp64Arg) may represent an independent risk factor for gallstone disease. METHODS The EMIL cross-sectional study investigated the health behavior and prevalence of chronic diseases in a small Southwestern German town of 12,475 inhabitants. From 3,893 randomly selected citizens 2,147 subjects were enrolled and screened for gallstones employing ultrasonography. Blood samples were drawn for biochemical analysis and isolation of genomic DNA. ADBR3 genotypes were determined by TaqMan SNP Assay. RESULTS We identified 171 (8%) gallstone carriers of whom 143 participated (46 male, 97 female), with a mean age of 51.4, and mean BMI of 29.3 kg/m2. For these subjects an age, gender and BMI matched partner without gallstones was recruited from the study population. Genotyping for ADRB3 revealed an Arg64 allele frequency of 5.9 versus 0.7% (HR = 11.9, P < 0.05) compared with controls. CONCLUSIONS Our results indicate that the ADRB3 Trp64Arg polymorphism is associated with gallstone disease thereby representing a genetic marker that identifies subjects at higher risk for gallstone formation.
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Affiliation(s)
- Dietmar M Klass
- Department of Internal Medicine I, University Hospital Ulm, Germany
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35
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Miyasaka K, Kanai S, Ohta M, Sekime A, Akimoto S, Takiguchi S, Funakoshi A. Susceptibility to obesity and gallbladder stasis produced by a protein- and fat-enriched diet in male mice compared with female mice. Nutr Metab (Lond) 2007; 4:14. [PMID: 17547774 PMCID: PMC1914076 DOI: 10.1186/1743-7075-4-14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2007] [Accepted: 06/05/2007] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The frequency of Japanese subjects over 20 years old with metabolic syndrome is 45.6% in men but just 16.7% in women. The reason why Japanese male subjects are more susceptible to metabolic syndrome than women is unknown. One possibility is the higher frequency of Japanese male subjects (40-70 years old) who had a drinking habit (67%), while that of female subjects was only 25%. In addition, daily fat intake was markedly increased in Japanese subjects (from 9% to 25%), and cholesterol cholelithiasis is one of the most rapidly increasing digestive diseases during the past 50 years. The object of this study is to examine whether a potential sex-related risk factor exists in the manifestation of metabolic syndrome as well as gallstone formation. METHODS Gallbladder dysmotility accerelates gallstone formation and gallbladder contraction depends on cholecystokinin (CCK) and its receptor (CCK-1R). We developed CCK-1R gene knockout (-/-) mice. The effects of the fat- and protein- enriched diet OA-2 on body weight, hyperlipidemia, and frequencies of sludge and gallstone formation were examined, and compared between wild-type and CCK-1R(-/-) male and female mice. The OA-2 diet contains slightly higher protein and fat (7.9 % fat and 27.6 % protein) compared with a standard diet (CRF-1) (5.6 % fat and 22.6 % protein), but their total energies are similar. After weaning, CRF-1 was provided until 3 months of age in all animals. Administration of an OA-2 diet was started when age-matched CCK-1R(-/-) and wild-type male and female mice reached maturity, at 3 months of age. Administration of CRF-1 was continued in the rest of the animals. Mice were sacrificed by guillotine at 6 and 12 months of age and the blood was collected to measure plasma levels of triglyceride and cholesterol. The gallbladder was removed and classified as normal (clear gallbladder), clouded (sludge formation), and/or containing gallstone formations. RESULTS As long as CRF-1 was provided, the frequency of sludge and/or gallstone formation in CCK-1R(-/-) male mice was 3 of 8 (35%) and 4 of 9 (45%) in females at 12 months of age, whereas no gallstone formation was observed at 6 months of age. On the other hand, male mice fed OA-2 increased their body weight and plasma lipid concentrations, compared with those fed CRF-1 regardless of genotype. Under the OA-2 diet, sludge and gallstone formation was observed at 6 months of age, not only in CCK-1R(-/-) male mice but also in wild-type male mice. In contrast, parameters in female mice did not differ between the two diets. CONCLUSION Male mice were more susceptible to protein- and fat-enriched diet-induced obesity than female mice, and hyper-nutritional status accelerated sludge and gallstone formation in male mice.
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Affiliation(s)
- Kyoko Miyasaka
- Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho Itabashiku 173-0015, Tokyo, Japan
| | - Setsuko Kanai
- Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho Itabashiku 173-0015, Tokyo, Japan
| | - Minoru Ohta
- Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho Itabashiku 173-0015, Tokyo, Japan
| | - Ayako Sekime
- Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho Itabashiku 173-0015, Tokyo, Japan
| | - Saeko Akimoto
- Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho Itabashiku 173-0015, Tokyo, Japan
| | - Soichi Takiguchi
- Department of Clinical Research, National Kyushu Cancer Center, 3-1-1 Notame, Minamiku Fukuoka 811-1396, Japan
| | - Akihiro Funakoshi
- Division of Gastroenterology, National Kyushu Cancer Center, 3-1-1 Notame, Minamiku Fukuoka 811-1396, Japan
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Miyasaka K, Kanai S, Ohta M, Hosoya H, Sekime A, Akimoto S, Takiguchi S, Funakoshi A. Age-associated gallstone formation in male and female CCK-1(A) receptor-deficient mice. J Gastroenterol 2007; 42:493-6. [PMID: 17671765 DOI: 10.1007/s00535-007-2036-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2006] [Accepted: 02/21/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND Gallbladder dysmotility accelerates cholelithiasis. In turn, gallbladder dysmotility can occur secondary to inflammation and excess cholesterol accumulation in gallbladder smooth muscle. METHODS The present study was designed to determine how much gallbladder dysmotility contributes to gallstone formation as a primary cause and whether a sex difference exists in gallstone formation by comparing cholecystokinin-1 receptor gene-deficient [CCK-1R(-/-)] male and female mice. RESULTS No sludge or gallstone formation was observed in mice at 6 months of age. The frequency of sludge and gallstone formation in mice at 12 and 24 months of age was slightly higher in female CCK-1R(-/-) mice than in males, but the difference was not significant. CONCLUSIONS Gallbladder dysmotility may have accelerated sludge and gallstone formation, but its contribution was limited. A 12-month period was required to produce gallstones, and after the mice reached 12 months of age, further ageing did not increase the frequency of gallstones. The effect of sex did not reach a significant level.
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Affiliation(s)
- Kyoko Miyasaka
- Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
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Abstract
With a prevalence of 10-15% in adults in Europe and the USA, gallstones are the most common digestive disease needing admission to hospital in the West. The interplay between interprandial and postprandial physiological responses to endogenous and dietary lipids underscores the importance of coordinated hepatobiliary and gastrointestinal functions to prevent crystallisation and precipitation of excess biliary cholesterol. Indeed, identifying the metabolic and transcriptional pathways that drive the regulation of biliary lipid secretion has been a major achievement in the field. We highlight scientific advances in protein and gene regulation of cholesterol absorption, synthesis, and catabolism, and biliary lipid secretion with respect to the pathogenesis of cholesterol gallstone disease. We discuss the physical-chemical mechanisms of gallstone formation in bile and the active role of the gallbladder and the intestine. We also discuss gaps in our knowledge of the pathogenesis of gallstone formation and the potential for gene targeting in therapy.
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Affiliation(s)
- Piero Portincasa
- Department of Internal and Public Medicine, University Medical School, Bari, Italy.
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Venneman NG, Besselink MGH, Keulemans YCA, Vanberge-Henegouwen GP, Boermeester MA, Broeders IAMJ, Go PMNYH, van Erpecum KJ. Ursodeoxycholic acid exerts no beneficial effect in patients with symptomatic gallstones awaiting cholecystectomy. Hepatology 2006; 43:1276-83. [PMID: 16729326 DOI: 10.1002/hep.21182] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ursodeoxycholic acid (UDCA) and impaired gallbladder motility purportedly reduce biliary pain and acute cholecystitis in patients with gallstones. However, the effect of UDCA in this setting has not been studied prospectively. This issue is important, as in several countries (including the Netherlands) scheduling problems result in long waiting periods for elective cholecystectomy. We conducted a randomized, double-blind, placebo-controlled trial on effects of UDCA in 177 highly symptomatic patients with gallstones scheduled for cholecystectomy. Patients were stratified for colic number in the preceding year (<3: 32 patients; > or =3: 145 patients). Baseline postprandial gallbladder motility was measured by ultrasound in 126 consenting patients. Twenty-three patients (26%) receiving UDCA and 29 (33%) receiving placebo remained colic-free during the waiting period (89 +/- 4; median [range]: 75[4-365] days) before cholecystectomy (P = .3). Number of colics, non-severe biliary pain, and analgesics intake were comparable. A low number of prior colics was associated with a higher likelihood of remaining colic-free (59% vs. 23%, P < .001), without effects on the risk of complications. In patients evaluated for gallbladder motility, 57% were weak and 43% were strong contractors (minimal gallbladder volume > respectively < or = 6 mL). Likelihood to remain colic-free was comparable in strong and weak contractors (31% vs. 33%). In weak contractors, UDCA decreased likelihood to remain colic-free (21% vs. 47%, P = .02). In the placebo group, 3 preoperative and 2 post-cholecystectomy complications occurred. In contrast, all 4 complications in the UDCA group occurred after cholecystectomy. In conclusion, UDCA does not reduce biliary symptoms in highly symptomatic patients. Early cholecystectomy is warranted in patients with symptomatic gallstones.
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Affiliation(s)
- Niels G Venneman
- Gastrointestinal Research Unit, Department of Gastroenterology, University Medical Center Utrecht, The Netherlands
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39
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Sackmann M. Long-term recurrence of gallbladder stones after shock-wave lithotripsy. Scand J Gastroenterol 2006; 41:249-51. [PMID: 16497609 DOI: 10.1080/00365520500495722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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40
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Carrilho-Ribeiro L, Pinto-Correia A, Velosa J, Carneiro De Moura M. A ten-year prospective study on gallbladder stone recurrence after successful extracorporeal shock-wave lithotripsy. Scand J Gastroenterol 2006; 41:338-42. [PMID: 16497623 DOI: 10.1080/00365520500483256] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The risk of recurrence has limited the acceptability of conservative therapies of gallbladder stones. The aim of the present study was to determine the long-term rate of stone recurrence and its risk factors after successful extracorporeal shock-wave lithotripsy (ESWL). MATERIAL AND METHODS The study comprised a prospective ultrasound follow-up at yearly intervals or whenever biliary pain was reported. A total of 192 consecutive patients (primary single stones, n=159; primary 2 or 3 stones, n=33) were followed for up to 11.2 years after becoming stone-free and after termination of adjuvant treatment with ursodeoxycholic acid (UDCA). RESULTS Eighty-four patients developed recurrent stones after a median of 2.6 years (maximum?=?8.8 years). The 108 patients without recurrence were followed for a median of 6.7 years (maximum=11.2 years). By actuarial analysis, the cumulative recurrence rates for these 192 stone-free patients were 27%+/-3%, 41%+/-4% and 54%+/-4% (observed +/-SE) at 3, 5 and 10 years, respectively. Cox's regression analysis was used to identify the presence of slight calcification in the primary stone(s) as a protective feature against recurrence (p=0.03). CONCLUSIONS 1) The risk of recurrence continues to increase over time, and although it rises less steeply after 5 years, it does not reach a plateau until at least 10 years. 2) Having had slightly calcified stone(s) seems to be associated with a reduced risk of recurrence and might signal a "burnt out" lithogenic process. 3) The long-term results are unsatisfactory and ESWL of gallbladder stones should be offered only in special cases.
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41
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Portincasa P, Moschetta A, Petruzzelli M, Palasciano G, Di Ciaula A, Pezzolla A. Gallstone disease: Symptoms and diagnosis of gallbladder stones. Best Pract Res Clin Gastroenterol 2006; 20:1017-29. [PMID: 17127185 DOI: 10.1016/j.bpg.2006.05.005] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The clinical aspects and the diagnostic features of gallstone disease are described. The natural history of silent gallstones is overviewed, and the risk of developing symptoms and complications is also discussed. The importance of colicky pain as a specific gallstone symptom is highlighted, and the role of both laboratory tests and diagnostic investigations for differential diagnosis is discussed. Finally, we describe the diagnostic features of gallbladder stone disease, including indications, sensitivity, specificity, and limitations of different test investigations under special circumstances.
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Affiliation(s)
- P Portincasa
- Clinica Medica A. Murri, Department of Internal and Public Medicine, University of Bari Medical School, Piazza Giulio Cesare 11-Policlinico-70124 Bari, Italy.
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42
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Montet JC, Caroli-Bosc FX, Ferrari P, Piche T, Baize N, Anty R, Montet AM, Rampal P, Tran A. Gallbladder motility and gut hormone plasma levels in subjects with and without gallstones. ACTA ACUST UNITED AC 2005; 29:569-72. [PMID: 15980753 DOI: 10.1016/s0399-8320(05)82131-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Hormonal control of gallbladder motility is still unclear in patients with cholelithiasis. In a case-control study, we determined the characteristics of gallbladder emptying evaluated sonographically and the hormone levels of somatostatin, gastrin, and pancreatic polypeptide, before and after a fatty meal in 10 gallstone patients compared with 20 healthy subjects. Patients with lithiasis had a larger residual volume (median 12,0 ml vs 6,5 ml; P = 0.01) and a lower gallbladder ejection fraction (43% vs 70%, P = 0.02) than healthy subjects. During fasting, plasma pancreatic polypeptide concentrations were significantly higher in lithiasis patients (P < 0.03). In contrast, no differences between the two groups of patients were observed during the post prandial period. Somatostatin and gastrin plasma levels were similar in the two groups. Lastly, the serum bile salt levels were in the normal range and were not different between groups both during fasting and postprandial states. We conclude that large basal plasma concentrations of pancreatic polypeptide, a gut peptide inducing gallbladder relaxation, may constitute a factor facilitating lithogenesis.
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43
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Rabenstein T, Radespiel-Tröger M, Höpfner L, Benninger J, Farnbacher M, Greess H, Lenz M, Hahn EG, Schneider HT. Ten years experience with piezoelectric extracorporeal shockwave lithotripsy of gallbladder stones. Eur J Gastroenterol Hepatol 2005; 17:629-39. [PMID: 15879725 DOI: 10.1097/00042737-200506000-00007] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND A critical review of the experience with extracorporeal shockwave lithotripsy (ESWL) of gallbladder stones is needed to clarify whether this method should continue to be applied to patients. METHODS Patients with symptomatic gallbladder stones were treated by piezoelectric ESWL according to a prospective protocol between 1988 and 1997. ESWL treatment was limited to a maximum of three (solitary stones <20 mm diameter) to five sessions (larger solitary or multiple stones) and 3000 pulses per session. Univariate and multivariate analyses of pretreatment and treatment variables were performed to investigate their impact on fragmentation efficacy and stone clearance. A tree-based analysis was used to identify prognostically homogenous subgroups of individuals with maximum benefit from ESWL. RESULTS Four hundred and eight patients, 76% female and 24% male, with a mean age of 46 (SD, 13) years, were selected for evaluation. Cox regression analysis identified three pretreatment variables with significant prognostic impact: (1) number of gallstones >1 (relative risk, 2.6 (95% CI, 1.9-3.5)), (2) size of stones >17 mm (1.7 (1.4-2.2)), and (3) computed tomography (CT) density of stones >55 Hounsfield units (H) (1.4 (1.1-1.8)). According to tree-based analysis, the stone clearance rate after 1 year was 85% (95% CI, 75-91%) for solitary stones <16 mm, 79% (70-86%) for solitary stones > or =16 mm with a CT density <84 H, 45% (32-55%) for solitary stones > or =16 mm with a CT density > or =84 H, and 42% (30-51%) for multiple stones. Five years after stone clearance, recurrence occurred in 43% of patients (95% CI, 39-47%). CONCLUSIONS ESWL treatment showed an acceptable stone clearance in the case of small solitary gallbladder stones (<16 mm) or larger solitary stones with a CT density <84 H, but a very low success rate in the case of multiple stones. The poor long-term success, however, is an important argument against the use of ESWL of gallbladder stones.
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Paumgartner G, Sauter GH. Extracorporeal shock wave lithotripsy of gallstones: 20th anniversary of the first treatment. Eur J Gastroenterol Hepatol 2005; 17:525-7. [PMID: 15827443 DOI: 10.1097/00042737-200505000-00009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Twenty years ago, in January 1985, extracorporeal shock wave lithotripsy (ESWL) was first applied successfully in a patient with gallbladder stones. In the following years, the conditions which influence the success rate of ESWL have been extensively investigated. It was shown that the characteristics of the stones, gallbladder emptying and the degree of stone fragmentation are the most important factors which determine the clearance of all fragments from the gallbladder after ESWL. Severe side effects, such as biliary pancreatitis and liver haematoma, were found to be rare and no deaths related to the procedure have been reported. One or more episodes of biliary pain were observed in about one third of patients within the first 3-4 months after ESWL. Follow-up studies after successful treatment, however, have shown that stone recurrence is considerable, limiting the use of ESWL as a non-invasive therapeutic option. Stone recurrence varies between different subgroups of patients indicating that gallbladder motor function and other less well defined factors may be of importance. The recurrence of stones after ESWL is one of the reasons why laparoscopic cholecystectomy has become the standard treatment of symptomatic gallbladder stones today. ESWL has kept its role only in the treatment of bile duct stones resistant to endoscopic extraction. Unless stone recurrence can be decreased by better patient selection and/or other measures to prevent gallstone recurrence, ESWL of gallbladder stones has little chance of surviving.
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Affiliation(s)
- Gustav Paumgartner
- Department of Medicine II, University Hospital Munich-Grosshadern, Germany.
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45
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Venneman NG, Renooij W, Rehfeld JF, VanBerge-Henegouwen GP, Go PMNYH, Broeders IAMJ, van Erpecum KJ. Small gallstones, preserved gallbladder motility, and fast crystallization are associated with pancreatitis. Hepatology 2005; 41:738-46. [PMID: 15793851 DOI: 10.1002/hep.20616] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Acute pancreatitis is a severe complication of gallstones with considerable mortality. We sought to explore the potential risk factors for biliary pancreatitis. We compared postprandial gallbladder motility (via ultrasonography) and, after subsequent cholecystectomy, numbers, sizes, and types of gallstones; gallbladder bile composition; and cholesterol crystallization in 21 gallstone patients with previous pancreatitis and 30 patients with uncomplicated symptomatic gallstones. Gallbladder motility was stronger in pancreatitis patients than in patients with uncomplicated symptomatic gallstones (minimum postprandial gallbladder volumes: 5.8 +/- 1.0 vs. 8.1 +/- 0.7 mL; P = .005). Pancreatitis patients had more often sludge (41% vs. 13%; P = .03) and smaller and more gallstones than patients with symptomatic gallstones (smallest stone diameters: 2 +/- 1 vs. 8 +/- 2 mm; P = .001). Also, crystallization occurred much faster in the bile of pancreatitis patients (1.0 +/- 0.0 vs. 2.5 +/- 0.4 days; P < .001), possibly because of higher mucin concentrations (3.3 +/- 1.9 vs. 0.8 +/- 0.2 mg/mL; P = .04). No significant differences were found in types of gallstones, relative biliary lipid contents, cholesterol saturation indexes, bile salt species composition, phospholipid classes, total protein or immunoglobulin (G, M, and A), haptoglobin, and alpha-1 acid glycoprotein concentrations. In conclusion, patients with small gallbladder stones and/or preserved gallbladder motility are at increased risk of pancreatitis. The potential benefit of prophylactic cholecystectomy in this patient category has yet to be explored.
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Affiliation(s)
- Niels G Venneman
- Gastrointestinal Research Unit, Departments of Gastroenterology and Surgery, University Medical Center, 3508 GA Utrecht, The Netherlands
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46
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Adamek HE, Rochlitz C, Von Bubnoff AC, Schilling D, Riemann JF. Predictions and associations of cholecystectomy in patients with cholecystolithiasis treated with extracorporeal shock wave lithotripsy. Dig Dis Sci 2004; 49:1938-42. [PMID: 15628729 DOI: 10.1007/s10620-004-9596-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Extracorporeal shock wave lithotripsy (ESWL) is effective in the treatment of symptomatic cholecystolithiasis in well-selected patients. We analyzed the predictors of cholecystectomy in a large series of gallstone patients after ESWL. This was a retrospective follow-up cohort-study of consecutive patients undergoing ESWL for symptomatic cholecystolithiasis over a 9-year period. It was possible to analyze a total of 297 patients; there were 211 women and 86 men, with a mean age of 52 years (range, 8-81 years). Patients that had been cholecystectomized after ESWL were compared to patients with their gallbladder still in situ and determinants of cholecystemctomy in terms of clinical, stone, and gallbladder parameters and symptoms analyzed. The mean duration of follow-up was 99 months (range, 27-134 months). During follow-up, 106 (36%) patients underwent a cholecystectomy at a mean of 34 months (range, 0-127 months) after ESWL. Histological data showed a normal gallbladder wall in only 4 cases; 101 examinations revealed some kind of (chronic) inflammation, which was not different from histological gallbladder results in patients without prior lithotripsy. Three gallbladder polyps were found, but no carcinoma. Cholecystectomy after ESWL of gallbladder stones was strongly associated with persitent and/or renewed biliary symtoms. Nevertheless, only three of four patients became asymptomatic after CE. Thus, ESWL proved to be a valuable organ-preserving alternative to cholecystectomy in selected patients.
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Affiliation(s)
- H E Adamek
- Department of Medicine, Klinikum Ludwigshafen, Academic Hospital of Johannes Gutenberg University of Mainz, Ludwigshafen, Germany.
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47
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Sato N, Miyasaka K, Suzuki S, Kanai S, Ohta M, Kawanami T, Yoshida Y, Takiguchi S, Noda T, Takata Y, Funakoshi A. Lack of cholecystokinin-A receptor enhanced gallstone formation: a study in CCK-A receptor gene knockout mice. Dig Dis Sci 2003. [PMID: 14627338 DOI: 10.1023/a: 1026110002713] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The etiology of gallstones is multifactorial, with interactions between genes and the environment. We generated cholecystokinin (CCK) -A receptor (R)-deficient (-/-) mice and found that CCK did not produce gallbladder contraction in CCK-AR(-/-) mice. The purpose of this study was to identify the role of CCK-AR on gallstone formation. Age-matched CCK-AR gene (+/+) and (-/-) progenies were used. Sludge and gallstone formation, as well as plasma cholesterol levels, were measured at 12 and 24 months of age. Sludge and gallstone formation were significantly higher in CCK-AR(-/-) mice than in CCK-AR(+/+) mice at 12 and 24 months of age, although these were not different between 12 and 24 months of age. The plasma cholesterol levels, daily food intake, and body weight were not significantly different between CCK-AR(+/+) and (-/-) mice. Sludge and gallstone formation were not observed at 6 months of age. In conclusion, deteriorated gallbladder contraction due to a lack of CCK-AR favored gallstone formation after the middle age of life.
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Affiliation(s)
- Norikazu Sato
- Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashiku, Tokyo-173-0015, Japan
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Dutt MK, Murphy GM, Thompson RPH. Unconjugated bilirubin in human bile: the nucleating factor in cholesterol cholelithiasis? J Clin Pathol 2003; 56:596-8. [PMID: 12890809 PMCID: PMC1770027 DOI: 10.1136/jcp.56.8.596] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
AIMS To investigate the concentrations of bilirubin, bilirubin conjugates, phospholipid, and cholesterol in the gall bladder bile obtained at surgery from patients with and without cholesterol gallstones. METHODS Gall bladder bile was collected during surgery, by puncture, from 20 patients with gallstones undergoing routine cholecystectomy and from eight patients with normal liver blood tests. Concentrations of bilirubin, bilirubin conjugates, phospholipid, and cholesterol were measured using standard procedures. RESULTS The proportion of total bilirubin that was unconjugated was significantly higher in the bile from patients with stones than in bile from control patients, whether or not the bile from either group was saturated with cholesterol or not. Indeed, the mean concentration of cholesterol was significantly higher in control bile samples. CONCLUSION The presence of stones was more closely related to the proportion of unconjugated bilirubin than to the degree of saturation of bile with cholesterol. Bilirubin and its metabolites probably play an important part in the formation of cholesterol gallstones.
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Affiliation(s)
- M K Dutt
- Gastrointestinal Laboratory, The Rayne Institute, St Thomas's Hospital, London SE1 7EH, UK
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49
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Portincasa P, Moschetta A, Colecchia A, Festi D, Palasciano G. Measurements of gallbladder motor function by ultrasonography: towards standardization. Dig Liver Dis 2003; 35 Suppl 3:S56-61. [PMID: 12974512 DOI: 10.1016/s1590-8658(03)00096-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
As real-time ultrasonography is a cheap, noninvasive, relatively easy, validated and reproducible technique, it can be repeated over time to document time-related changes of gallbladder motor function. Ultimately, functional ultrasonography estimates gallbladder shape and volume in fasting state and in response to a test meal (liquid or mixed solid-liquid, provided there is sufficient fat content) or exogenous stimulus (e.g., i.v. cholecystokinin or ceruletide). Although functional ultrasonography of the gallbladder has been mainly used for research purposes in specific referral centres, its simplicity makes such a technique appealing in the clinical setting to assess gallbladder motor function in both health and disease. Indications include the study of healthy subjects and of patients during pathophysiologically relevant conditions; in particular when subjects are at risk for gallbladder stasis and gallstone disease or during gallstone disease when a decision concerning medical dissolution therapy is required.
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Affiliation(s)
- P Portincasa
- Section of Internal Medicine, Department of Internal Medicine and Public Medicine, University Medical School of Bari, Piazza G. Cesare, 70124 Bari, Italy.
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50
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Lanzini A, Lanzarotto F, Baisini O, Amato M, Benini F. Value of measuring gallbladder motility in clinical practice. Dig Liver Dis 2003; 35 Suppl 3:S46-50. [PMID: 12974510 DOI: 10.1016/s1590-8658(03)00094-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Measurement of gallbladder motility is a powerful research tool, but its value in clinical practice is uncertain. Three main conditions have been investigated for potential clinical application of this measurement. The first potential application is for identification of patients at risk of recurrence following gallstone dissolution with medical therapy. Results in this clinical setting are disappointing due to the low positive predictive value for gallstone recurrence in sluggish gallbladder emptying. The second potential application is for identification of obese patients at risk of gallstone formation during rapid weight loss. In this condition, a high negative predictive value has been reported for a normal gallbladder emptying pattern. The third potential application is for patients with recurrent biliary colic and acalcolous gallbladder disease. The diagnostic value of a provocative test involving intravenous cholecystokinin injection as a method of identifying patients likely to benefit from cholecystectomy is uncertain, partly as a consequence of non-standardized methodology. The balance of evidence reported in this review suggests a low inherent value of measurement of gallbladder motility in clinical practice. Acalcolous gallbladder disease is the clinical setting deserving further investigation on the value of the cholecystokinin provocative test, but this test needs to be standardized.
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Affiliation(s)
- A Lanzini
- Internal Medicine 1, Spedali Civili and University of Brescia, 25100 Brescia, Italy.
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