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Liu Y, Chen L, Hao W, Zhao K, Li C. Causal association between type 1 diabetes and autoimmune cholestasis: A bi-directional Mendelian randomized study. Int J Immunopathol Pharmacol 2025; 39:3946320251327621. [PMID: 40216386 PMCID: PMC12033451 DOI: 10.1177/03946320251327621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 02/28/2025] [Indexed: 04/29/2025] Open
Abstract
Explore the causal relationship of risk between type 1 diabetes and primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). A causal association between type 1 diabetes and autoimmune liver disease remains ambiguous. This study explored potential causality between different autoimmune conditions, indicating that caution should be taken of the occurrence of autoimmune liver diseases in daily management of T1D patients. Genetic variants were extracted as instrumental variables from the genome-wide association study (GWAS) of PBC, PSC, type 1 diabetes (T1D), and type 2 diabetes (T2D). Associations between four primary liver enzymes, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine transferase (ALT), and glutamyl transaminase (GGT), and blood glucose-related indicators such as 2h-glucose post-challenge (2hGlu), fasting glucose (FG), fasting insulin (FI), and glycated hemoglobin (HbA1c) were also evaluated (GWAS p-value < 5 × 10-8). A bi-directional two-sample Mendelian randomization (MR) design was used to assess causality between type 1 diabetes and autoimmune cholestasis. Genetic susceptibility to T1D increased the risk of PSC and PBC. Genetic susceptibility to T2D reduced the risk of PSC and showed no correlation with PBC. Genetically susceptibility to PBC increased the risk of T1D and showed no correlation with T2D. Genetically susceptibility to PSC did not impact the risk of T1D and T2D. T1D patients have an increased risk of PBC/PSC, but such causation is not mediated or explained by the altered blood glucose levels. A bi-directional causal association was identified between type 1 diabetes and autoimmune cholestasis. The findings provide new insight into the management of patients with these conditions.
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Affiliation(s)
- Yuanda Liu
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Lanlan Chen
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, the First Hospital of Jilin University, Changchun, Jilin, China
| | - Wei Hao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, the First Hospital of Jilin University, Changchun, Jilin, China
| | - Kun Zhao
- Department of PET-CT Imaging Centery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital South Campus, Shanghai, China
| | - Changfeng Li
- Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China
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Sun J, Yao J, Olén O, Halfvarsson J, Bergman D, Ebrahimi F, Carlsson S, Ludvigsson J, Ludvigsson JF. Bidirectional association between inflammatory bowel disease and type 1 diabetes: a nationwide matched cohort and case-control study. THE LANCET REGIONAL HEALTH. EUROPE 2024; 46:101056. [PMID: 39286331 PMCID: PMC11402305 DOI: 10.1016/j.lanepe.2024.101056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 09/19/2024]
Abstract
Background Co-occurrence of inflammatory bowel disease (IBD) and type 1 diabetes (T1D) has been linked to poor clinical outcomes, but evidence on their bidirectional associations remain scarce. This study aims to investigate their bidirectional associations. Methods A nationwide matched cohort and case-control study with IBD patients identified between 1987 and 2017. The cohort study included 20,314 IBD patients (≤28 years; Crohn's disease [CD, n = 7277], ulcerative colitis [UC, n = 10,112], and IBD-unclassified [IBD-U, n = 2925]) and 99,200 individually matched reference individuals, with a follow-up until December 2021. The case-control study enrolled 87,001 IBD patients (no age restriction) and 431,054 matched controls. We estimated adjusted hazard ratio (aHR) of incident T1D in the cohort study with flexible parametric survival model and adjusted odds ratio (aOR) of having a prior T1D in the case-control study with conditional logistic regression model, with 95% confidence intervals (CI). Findings During a median follow-up of 14 years, 116 IBD patients and 353 reference individuals developed T1D. Patients with IBD had a higher hazard of developing T1D (aHR = 1.58 [95% CI = 1.27-1.95]). The hazard was increased in UC (aHR = 2.02 [1.51-2.70]) but not in CD or IBD-U. In the case-control study, a total of 1018 (1.2%) IBD patients and 3496 (0.8%) controls had been previously diagnosed with T1D. IBD patients had higher odds of having prior T1D (aOR = 1.36 [1.26-1.46]). Such positive association was observed in all IBD subtypes. The sibling comparison analyses showed similar associations between IBD and T1D (aHR = 1.44 [0.97-2.15] and aOR = 1.32 [1.18-1.49]). Interpretation Patients with IBD had a moderately increased hazard of developing T1D and higher odds of having prior T1D. Their bidirectional associations may be partially independent of shared familial factors. Funding European Crohn's and Colitis Organisation, Stiftelsen Professor Nanna Svartz Fond, SSMF (project#: PG-23-0315-H-02), Ruth and Richard Julin Foundation; and FORTE (project#: 2016-00424).
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Affiliation(s)
- Jiangwei Sun
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jialu Yao
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Ola Olén
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Sachs' Children and Youth Hospital, Stockholm South General Hospital, Stockholm, Sweden
- Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Jonas Halfvarsson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - David Bergman
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Fahim Ebrahimi
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Gastroenterology and Hepatology, University Digestive Health Care Center Basel - Clarunis, Basel, Switzerland
| | - Sofia Carlsson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Johnny Ludvigsson
- Crown Princess Victoria's Children's Hospital, Region Östergötland, Linköping, Sweden
- Division of Paediatrics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
- Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, USA
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Cho JM, Koh JH, Kim SG, Lee S, Kim Y, Cho S, Kim K, Kim YC, Han SS, Lee H, Lee JP, Joo KW, Lim CS, Kim YS, Kim DK, Park S. Primary sclerosing cholangitis causally affects kidney function decline: A Mendelian randomization study. J Gastroenterol Hepatol 2024; 39:185-192. [PMID: 37726875 DOI: 10.1111/jgh.16355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/17/2023] [Accepted: 09/01/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND AND AIM The causal linkage between primary sclerosing cholangitis (PSC) and kidney function is unexplored despite their potential for long-term detrimental effects on kidney function. METHODS Two-sample summary-level Mendelian randomization (MR) study was conducted to identify the association between PSC and kidney function. The genetic variants were extracted from the PSC-specific multi-trait analyzed genome-wide association study (GWAS) of European ancestry. Summary-level data for kidney function traits, including estimated glomerular filtration rate (eGFR), annual eGFR decline, and chronic kidney disease (CKD), were obtained from the CKDGen consortium. Multiplicative random-effects inverse-variance weighted (MR-IVW), and a series of pleiotropy-robust analyses were performed to investigate the causal effects and ascertain their robustness. RESULTS Significant causal associations between genetically predicted PSC and kidney function traits were identified. Genetically predicted PSC was associated with decreased log-transformed eGFR (MR-IVW; beta = -0.41%; standard error [SE] = 0.02%; P < 0.001), increased rate of annual eGFR decline (MR-IVW; beta = 2.43%; SE = 0.18%; P < 0.001), and higher risk of CKD (MR-IVW; odds ratio = 1.07; 95% confidence interval = 1.06-1.08; P < 0.001). The main findings were supported by pleiotropy-robust analysis, including MR-Egger with bootstrapped error and weighted median. CONCLUSIONS Our study demonstrates that genetically predicted PSC is causally associated with kidney function impairment. Further studies are warranted to identify the underlying mechanisms.
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Affiliation(s)
- Jeong Min Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Jung Hun Koh
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Seong Geun Kim
- Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul, South Korea
| | - Soojin Lee
- Department of Internal Medicine, Uijeongbu Eulji University Medical Center, Seoul, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Yaerim Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea
| | - Semin Cho
- Department of Internal Medicine, Chung-Ang University Gwangmyeong Hospital, Gwangmyeong, South Korea
| | - Kwangsoo Kim
- Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, South Korea
| | - Yong Chul Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Seung Seok Han
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Kidney Research Institute, Seoul National University, Seoul, South Korea
| | - Hajeong Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Jung Pyo Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Kidney Research Institute, Seoul National University, Seoul, South Korea
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Kwon Wook Joo
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Kidney Research Institute, Seoul National University, Seoul, South Korea
| | - Chun Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Kidney Research Institute, Seoul National University, Seoul, South Korea
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Yon Su Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Kidney Research Institute, Seoul National University, Seoul, South Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
| | - Dong Ki Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
- Kidney Research Institute, Seoul National University, Seoul, South Korea
| | - Sehoon Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
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Jensen ASH, Winther-Sørensen M, Burisch J, Bergquist A, Ytting H, Gluud LL, Wewer Albrechtsen NJ. Autoimmune liver diseases and diabetes: A propensity score matched analysis and a proportional meta-analysis. Liver Int 2023; 43:2479-2491. [PMID: 37752719 DOI: 10.1111/liv.15720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/20/2023] [Accepted: 08/24/2023] [Indexed: 09/28/2023]
Abstract
BACKGROUND AND AIMS Patients with some chronic liver diseases have increased risk of diabetes. Whether this is also the case for patients with autoimmune liver diseases is unknown. The study aimed to calculate risk and worldwide prevalence of diabetes in patients with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). METHODS We performed a case-control study using data from the United Kingdom Biobank (UKB) and compared frequency of type 1 diabetes (T1D) and type 2 diabetes (T2D) in AIH and PBC with age-, sex-, BMI- and ethnicity-matched controls. Next, we performed a systematic review and proportional meta-analysis searching PubMed, Embase, Cochrane Library and Web of Science (inception to 1 May 2022 [AIH]; 20 August 2022 [PBC]; 11 November 2022 [PSC]). The pooled prevalence of diabetes was calculated using an inverse method random effects model. RESULTS Three hundred twenty-eight AIH patients and 345 PBC patients were identified in UKB and risk of T1D and T2D significantly increased compared with matched controls. Our systematic search identified 6914 records including the UKB study. Of these, 77 studies were eligible for inclusion comprising 36 467, 39 924 and 4877 individuals with AIH, PBC and PSC, respectively. The pooled prevalence of T1D was 3.8% (2.6%-5.7%), 1.7% (0.9%-3.1%), 3.1% (1.9%-4.8%) and of T2D 14.8% (11.1%-19.5%), 18.1% (14.6%-22.2%), 6.3% (2.8%-13.3%) in patients with AIH, PBC and PSC, respectively. CONCLUSIONS Patients with autoimmune liver diseases have increased risk of diabetes. Increased awareness of diabetes risk in patients with autoimmune liver diseases is warranted.
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Affiliation(s)
- Anne-Sofie H Jensen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre, Denmark
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
| | - Marie Winther-Sørensen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
| | - Johan Burisch
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre, Denmark
| | - Annika Bergquist
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Henriette Ytting
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark
| | - Lise L Gluud
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
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5
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Jensen ASH, Ytting H, Winther-Sørensen M, Burisch J, Bergquist A, Gluud LL, Wewer Albrechtsen NJ. Autoimmune liver diseases and diabetes. Eur J Gastroenterol Hepatol 2023; 35:938-947. [PMID: 37505973 DOI: 10.1097/meg.0000000000002594] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/30/2023]
Abstract
Autoimmune liver diseases include autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. They are chronic, heterogenous diseases affecting the liver which is a key metabolic organ that ensures glucose homeostasis. It is well known that patients with other chronic liver diseases such as cirrhosis and nonalcoholic fatty liver disease (NAFLD) display glucose disturbances like insulin resistance and have an increased risk of diabetes. Previous evidence on glucose disturbances in patients with autoimmune liver disease is scarce but does point towards a potentially increased risk of type 1 diabetes and type 2 diabetes. The underlying mechanisms are unknown but may reflect genetic predisposition, concurrent NAFLD and or cirrhosis development, and treatment (steroid) related impairment of glucose homeostasis. Therefore, increased awareness and surveillance of diabetes development in patients with autoimmune liver disease may be important. Overall, detection and treatment of diabetes generally follow the usual diabetes guidelines; however, in patients with advanced liver cirrhosis, HbA1c may not be a reliable marker of average glucose levels, and treatment with insulin is generally recommended. In addition, it has recently been suggested that sodium-glucose cotransporter 2 inhibitors may be beneficial in treating refractory ascites. Further research on diabetes risk in autoimmune liver disease is warranted.
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Affiliation(s)
- Anne-Sofie H Jensen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
| | - Henriette Ytting
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Rigshospitalet
- Institute for Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen
| | - Marie Winther-Sørensen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
| | - Johan Burisch
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
| | - Annika Bergquist
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
- Department of Upper GI Diseases, Karolinska University Hospital, Department of Medicine, Karolinska Institutet, Stockholm
| | - Lise Lotte Gluud
- Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre Hospital, Hvidovre
- Institute for Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen
| | - Nicolai J Wewer Albrechtsen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen
- Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
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6
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Han Y, Byun J, Zhu C, Sun R, Roh JY, Cordell HJ, Lee HS, Shaw VR, Kang SW, Razjouyan J, Cooley MA, Hassan MM, Siminovitch KA, Folseraas T, Ellinghaus D, Bergquist A, Rushbrook SM, Franke A, Karlsen TH, Lazaridis KN, McGlynn KA, Roberts LR, Amos CI. Multitrait genome-wide analyses identify new susceptibility loci and candidate drugs to primary sclerosing cholangitis. Nat Commun 2023; 14:1069. [PMID: 36828809 PMCID: PMC9958016 DOI: 10.1038/s41467-023-36678-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 02/10/2023] [Indexed: 02/26/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a rare autoimmune bile duct disease that is strongly associated with immune-mediated disorders. In this study, we implemented multitrait joint analyses to genome-wide association summary statistics of PSC and numerous clinical and epidemiological traits to estimate the genetic contribution of each trait and genetic correlations between traits and to identify new lead PSC risk-associated loci. We identified seven new loci that have not been previously reported and one new independent lead variant in the previously reported locus. Functional annotation and fine-mapping nominated several potential susceptibility genes such as MANBA and IRF5. Network-based in silico drug efficacy screening provided candidate agents for further study of pharmacological effect in PSC.
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Affiliation(s)
- Younghun Han
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Jinyoung Byun
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Catherine Zhu
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Ryan Sun
- Department of Biostatistics, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA
| | - Julia Y Roh
- Department of Pharmacy, Ochsner Health, New Orleans, LA, USA
| | - Heather J Cordell
- Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Hyun-Sung Lee
- David J. Sugarbaker Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Vikram R Shaw
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Sung Wook Kang
- David J. Sugarbaker Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Javad Razjouyan
- VA HSR&D, Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center, Houston, TX, USA
- Big Data Scientist Training Enhancement Program (BD-STEP), VA Office of Research and Development, Washington, DC, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- VA Quality Scholars Coordinating Center, IQuESt, Michael E. DeBakey VA Medical Center, Houston, TX, USA
| | - Matthew A Cooley
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA
| | - Manal M Hassan
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Katherine A Siminovitch
- Departments of Medicine, Immunology and Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada
| | - Trine Folseraas
- Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - David Ellinghaus
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Annika Bergquist
- Department of Medicine Huddinge, Unit of Gastroenterology and Rheumatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Simon M Rushbrook
- Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, United Kingdom
- Norwich Medical School, University of East Anglia, Norfolk, United Kingdom
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Tom H Karlsen
- Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway
| | - Konstantinos N Lazaridis
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Katherine A McGlynn
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Lewis R Roberts
- Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway
| | - Christopher I Amos
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
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7
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Hu WS, Lin CL. Cholangitis in patients with atrial fibrillation: A retrospective cohort study in Taiwan. Medicine (Baltimore) 2022; 101:e28797. [PMID: 35147112 PMCID: PMC8830825 DOI: 10.1097/md.0000000000028797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 01/21/2022] [Indexed: 01/04/2023] Open
Abstract
The purpose of this study is to investigate whether atrial fibrillation (AF) and cholangitis is associated.This is a propensity-matched retrospective cohort report from the Taiwan National Health Insurance Research Database. We included patients who had AF but didn't have cholangitis, and matched controls between January 1, 2000 and December 31, 2012. The AF cohort comprised 114,572 patients and the comparison cohort comprised 114,572 subjects. All participants were followed up until developing cholangitis, death, or December 31, 2013, whichever came first. The cox model was used to calculate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for comparing the risk of cholangitis in the AF cohort and non-AF cohort.The incidence of cholangitis was higher in patients with AF than in those without AF [4.2 and 2.54 per 1000 person-years; adjusted HR (95%CI), 1.92 (1.54, 2.41)]. Comparing to subjects without AF, patients with AF had higher risk of cholangitis in the subgroup of ≥65 years (adjusted HR = 1.76, 95%CI = 1.40-2.21), female (adjusted HR = 2.51, 95%CI = 1.74-3.63), male (adjusted HR = 1.60, 95%CI = 1.19-2.14), without comorbidities (adjusted HR = 1.79, 95%CI = 1.23-2.61), and with comorbidities (adjusted HR = 1.85, 95%CI = 1.73-1.99).AF is associated with a higher incidence of cholangitis. The need of further investigations is mandatory because of the inherent limitations of observational study.
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Affiliation(s)
- Wei-Syun Hu
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
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8
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Khoury T, Sbeit W. Diabetes mellitus is associated with a higher rate of acute cholangitis among patients with common bile duct stones: A retrospective study. Medicine (Baltimore) 2022; 101:e28687. [PMID: 35089221 PMCID: PMC8797537 DOI: 10.1097/md.0000000000028687] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 12/06/2021] [Accepted: 01/01/2022] [Indexed: 01/05/2023] Open
Abstract
Common bile duct (CBD) stone is a commonly encountered disease that is associated with various clinical presentations ranging from the mild form of biliary colic to the severe complication of acute cholangitis. Recently, diabetes mellitus (DM) has been linked to the development of biliary diseases; however, no data regarding the association of DM with acute cholangitis development in the setting of CBD stone exist. The aim of the current study was to investigate whether DM represents a risk factor for acute cholangitis in patients with CBD stone. We performed a retrospective cross-sectional study from January 1, 2010 till June 1, 2020 of all patients presenting to Galilee Medical Center with various clinical presentations of documented CBD stone, including cholangitis, biliary pancreatitis, and biliary colic with abnormal liver enzymes. Overall, 687 patients were included in the final analysis. Among them, 101 patients (14.7%) had CBD stone associated with acute cholangitis (group A), as compared to 586 patients (85.3%) without acute cholangitis (group B). The average ages in groups A and B were 77.7 ± 13.6 and 62.5 ± 20.5 years, respectively (P < .0001). The prevalence of DM was significantly higher in group A as compared to group B (52.5% vs 36.3%, P = .001). On univariate analysis, age (odds ratio [OR] 1.05, P < .0001), male gender (OR 1.54, P = .04), and DM (OR 1.92, P = .002) were associated with acute cholangitis development, and on multivariate logistic regression analysis, the correlation was preserved for DM (OR 1.93, 95% confidence interval 1.26-2.96, P = .002). DM showed a significant association with acute cholangitis development among patients with CBD stone. Identification of bile duct stones in diabetic patients is of paramount importance since early diagnosis and treatment might prevent further life-threatening complications.
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Affiliation(s)
- Tawfik Khoury
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel
- Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel
| | - Wisam Sbeit
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel
- Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel
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9
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Yano K, Moroi R, Shiga H, Tarasawa K, Shimoyama Y, Kuroha M, Hamada S, Kakuta Y, Fushimi K, Fujimori K, Kinouchi Y, Masamune A. Analysis of the disease activity of ulcerative colitis with and without concomitant primary sclerosing cholangitis: An investigation using a nationwide database in Japan. JGH Open 2022; 6:50-56. [PMID: 35071788 PMCID: PMC8762614 DOI: 10.1002/jgh3.12693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/22/2021] [Accepted: 12/01/2021] [Indexed: 11/07/2022]
Abstract
Aims Primary sclerosing cholangitis (PSC) is a relatively common complication of ulcerative colitis (UC). Only a few studies have investigated the impact of PSC on the clinical course of UC, and their conclusions are contradictory. Therefore, we aimed to compare the disease activity of UC with and without PSC. Methods and Results We collected UC patient data using the Diagnosis Procedure Combination database system in Japan and classified eligible admissions into two groups based on their diagnosis of either UC alone or UC associated with PSC. We then compared therapeutic details (medical treatment and surgery) between the two groups. Multivariable logistic regression analysis and propensity score matching was also performed. The rates of systemic steroid injection and infliximab administration in patients with PSC were lower than those in patients without PSC (21% vs. 28%, P = 0.012, 9.6% vs. 16%, P = 0.01, respectively). The rates of surgery, colorectal cancer, duration of hospital stay, and in-hospital mortality did not differ between the two groups. Multivariable analysis revealed that concomitant PSC was a clinical factor that reduced the odds of systemic steroid injection (odds ratio [OR] = 0.66, 95% confidence interval [CI]: 0.49-0.90, P = 0.008) and infliximab (OR = 0.48, 95% CI: 0.32-0.74, P = 0.0008) administration. Conclusion UC patients with PSC might have less UC disease activity than those with UC alone.
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Affiliation(s)
- Kota Yano
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Rintaro Moroi
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Hisashi Shiga
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Kunio Tarasawa
- Department of Health Administration and Policy Tohoku University Graduate School of Medicine Sendai Japan
| | - Yusuke Shimoyama
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Masatake Kuroha
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Shin Hamada
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Yoichi Kakuta
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Kiyohide Fushimi
- Department of Health Policy and Informatics Tokyo Medical and Dental University Graduate School of Medicine Bunkyo Japan
| | - Kenji Fujimori
- Department of Health Administration and Policy Tohoku University Graduate School of Medicine Sendai Japan
| | - Yoshitaka Kinouchi
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan
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10
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Fründt T, Schröder N, Hölzemer A, Pinnschmidt H, de Heer J, Behrends BC, Renne T, Lautenbach A, Lohse AW, Schrader J. Prevalence and risk factors of undiagnosed diabetes mellitus among gastroenterological patients: a HbA1c-based single center experience. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 60:1306-1313. [PMID: 34157754 DOI: 10.1055/a-1482-8840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND Diabetes mellitus is a major risk factor for microvascular disease, leading to chronic kidney injury or cardiovascular disease, but there is a tremendous proportion of patients worldwide who suffer from undiagnosed diabetes. Until now, little is known about the prevalence of undiagnosed diabetes in gastroenterology inpatients. OBJECTIVE To improve detection of undiagnosed diabetes, a routine screening procedure for gastroenterology inpatients, based on hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) measurement, was established. METHODS We conducted a retrospective analysis of the implemented diabetes screening. Diabetes mellitus was diagnosed according to the guideline of the German Diabetes Association in patients with an HbA1c of ≥6.5% anld/or fasting plasma glucose (FPG) ≥126 mg/dL. Univariate and multivariate analyses were performed to identify independent risk factors for undiagnosed diabetes. RESULTS Within a 3-month period, 606 patients were eligible for a diabetes screening. Pre-existing diabetes was documented in 120 patients (19.8 %), undiagnosed diabetes was found in 24 (3.9%), and 162 patients (26.7%) met the definition for prediabetes. Steroid medication use, age, and liver cirrhosis due to primary sclerosing cholangitis (PSC) were identified as risk factors for undiagnosed diabetes. CONCLUSION The prevalence of undiagnosed diabetes in gastroenterology inpatients is markedly elevated in comparison to the general population, and a substantial number of inpatients are in a prediabetic status, underlining the need for diabetes screening. In addition to previously described risk factors of patient age and steroid medication use, we identified PSC-related liver cirrhosis (but not liver cirrhosis due to another etiology) as an independent risk factor for undiagnosed diabetes.
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Affiliation(s)
- Thorben Fründt
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Niko Schröder
- Department of Internal Medicine, Gastroenterology, Hepatology, Endoscopy and Diabetology, Osnabrück, Germany
| | - Angelique Hölzemer
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hans Pinnschmidt
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jocelyn de Heer
- Department of Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Berit C Behrends
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Renne
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anne Lautenbach
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jörg Schrader
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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11
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Cione E, Caroleo MC, Kagechika H, Manetti F. Pharmacophore-guided repurposing of fibrates and retinoids as GPR40 allosteric ligands with activity on insulin release. J Enzyme Inhib Med Chem 2021; 36:377-383. [PMID: 33525941 PMCID: PMC8759729 DOI: 10.1080/14756366.2020.1864629] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
A classical drug repurposing approach was applied to find new putative GPR40 allosteric binders. A two-step computational protocol was set up, based on an initial pharmacophoric-based virtual screening of the DrugBank database of known drugs, followed by docking simulations to confirm the interactions between the prioritised compounds and GPR40. The best-ranked entries showed binding poses comparable to that of TAK-875, a known allosteric agonist of GPR40. Three of them (tazarotenic acid, bezafibrate, and efaproxiral) affect insulin secretion in pancreatic INS-1 832/13 β-cells with EC50 in the nanomolar concentration (5.73, 14.2, and 13.5 nM, respectively). Given the involvement of GPR40 in type 2 diabetes, the new GPR40 modulators represent a promising tool for therapeutic intervention towards this disease. The ability to affect GPR40 was further assessed in human breast cancer MCF-7 cells in which this receptor positively regulates growth activities (EC50 values were 5.6, 21, and 14 nM, respectively).
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Affiliation(s)
- Erika Cione
- Department of Pharmacy, Health and Nutritional Sciences (Department of Excellence 2018-2022), University of Calabria, Rende, Italy
| | - Maria Cristina Caroleo
- Department of Pharmacy, Health and Nutritional Sciences (Department of Excellence 2018-2022), University of Calabria, Rende, Italy
| | - Hiroyuki Kagechika
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Fabrizio Manetti
- Department of Biotechnology, Chemistry and Pharmacy (Department of Excellence 2018-2022), University of Siena, Siena, Italy
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12
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Aune D, Sen A, Norat T, Riboli E, Folseraas T. Primary sclerosing cholangitis and the risk of cancer, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of cohort studies. Sci Rep 2021; 11:10646. [PMID: 34017024 PMCID: PMC8137938 DOI: 10.1038/s41598-021-90175-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 05/07/2021] [Indexed: 02/03/2023] Open
Abstract
A diagnosis of primary sclerosing cholangitis (PSC) has been associated with increased risk of hepatobiliary cancers, colorectal cancer and all-cause mortality in several studies, while associations with cardiovascular disease have been inconsistent. We conducted a systematic review and meta-analysis of published cohort studies on the topic to summarize these associations. PubMed and Embase databases were searched up to January 13th, 2020. Cohort studies on PSC and risk of cancer, cardiovascular disease, or mortality were included. Summary relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated using random effects models. The summary RR (95% CI) comparing persons with PSC to persons without PSC was 584.37 (269.42-1267.51, I2 = 89%, n = 4) for cholangiocarcinoma (CCA), 155.54 (125.34-193.02, I2 = 0%, n = 3) for hepatobiliary cancer, 30.22 (11.99-76.17, I2 = 0%, n = 2) for liver cancer, 16.92 (8.73-32.78, I2 = 88%, n = 4) for gastrointestinal cancer, 7.56 (2.42-23.62, I2 = 0%, n = 3) for pancreatic cancer, 6.10 (4.19-8.87, I2 = 14%, n = 7) for colorectal cancer (CRC), 4.13 (2.99-5.71, I2 = 80%, n = 5) for total cancer, 3.55 (2.94-4.28, I2 = 46%, n = 5) for all-cause mortality, and 1.57 (0.25-9.69, I2 = 79%, n = 2) for cardiovascular disease. Strong positive associations were observed between PSC and risk of CCA, hepatobiliary cancer, liver cancer, gastrointestinal cancer, pancreatic cancer, CRC, total cancer, and all-cause mortality, but not for cardiovascular disease.
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Affiliation(s)
- Dagfinn Aune
- grid.7445.20000 0001 2113 8111Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St. Mary’s Campus, Norfolk Place, Paddington, London, W2 1PG UK ,grid.510411.00000 0004 0578 6882Department of Nutrition, Bjørknes University College, Oslo, Norway ,grid.55325.340000 0004 0389 8485Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital Ullevål, Oslo, Norway ,grid.4714.60000 0004 1937 0626Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Abhijit Sen
- grid.5947.f0000 0001 1516 2393Department of Public Health and Nursing, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway ,Center for Oral Health Services and Research (TkMidt), Trondheim, Norway
| | - Teresa Norat
- grid.7445.20000 0001 2113 8111Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St. Mary’s Campus, Norfolk Place, Paddington, London, W2 1PG UK
| | - Elio Riboli
- grid.7445.20000 0001 2113 8111Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St. Mary’s Campus, Norfolk Place, Paddington, London, W2 1PG UK
| | - Trine Folseraas
- grid.55325.340000 0004 0389 8485Division of Surgery, Inflammatory Medicine and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway ,grid.5510.10000 0004 1936 8921Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway ,grid.55325.340000 0004 0389 8485Division of Surgery, Inflammatory Medicine and Transplantation, Section for Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
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13
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Governa P, Caroleo MC, Carullo G, Aiello F, Cione E, Manetti F. FFAR1/GPR40: One target, different binding sites, many agonists, no drugs, but a continuous and unprofitable tug-of-war between ligand lipophilicity, activity, and toxicity. Bioorg Med Chem Lett 2021; 41:127969. [PMID: 33771587 DOI: 10.1016/j.bmcl.2021.127969] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/09/2021] [Accepted: 03/12/2021] [Indexed: 12/31/2022]
Abstract
The progress made so far in the elucidation of the structure of free fatty acid receptor 1 (FFAR1) and its secondary and ternary complexes with partial and full allosteric ligands led to the discovery of various putative binding regions on the FFAR1 surface. Attempts to develop FFAR1 agonists culminated with the identification of TAK-875 (1), whose phase 3 clinical trials were terminated due to potential liver toxicity. In the search of safer agonists, numerous classes of new compounds were designed, synthesized, and tested. Chemical decoration of the scaffolds was rationalized to reach a good balance between lipophilicity, activity, and toxicity. Today, targeting FFAR1 with positive modulators represents an attractive pharmacological tool for the treatment of type 2 diabetes mellitus (T2DM), mainly because of the lack of hypoglycaemic side effects associated with several antidiabetic drugs currently available. Moreover, considering the involvement of FFAR1 in many physio-pathological processes, its agonists are also emerging as possible therapeutic tools for alleviating organ inflammation and fibrosis, as well as for the treatment of CNS disorders, such as Alzheimer's disease and dementia.
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Affiliation(s)
- Paolo Governa
- Department of Biotechnology, Chemistry and Pharmacy-Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, I-53100 Siena, Italy
| | - Maria Cristina Caroleo
- Department of Pharmacy, Health and Nutritional Sciences-Department of Excellence 2018-2022, University of Calabria, Ed. Polifunzionale, I-87036 Arcavacata di Rende, CS, Italy
| | - Gabriele Carullo
- Department of Biotechnology, Chemistry and Pharmacy-Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, I-53100 Siena, Italy
| | - Francesca Aiello
- Department of Pharmacy, Health and Nutritional Sciences-Department of Excellence 2018-2022, University of Calabria, Ed. Polifunzionale, I-87036 Arcavacata di Rende, CS, Italy.
| | - Erika Cione
- Department of Pharmacy, Health and Nutritional Sciences-Department of Excellence 2018-2022, University of Calabria, Ed. Polifunzionale, I-87036 Arcavacata di Rende, CS, Italy.
| | - Fabrizio Manetti
- Department of Biotechnology, Chemistry and Pharmacy-Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, I-53100 Siena, Italy.
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14
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Zhang R, Ma WQ, Fu MJ, Li J, Hu CH, Chen Y, Zhou MM, Gao ZJ, He YL. Overview of bile acid signaling in the cardiovascular system. World J Clin Cases 2021; 9:308-320. [PMID: 33521099 PMCID: PMC7812903 DOI: 10.12998/wjcc.v9.i2.308] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/28/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Bile acids (BAs) are classically known to play a vital role in the metabolism of lipids and in absorption. It is now well established that BAs act as signaling molecules, activating different receptors (such as farnesoid X receptor, vitamin D receptor, Takeda G-protein-coupled receptor 5, sphingosine-1-phosphate, muscarinic receptors, and big potassium channels) and participating in the regulation of energy homeostasis and lipid and glucose metabolism. In addition, increased BAs can impair cardiovascular function in liver cirrhosis. Approximately 50% of patients with cirrhosis develop cirrhotic cardiomyopathy. Exposure to high concentrations of hydrophobic BAs has been shown to be related to adverse effects with respect to vascular tension, endothelial function, arrhythmias, coronary atherosclerotic heart disease, and heart failure. The BAs in the serum BA pool have relevant through their hydrophobicity, and the lipophilic BAs are more harmful to the heart. Interestingly, ursodeoxycholic acid is a hydrophilic BA, and it is used as a therapeutic drug to reverse and protect the harmful cardiac effects caused by hydrophobic elevated BAs. In order to elucidate the mechanism of BAs and cardiovascular function, abundant experiments have been conducted in vitro and in vivo. The aim of this review was to explore the mechanism of BAs in the cardiovascular system.
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Affiliation(s)
- Rou Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Wen-Qi Ma
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Meng-Jun Fu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Juan Li
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Chun-Hua Hu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Yi Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Mi-Mi Zhou
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Zhi-Jie Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Ying-Li He
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
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15
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Abstract
OBJECTIVES Chronic cholestatic liver diseases are often associated with disturbed lipid metabolism, which may potentially increase cardiovascular (CV) risk but the evidence is scarce. The aim of the study was to assess factors associated with increased CV risk in children with Alagille syndrome (AGS) and biliary atresia (BA). METHODS We investigated 17 patients with AGS, ages 11.0 years (8.4-13.4) and 19 with BA, ages 13.5 years (10.4-15.1) in whom we performed thorough biochemical assessment including lipid profiles and oxidative stress biomarkers, blood pressure (BP)-systolic, diastolic and mean, carotid intima-media thickness (cIMT), and pulse wave velocity (PWV). RESULTS There were abnormal lipid profiles in 82% of children with AGS and 52.6% with BA. In AGS group, we observed significantly higher levels of TC, LDL C, APO B, lower glutathione concentration and glutathione peroxidase activity and lower blood pressure, lower cIMT (P = 0.02), cIMT-SDS (P = 0.04), and PWV (P = 0.04). We, however, observed elevated blood pressure in 2/19 patients with BA and none-with AGS (BA vs AGS: P = 0.12), whereas cIMT-SDS was increased only in 2/17 patients with AGS and in 6/19 with BA (P = 0.24), and abnormal PWV-SDS values were detected in 3/17 of AGS and 8/19 of BA patients (P = 0.15). Neither presence of dyslipidemia nor Lp-X correlated with vascular parameters. CONCLUSIONS Children with BA and AGS may present with increased cardiovascular risk factors but vascular parameters are not directly related to lipid abnormalities. cIMT and BP should be considered for clinical practice in these cholestatic disorders so as to determine individuals with potential CV risk.
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16
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Rahmani B, Gandhi J, Joshi G, Smith NL, Reid I, Khan SA. The Role of Diabetes Mellitus in Diseases of the Gallbladder and Biliary Tract. Curr Diabetes Rev 2020; 16:931-948. [PMID: 32133965 DOI: 10.2174/1573399816666200305094727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 02/18/2020] [Accepted: 02/21/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The increasing prevalence of diabetes mellitus worldwide continues to pose a heavy burden. Though its gastrointestinal impact is appropriately recognized, the lesser known associations may be overlooked. OBJECTIVE We aim to review the negative implications of diabetes on the gallbladder and the biliary tract. METHODS A MEDLINE® database search of literature was conducted with emphasis on the previous five years, combining keywords such as "diabetes," "gallbladder," and "biliary". RESULTS The association of diabetes to the formation of gallstones, gallbladder cancer, and cancer of the biliary tract are discussed along with diagnosis and treatment. CONCLUSION Though we uncover the role of diabetic neuropathy in gallbladder and biliary complications, the specific individual diabetic risk factors behind these developments is unclear. Also, in addition to diabetes control and surgical gallbladder management, the treatment approach also requires further focus.
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Affiliation(s)
- Benjamin Rahmani
- Department of Physiology and Biophysics, Renaissance School of Medicine at Stony Brook University, Stony Brook,
NY, USA
| | - Jason Gandhi
- Department of Physiology and Biophysics, Renaissance School of Medicine at Stony Brook University, Stony Brook,
NY, USA
- Medical Student Research Institute, St. George’s University School of Medicine, Grenada, West Indies
| | - Gunjan Joshi
- Department of Internal Medicine, Stony Brook Southampton Hospital, Southampton, NY, USA
| | | | - Inefta Reid
- Department of Physiology and Biophysics, Renaissance School of Medicine at Stony Brook University, Stony Brook,
NY, USA
| | - Sardar Ali Khan
- Department of Physiology and Biophysics, Renaissance School of Medicine at Stony Brook University, Stony Brook,
NY, USA
- Department of Urology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
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17
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Vasavan T, Ferraro E, Ibrahim E, Dixon P, Gorelik J, Williamson C. Heart and bile acids - Clinical consequences of altered bile acid metabolism. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1345-1355. [PMID: 29317337 DOI: 10.1016/j.bbadis.2017.12.039] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 12/18/2017] [Accepted: 12/22/2017] [Indexed: 12/11/2022]
Abstract
Cardiac dysfunction has an increased prevalence in diseases complicated by liver cirrhosis such as primary biliary cholangitis and primary sclerosing cholangitis. This observation has led to research into the association between abnormalities in bile acid metabolism and cardiac pathology. Approximately 50% of liver cirrhosis cases develop cirrhotic cardiomyopathy. Bile acids are directly implicated in this, causing QT interval prolongation, cardiac hypertrophy, cardiomyocyte apoptosis and abnormal haemodynamics of the heart. Elevated maternal serum bile acids in intrahepatic cholestasis of pregnancy, a disorder which causes an impaired feto-maternal bile acid gradient, have been associated with fatal fetal arrhythmias. The hydrophobicity of individual bile acids in the serum bile acid pool is of relevance, with relatively lipophilic bile acids having a more harmful effect on the heart. Ursodeoxycholic acid can reverse or protect against these detrimental cardiac effects of elevated bile acids.
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Affiliation(s)
- Tharni Vasavan
- Department of Women and Children's Health, King's College London, Guy's Campus, Hodgkin Building, SE1 1UL London, United Kingdom
| | - Elisa Ferraro
- National Heart and Lung Institute, Imperial Centre for Translational and Experimental Medicine, Imperial College London, Du Cane Road, W12 0NN London, United Kingdom
| | - Effendi Ibrahim
- National Heart and Lung Institute, Imperial Centre for Translational and Experimental Medicine, Imperial College London, Du Cane Road, W12 0NN London, United Kingdom; Faculty of Medicine, MARA University of Technology, 40000 Sungai Buloh, Malaysia
| | - Peter Dixon
- Department of Women and Children's Health, King's College London, Guy's Campus, Hodgkin Building, SE1 1UL London, United Kingdom
| | - Julia Gorelik
- National Heart and Lung Institute, Imperial Centre for Translational and Experimental Medicine, Imperial College London, Du Cane Road, W12 0NN London, United Kingdom
| | - Catherine Williamson
- Department of Women and Children's Health, King's College London, Guy's Campus, Hodgkin Building, SE1 1UL London, United Kingdom.
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18
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Lin M, Pappas SC. Diabetes, Specific Hepatobiliary Diseases, and Treatment. MANAGING GASTROINTESTINAL COMPLICATIONS OF DIABETES 2017:93-105. [DOI: 10.1007/978-3-319-48662-8_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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19
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Kummen M, Vesterhus M, Trøseid M, Moum B, Svardal A, Boberg KM, Aukrust P, Karlsen TH, Berge RK, Hov JR. Elevated trimethylamine- N-oxide (TMAO) is associated with poor prognosis in primary sclerosing cholangitis patients with normal liver function. United European Gastroenterol J 2016; 5:532-541. [PMID: 28588885 DOI: 10.1177/2050640616663453] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 07/14/2016] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Trimethylamine-N-oxide (TMAO) is produced in the liver from trimethylamine, which is exclusively generated by gut bacteria. OBJECTIVE The objective of this article is to investigate the relationship between TMAO and primary sclerosing cholangitis (PSC) and its clinical characteristics. METHODS Serum TMAO was measured in 305 PSC patients, 90 ulcerative colitis patients and 99 healthy controls. RESULTS In PSC patients with normal liver function (n = 197), TMAO was higher in patients reaching liver transplantation or death during follow-up than those who did not, with an optimal TMAO cut-off of 4.1 µM (AUC = 0.64, p < 0.001). PSC patients with high TMAO (>4.1 µM, n = 77) exhibited shorter transplantation-free survival than patients with low TMAO (n = 120, log-rank test: p < 0.0001). High TMAO (>4.1 µM) was associated with reduced transplantation-free survival (HR 1.87, p = 0.011), independently of the Mayo risk score (HR 1.74, p < 0.001). Overall, PSC patients demonstrated reduced TMAO values compared with ulcerative colitis and healthy controls, mainly caused by PSC patients with reduced liver function (INR > 1.2), suggesting impaired oxidation of trimethylamine to TMAO. PSC patients with and without inflammatory bowel disease had similar TMAO levels. CONCLUSION In PSC patients with normal liver function, elevated TMAO was associated with shorter transplantation-free survival, potentially reflecting clinically relevant metabolic changes resulting from dietary interactions with the gut microbiota.
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Affiliation(s)
- Martin Kummen
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Mette Vesterhus
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Department of Medicine, National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway
| | - Marius Trøseid
- K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Bjørn Moum
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Division of Medicine, Department of Gastroenterology, Oslo University Hospital Ullevål, Oslo, Norway
| | - Asbjørn Svardal
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Kirsten Muri Boberg
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Section of Gastroenterology, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Pål Aukrust
- K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Tom Hemming Karlsen
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Rolf Kristian Berge
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | - Johannes Roksund Hov
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
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Marchioni Beery RM, Vaziri H, Forouhar F. Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis: a Review Featuring a Women's Health Perspective. J Clin Transl Hepatol 2014; 2:266-84. [PMID: 26357630 PMCID: PMC4521232 DOI: 10.14218/jcth.2014.00024] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Revised: 10/15/2014] [Accepted: 10/19/2014] [Indexed: 12/12/2022] Open
Abstract
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are two major types of chronic cholestatic liver disease. Each disorder has distinguishing features and variable progression, but both may ultimately result in cirrhosis and hepatic failure. The following offers a review of PBC and PSC, beginning with a general overview of disease etiology, pathogenesis, diagnosis, clinical features, natural course, and treatment. In addition to commonly associated manifestations of fatigue, pruritus, and fat-soluble vitamin deficiency, select disease-related topics pertaining to women's health are discussed including metabolic bone disease, hyperlipidemia and cardiovascular risk, and pregnancy-related issues influencing maternal disease course and birth outcomes. This comprehensive review of PBC and PSC highlights some unique clinical considerations in the care of female patients with cholestatic liver disease.
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Affiliation(s)
- Renée M. Marchioni Beery
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- Correspondence to: Renée M. Marchioni Beery, DO, Division of Internal Medicine, Department of Gastroenterology and Hepatology, 263 Farmington Avenue, Farmington, CT 06030-1845, USA. Tel: +01-860-679-3158, Fax: +01-860-679-3159. E-mail:
| | - Haleh Vaziri
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - Faripour Forouhar
- Department of Pathology and Lab Medicine, University of Connecticut Health Center, Farmington, CT, USA
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Tsai MS, Lee PH, Lin CL, Peng CL, Kao CH. Type II diabetes mellitus is associated with a reduced risk of cholangiocarcinoma in patients with biliary tract diseases. Int J Cancer 2014; 136:2409-17. [PMID: 25348605 DOI: 10.1002/ijc.29292] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 10/20/2014] [Indexed: 12/15/2022]
Abstract
It has not yet been reported whether Type II diabetes mellitus (DM) is associated with an increased cholangiocarcinoma (CC) risk in patients with biliary tract diseases. We identified 123,050 patients concomitantly diagnosed with biliary tract diseases and DM between 1998 and 2010. The control cohort consisted of 122,721 individuals with biliary tract diseases but not DM. Both cohorts were followed-up until the end of 2010 to estimate the risk of CC. We also compared the risk of CC between DM and non-DM cohorts without biliary tract diseases. Overall, the incidence of CC was 21% lower among the DM patients than among the control patients (1.11 vs. 1.41 per 1,000 person-years). DM cohorts exhibited significantly reduced risks for both intrahepatic and extrahepatic CC. A multivariable Cox proportional hazards regression model was used, and the adjusted hazard ratio (HR) of CC was 0.74 (95% confidence interval [CI], 0.66-0.82) for the DM cohort in comparison with the control cohort. The age-specific data indicated that compared with the control patients, the adjusted HRs for the DM patients were significantly lower among patients 50-64 (adjusted HR = 0.67; 95% CI = 0.55-0.82) and 65-74 years old (adjusted HR = 0.70; 95% CI, 0.59-0.84). Furthermore, DM was associated with a lower risk of CC among patients with biliary diseases, regardless of the presence of comorbidities and the status of cholecystectomy. In the patients without biliary tract diseases, DM is associated with significantly increased risk of CC (adjusted HR = 1.58; 95% CI, 1.37-1.82).
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Affiliation(s)
- Ming-Shian Tsai
- Department of General Surgery, E-Da Hospital and I-Shou University, Kaohsiung, Taiwan
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PSC: Novel disease associations providing pathogenetic clues? J Hepatol 2014; 60:687-8. [PMID: 24434501 DOI: 10.1016/j.jhep.2014.01.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 01/10/2014] [Indexed: 12/04/2022]
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