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Tewari R, Yang SJ, McClain ED, Hu A, Mortensen E, DeSchmidt A, Chen J, Kancharla A, Singh AK, James EA, Burman BE, Siddique A, Rawlings DJ, Patel C, Cerosaletti K, Buckner JH. Identification of a novel PDC-E2 epitope in primary biliary cholangitis: Application for engineered Treg therapy. J Autoimmun 2024; 149:103327. [PMID: 39476446 DOI: 10.1016/j.jaut.2024.103327] [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: 07/26/2024] [Revised: 10/11/2024] [Accepted: 10/24/2024] [Indexed: 12/15/2024]
Abstract
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease, characterized by progressive destruction of small intrahepatic bile ducts and portal inflammation. Treatment options are limited, with reliance on liver transplantation in advanced cases. The adaptive immune response is implicated in disease pathogenesis by the presence of anti-mitochondrial antibodies targeting the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2) in 90-95 % of patients and T cells infiltrating the portal tracts. Here, we examined T cell responses to peptides derived from PDC-E2, with a focus on CD4 T cell responses restricted to HLA Class II DRB4∗01:01, an allele found in 62 % of PBC patients, to uncover PDC-E2 epitopes that could be used for engineered regulatory T cell (Treg; EngTreg) therapy. Using an activation-induced marker assay and single cell RNA-sequencing, we found clonal expansion of CD4 T cells reactive to PDC-E2 epitopes among both T conventional (Tconv) and Tregs. Those T cell receptor (TCR) repertoires were non-overlapping and private and included TCRs specific for a novel PDC-E2 epitope restricted to DRB4∗01:01. CD4 Tconv cells reactive to the PDC-E2 novel epitope showed phenotypic heterogeneity skewed towards T follicular helper cells. Using a TCR specific for this novel PDC-E2 epitope, we created an EngTreg that suppressed PDC-E2-specific polyclonal CD4 Tconv cells from PBC patients. This study advances knowledge of PDC-E2-specific T cell responses and introduces a novel PDC-E2 epitope recognized by both Tconv and Tregs. Generation of EngTreg specific for this epitope provides therapeutic potential for PBC.
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MESH Headings
- Humans
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Liver Cirrhosis, Biliary/immunology
- Liver Cirrhosis, Biliary/therapy
- Epitopes, T-Lymphocyte/immunology
- Dihydrolipoyllysine-Residue Acetyltransferase/immunology
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/metabolism
- Autoantigens/immunology
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Affiliation(s)
- Ritika Tewari
- Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Soo Jung Yang
- Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Ethan D McClain
- Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Alex Hu
- Systems Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Emma Mortensen
- Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Aleah DeSchmidt
- Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Janice Chen
- Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | | | | | - Eddie A James
- Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Blaire E Burman
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, USA
| | - Asma Siddique
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, USA
| | - David J Rawlings
- Center for Immunity and Immunotherapies and the Program for Cell and Gene Therapy, Seattle Children's Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA
| | | | - Karen Cerosaletti
- Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Jane H Buckner
- Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Department of Immunology, University of Washington, Seattle, WA, USA.
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Abdelghany TM, Hedya SA, Charlton A, Aljehani FA, Alanazi K, Budastour AA, Marin L, Wright MC. Undifferentiated HepaRG cells show reduced sensitivity to the toxic effects of M8OI through a combination of CYP3A7-mediated oxidation and a reduced reliance on mitochondrial function. Food Chem Toxicol 2024; 188:114681. [PMID: 38677401 DOI: 10.1016/j.fct.2024.114681] [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: 02/06/2024] [Revised: 04/15/2024] [Accepted: 04/21/2024] [Indexed: 04/29/2024]
Abstract
The methylimidazolium ionic liquid M8OI (1-octyl-3-methylimidazolium chloride, also known as [C8mim]Cl) has been detected in the environment and may represent a hazard trigger for the autoimmune liver disease primary biliary cholangitis, based in part on studies using a rat liver progenitor cell. The effect of M8OI on an equivalent human liver progenitor (undifferentiated HepaRG cells; u-HepaRG) was therefore examined. u-HepaRG cells were less sensitive (>20-fold) to the toxic effects of M8OI. The relative insensitivity of u-HepaRG cells to M8OI was in part, associated with a detoxification by monooxygenation via CYP3A7 followed by further oxidation to a carboxylic acid. Expression of CYP3A7 - in contrast to the related adult hepatic CYP3A4 and CYP3A5 forms - was confirmed in u-HepaRG cells. However, blocking M8OI metabolism with ketoconazole only partly sensitized u-HepaRG cells. Despite similar proliferation rates, u-HepaRG cells consumed around 75% less oxygen than B-13 cells, reflective of reduced dependence on mitochondrial activity (Crabtree effect). Replacing glucose with galactose, resulted in an increase in u-HepaRG cell sensitivity to M8OI, near similar to that seen in B-13 cells. u-HepaRG cells therefore show reduced sensitivity to the toxic effects of M8OI through a combination of metabolic detoxification and their reduced reliance on mitochondrial function.
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Affiliation(s)
- Tarek M Abdelghany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt; Institute of Education in Healthcare and Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresthill, Aberdeen, AB25 2ZD, United Kingdom
| | - Shireen A Hedya
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt
| | - Alex Charlton
- School of Natural and Environmental Sciences, Bedson Building, Newcastle University, NE1 8QB, United Kingdom
| | - Fahad A Aljehani
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Khalid Alanazi
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Alaa A Budastour
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Larissa Marin
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Matthew C Wright
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom.
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3
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Hazelton ML. Shrinkage estimators of the spatial relative risk function. Stat Med 2023; 42:4556-4569. [PMID: 37599209 DOI: 10.1002/sim.9875] [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: 01/30/2023] [Revised: 06/26/2023] [Accepted: 08/01/2023] [Indexed: 08/22/2023]
Abstract
The spatial relative risk function describes differences in the geographical distribution of two types of points, such as locations of cases and controls in an epidemiological study. It is defined as the ratio of the two underlying densities. Estimation of spatial relative risk is typically done using kernel estimates of these densities, but this procedure is often challenging in practice because of the high degree of spatial inhomogeneity in the distributions. This makes it difficult to obtain estimates of the relative risk that are stable in areas of sparse data while retaining necessary detail elsewhere, and consequently difficult to distinguish true risk hotspots from stochastic bumps in the risk function. We study shrinkage estimators of the spatial relative risk function to address these problems. In particular, we propose a new lasso-type estimator that shrinks a standard kernel estimator of the log-relative risk function towards zero. The shrinkage tuning parameter can be adjusted to help quantify the degree of evidence for the existence of risk hotspots, or selected to optimize a cross-validation criterion. The performance of the lasso estimator is encouraging both on a simulation study and on real-world examples.
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Affiliation(s)
- Martin L Hazelton
- Department of Mathematics and Statistics, University of Otago, Dunedin, New Zealand
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Lambio C, Schmitz T, Elson R, Butler J, Roth A, Feller S, Savaskan N, Lakes T. Exploring the Spatial Relative Risk of COVID-19 in Berlin-Neukölln. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:ijerph20105830. [PMID: 37239558 DOI: 10.3390/ijerph20105830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/28/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023]
Abstract
Identifying areas with high and low infection rates can provide important etiological clues. Usually, areas with high and low infection rates are identified by aggregating epidemiological data into geographical units, such as administrative areas. This assumes that the distribution of population numbers, infection rates, and resulting risks is constant across space. This assumption is, however, often false and is commonly known as the modifiable area unit problem. This article develops a spatial relative risk surface by using kernel density estimation to identify statistically significant areas of high risk by comparing the spatial distribution of address-level COVID-19 cases and the underlying population at risk in Berlin-Neukölln. Our findings show that there are varying areas of statistically significant high and low risk that straddle administrative boundaries. The findings of this exploratory analysis further highlight topics such as, e.g., Why were mostly affluent areas affected during the first wave? What lessons can be learned from areas with low infection rates? How important are built structures as drivers of COVID-19? How large is the effect of the socio-economic situation on COVID-19 infections? We conclude that it is of great importance to provide access to and analyse fine-resolution data to be able to understand the spread of the disease and address tailored health measures in urban settings.
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Affiliation(s)
- Christoph Lambio
- Geography Department, Applied Geoinformation Science Lab, Humboldt-University Berlin, 10099 Berlin, Germany
| | - Tillman Schmitz
- Geography Department, Applied Geoinformation Science Lab, Humboldt-University Berlin, 10099 Berlin, Germany
| | - Richard Elson
- UK Health Security Agency, 61, Colindale Avenue, London NW9 5EQ, UK
- School of Environmental Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK
| | - Jeffrey Butler
- Geography Department, Applied Geoinformation Science Lab, Humboldt-University Berlin, 10099 Berlin, Germany
| | - Alexandra Roth
- Local Health Department Berlin-Neukölln, Gesundheitsamt Neukölln, Blaschkoallee 32, 12359 Berlin, Germany
| | - Silke Feller
- Local Health Department Berlin-Neukölln, Gesundheitsamt Neukölln, Blaschkoallee 32, 12359 Berlin, Germany
| | - Nicolai Savaskan
- Local Health Department Berlin-Neukölln, Gesundheitsamt Neukölln, Blaschkoallee 32, 12359 Berlin, Germany
| | - Tobia Lakes
- Geography Department, Applied Geoinformation Science Lab, Humboldt-University Berlin, 10099 Berlin, Germany
- IRI THESys, Integrative Research Institute on Transformations of Human-Environment Systems, Humboldt-Universität zu Berlin, 10099 Berlin, Germany
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Abstract
BACKGROUND Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies. AIMS Describe the key epigenetic and genetic mechanisms that could account for missing causality and heritability in autoimmune hepatitis; indicate the prospects of these mechanisms as pivotal factors; and encourage investigations of their pathogenic role and therapeutic potential. METHODS English abstracts were identified in PubMed using multiple key search phases. Several hundred abstracts and 210 full-length articles were reviewed. RESULTS Environmental induction of epigenetic changes is the prime candidate for explaining the missing causality of autoimmune hepatitis. Environmental factors (diet, toxic exposures) can alter chromatin structure and the production of micro-ribonucleic acids that affect gene expression. Epistatic interaction between unsuspected genes is the prime candidate for explaining the missing heritability. The non-additive, interactive effects of multiple genes could enhance their impact on the propensity and phenotype of autoimmune hepatitis. Transgenerational inheritance of acquired epigenetic marks constitutes another mechanism of transmitting parental adaptations that could affect susceptibility. Management strategies could range from lifestyle adjustments and nutritional supplements to precision editing of the epigenetic landscape. CONCLUSIONS Autoimmune hepatitis has a missing causality that might be explained by epigenetic changes induced by environmental factors and a missing heritability that might reflect epistatic gene interactions or transgenerational transmission of acquired epigenetic marks. These unassessed or under-evaluated areas warrant investigation.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
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Murillo Perez CF, Gerussi A, Trivedi PJ, Corpechot C, van der Meer AJ, Maria Battezzati P, Lindor KD, Nevens F, Kowdley KV, Bruns T, Cazzagon N, Floreani A, Tanaka A, Ma X, Mason AL, Gulamhusein A, Ponsioen CY, Carbone M, Lleo A, Mayo MJ, Dalekos GN, Gatselis NK, Thorburn D, Verhelst X, Parés A, Janssen HLA, Hirschfield GM, Hansen BE, Invernizzi P, Lammers WJ. Geographical region and clinical outcomes of patients with primary biliary cholangitis from Western Europe. Eur J Gastroenterol Hepatol 2023; 35:112-119. [PMID: 36468575 DOI: 10.1097/meg.0000000000002464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND AIMS The are geographic variations in the incidence and prevalence of primary biliary cholangitis (PBC). The aim was to explore whether clinical outcomes of patients within Western Europe differ according to geographical region. METHODS Ursodeoxycholic acid-treated patients from European centers from the Global PBC database diagnosed from 1990 onwards were included. Patients with a time lag > 1 year from diagnosis to start of follow-up were excluded. Differences in baseline characteristics were studied according to North/South and East/West, whereas outcomes (transplant-free survival and decompensation) were studied with center latitude and longitude. Cox regression analyses were adjusted for age, sex, diagnosis year, biochemical markers, and cirrhosis as a time-dependent covariate. RESULTS One thousand eight hundred seventy-eight patients were included, and there were no geographical differences in age or sex, with a mean age of 54 years and 89% female patients. Those in North Europe were more often of a moderately advanced/advanced Rotterdam biochemical stage (28.4%) compared with South Europe (20.6%). Additionally, they exhibited higher median alkaline phosphatase (2.0 ×ULN vs. 1.4 ×ULN) and transaminases. In multivariable analysis, there was a significant interaction between center latitude and longitude for decompensation (P < 0.001) and a trend for transplant-free survival, in which the Northwestern area demonstrated an increased risk for poor outcomes as compared to the reference (Paris). CONCLUSION We describe geographic variations in outcomes for patients across Europe from specialist centers in the Global PBC Study Group. Further study is important to explore the potential individual, environmental, and healthcare-related factors that may be contributors.
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Affiliation(s)
- Carla F Murillo Perez
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Alessio Gerussi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza, Italy
| | - Palak J Trivedi
- National Institute for Health Research Birmingham Biomedical Research Centre and Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - Christophe Corpechot
- Centre de Référence des Maladies Inflammatoires des VoiesBiliaires, Hôpital Saint-Antoine, Paris, France
| | - Adriaan J van der Meer
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | | | - Frederik Nevens
- Department of Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Kris V Kowdley
- Liver Care Network, Swedish Medical Center, Seattle, Washington, USA
| | - Tony Bruns
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Jena
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Nora Cazzagon
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua
- IRCCS Negrar, Verona, Italy
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Xiong Ma
- Shanghai Jiao Tong University School of Medicine, Shanghai Renji Hospital, Shanghai, China
| | - Andrew L Mason
- Divison of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada
| | - Aliya Gulamhusein
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza, Italy
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Humanitas Clinical Research Center IRCSS, Humanitas University, Milan, Italy
| | - Marlyn J Mayo
- Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly, Larissa, Greece
| | - Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly, Larissa, Greece
| | - Douglas Thorburn
- The Sheila Sherlock Liver Centre, The Royal Free Hospital, London, UK
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Albert Parés
- Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza, Italy
| | - Willem J Lammers
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
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Lleo A. Geoepidemiology and the key role of sex chromosomes on autoimmune diseases. PRINCIPLES OF GENDER-SPECIFIC MEDICINE 2023:331-346. [DOI: 10.1016/b978-0-323-88534-8.00051-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Shaker M, Mansour N, John BV. Primary Biliary Cholangitis in Males: Pathogenesis, Clinical Presentation, and Prognosis. Clin Liver Dis 2022; 26:643-655. [PMID: 36270721 DOI: 10.1016/j.cld.2022.06.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an immune-mediated chronic liver disease characterized by progressive cholestasis, bile duct destruction, biliary fibrosis, and cirrhosis. Patients who respond to ursodeoxycholic acid have an expected survival similar to the general population. Although PBC primarily affects females, the prevalence in males is higher than was previously believed, with contemporary studies suggesting a female-to-male ratio of 4-6:1. A diagnosis of PBC is often delayed among males because of the myth that PBC is rare in males.
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Affiliation(s)
- Mina Shaker
- Division of Hepatology, Miami VA Medical Center 1201 NW 16th Street, Miami, FL 33125 USA.
| | - Natalie Mansour
- Division of Hepatology, Miami VA Medical Center 1201 NW 16th Street, Miami, FL 33125 USA
| | - Binu V John
- Division of Hepatology, Miami VA Medical Center 1201 NW 16th Street, Miami, FL 33125 USA; Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
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Gerussi A, Paraboschi EM, Cappadona C, Caime C, Binatti E, Cristoferi L, Asselta R, Invernizzi P. The Role of Epigenetics in Primary Biliary Cholangitis. Int J Mol Sci 2022; 23:4873. [PMID: 35563266 PMCID: PMC9105933 DOI: 10.3390/ijms23094873] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 04/25/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022] Open
Abstract
Primary Biliary Cholangitis (PBC) is a rare autoimmune disease of the liver, affecting mostly females. There is evidence that epigenetic changes have a pathogenic role in PBC. Epigenetic modifications are related to methylation of CpG DNA islands, post-translational modifications of histone proteins, and non-coding RNAs. In PBC, there are data showing a dysregulation of all these levels, especially in immune cells. In addition, epigenetics seems to be involved in complex phenomena such as X monosomy or abnormalities in the process of X chromosome inactivation, which have been reported in PBC and appear to influence its sex imbalance and pathogenesis. We review here historical data on epigenetic modifications in PBC, present new data, and discuss possible links among X-chromosome abnormalities at a genetic and epigenetic level, PBC pathogenesis, and PBC sex imbalance.
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Affiliation(s)
- Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (A.G.); (C.C.); (E.B.); (L.C.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Elvezia Maria Paraboschi
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (E.M.P.); (C.C.); (R.A.)
- Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano, Italy
| | - Claudio Cappadona
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (E.M.P.); (C.C.); (R.A.)
- Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano, Italy
| | - Chiara Caime
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (A.G.); (C.C.); (E.B.); (L.C.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Eleonora Binatti
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (A.G.); (C.C.); (E.B.); (L.C.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Laura Cristoferi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (A.G.); (C.C.); (E.B.); (L.C.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Rosanna Asselta
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (E.M.P.); (C.C.); (R.A.)
- Humanitas Clinical and Research Center, IRCCS, Via Manzoni 56, 20089 Rozzano, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (A.G.); (C.C.); (E.B.); (L.C.)
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
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10
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Garcia-Morata M, Gonzalez-Rubio J, Segura T, Najera A. Spatial analysis of COVID-19 hospitalised cases in an entire city: The risk of studying only lattice data. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 806:150521. [PMID: 34844333 PMCID: PMC8461325 DOI: 10.1016/j.scitotenv.2021.150521] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/18/2021] [Accepted: 09/18/2021] [Indexed: 06/01/2023]
Abstract
We live in a global pandemic caused by the COVID-19 disease where severe social distancing measures are necessary. Some of these measures have been taken into account by the administrative boundaries within cities (neighborhoods, postal districts, etc.). However, considering only administrative boundaries in decision making can prove imprecise, and could have consequences when it comes to taking effective measures. To solve the described problems, we present an epidemiological study that proposes using spatial point patterns to delimit spatial units of analysis based on the highest local incidence of hospitalisations instead of administrative limits during the first COVID-19 wave. For this purpose, the 579 addresses of the cases hospitalised between March 3 and April 6, 2020, in Albacete (Spain), and the addresses of the random sample of 383 controls from the Inhabitants Register of the city of Albacete, were georeferenced. The risk ratio in those hospitalised for COVID-19 was compatible with the constant risk ratio in Albacete (p = 0.49), but areas with a significantly higher risk were found and coincided with those with greater economic inequality (Gini Index). Moreover, two districts had areas with a significantly high incidence that were masked by others with a significantly low incidence. In conclusion, taking measures conditioned exclusively by administrative limits in a pandemic can cause problems caused by managing entire districts with lax measures despite having interior areas with high significant incidences. In a pandemic context, georeferencing disease cases in real time and spatially comparing them to updated random population controls to automatically and accurately detect areas with significant incidences are suggested. This would facilitate decision making, which must be fast and accurate in these situations.
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Affiliation(s)
- Marta Garcia-Morata
- Department of Medical Sciences, Faculty of Medicine of Albacete, University of Castilla-La Mancha, Albacete, Spain.
| | - Jesus Gonzalez-Rubio
- Department of Medical Sciences, Faculty of Medicine of Albacete, University of Castilla-La Mancha, Albacete, Spain; Centro Regional de Investigaciones Biomédicas (CRIB), University of Castilla-La Mancha, Albacete, Spain.
| | - Tomas Segura
- Department of Medical Sciences, Faculty of Medicine of Albacete, University of Castilla-La Mancha, Albacete, Spain; Servicio de Neurología, Hospital General Universitario de Albacete, Albacete, Spain; Instituto de Investigación en Discapacidades Neurológicas (IDINE), University of Castilla-La Mancha, Albacete, Spain.
| | - Alberto Najera
- Department of Medical Sciences, Faculty of Medicine of Albacete, University of Castilla-La Mancha, Albacete, Spain; Centro Regional de Investigaciones Biomédicas (CRIB), University of Castilla-La Mancha, Albacete, Spain.
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11
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Beier JI, Arteel GE. Environmental exposure as a risk-modifying factor in liver diseases: Knowns and unknowns. Acta Pharm Sin B 2021; 11:3768-3778. [PMID: 35024305 PMCID: PMC8727918 DOI: 10.1016/j.apsb.2021.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/24/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023] Open
Abstract
Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology. However, inheritance drives the ability to appropriately adapt to environmental stressors, and disease is the culmination of a maladaptive response. Thus “pure” genetic and “pure” xenobiotic liver diseases are modified by each other and other factors, identified or unknown. The purpose of this review is to highlight the knowledgebase of environmental exposure as a potential risk modifying agent for the development of liver disease by other causes. This exercise is not to argue that all liver diseases have an environmental component, but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a possibility. This review also discusses key new tools and approaches that will likely be critical to address this question in the future. Taken together, identifying the key gaps in our understanding is critical for the field to move forward, or at the very least to “know what we don't know.”
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Affiliation(s)
- Juliane I. Beier
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center and University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Environmental and Occupational Health, University of Pittsburgh, PA 15213, USA
- Corresponding authors.
| | - Gavin E. Arteel
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Pittsburgh Liver Research Center and University of Pittsburgh, Pittsburgh, PA 15213, USA
- Corresponding authors.
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12
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Early histopathologic changes in primary biliary cholangitis: does 'minimal change' primary biliary cholangitis exist? A pathologist's view. Eur J Gastroenterol Hepatol 2021; 33:e7-e12. [PMID: 32804848 DOI: 10.1097/meg.0000000000001876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an autoimmune, slowly progressive, cholestatic liver disease characterized by nonsuppurative destructive cholangitis, and interlobular bile duct destruction. Necroinflammatory activities of the hepatic parenchyma and limiting plates of milder form along with late liver fibrosis may develop. Serum liver tests include elevated serum alkaline phosphatase along with a positive antimitochondrial antibody (AMA) in nearly 95% of patients. Liver biopsies are an important confirmatory and staging tool and are additionally very helpful when AMA is negative. More specifically, the earliest changes in liver biopsy suspicious for PBC can be detected, namely loss of the canals of Hering (CoH), as proposed by various authors recently. CoH loss has been described as an early feature of PBC. We focus on early histologic features of PBC, investigating through the literature the possible role of 'minimal change' supporting the clinical diagnosis of PBC, even in the absence of characteristic granulomatous duct destructive lesions.
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13
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Leitch AC, Ibrahim I, Abdelghany TM, Charlton A, Roper C, Vidler D, Palmer JM, Wilson C, Jones DE, Blain PG, Wright MC. The methylimidazolium ionic liquid M8OI is detectable in human sera and is subject to biliary excretion in perfused human liver. Toxicology 2021; 459:152854. [PMID: 34271081 PMCID: PMC8366605 DOI: 10.1016/j.tox.2021.152854] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/28/2021] [Accepted: 07/07/2021] [Indexed: 12/14/2022]
Abstract
M8OI was recently found to be contaminating the environment. M8OI was detected in the sera from 5/20 PBC patients and 1/10 controls. M8OI is taken up by human liver hepatocytes. M8OI is sequentially metabolised by CYPs followed by oxidation by dehydrogenases. The final carboxylic acid metabolite COOH7IM is, in part, excreted into human bile. A methylimidizolium ionic liquid (M8OI) was recently found to be contaminating the environment and to be related to and/or potentially a component of an environmental trigger for the autoimmune liver disease primary biliary cholangitis (PBC). The aims of this study were to investigate human exposure to M8OI, hepatic metabolism and excretion. PBC patient and control sera were screened for the presence of M8OI. Human livers were perfused with 50μM M8OI in a closed circuit and its hepatic disposition examined. Metabolism was examined in cultured human hepatocytes and differentiated HepaRG cells by the addition of M8OI and metabolites in the range 10–100 μM. M8OI was detected in the sera from 5/20 PBC patients and 1/10 controls. In perfused livers, M8OI was cleared from the plasma with its appearance – primarily in the form of its hydroxylated (HO8IM) and carboxylated (COOH7IM) products – in the bile. Metabolism was reflected in cultured hepatocytes with HO8IM production inhibited by the cytochrome P450 inhibitor ketoconazole. Further oxidation of HO8IM to COOH7IM was sequentially inhibited by the alcohol and acetaldehyde dehydrogenase inhibitors 4-methyl pyrazole and disulfiram respectively. Hepatocytes from 1 donor failed to metabolise M8OI to COOH7IM over a 24 h period. These results demonstrate exposure to M8OI in the human population, monooxygenation by cytochromes P450 followed by alcohol and acetaldehyde dehydrogenase oxidation to a carboxylic acid that are excreted, in part, via the bile in human liver.
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Affiliation(s)
- Alistair C Leitch
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Ibrahim Ibrahim
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Freeman Hospital, Newcastle upon Tyne, Tyne and Wear, NE7 7DN, United Kingdom
| | - Tarek M Abdelghany
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt
| | - Alex Charlton
- School of Natural and Environmental Sciences, Bedson Building, Newcastle University, NE1 8QB, United Kingdom
| | - Clair Roper
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Dan Vidler
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Jeremy M Palmer
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Colin Wilson
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Freeman Hospital, Newcastle upon Tyne, Tyne and Wear, NE7 7DN, United Kingdom
| | - David E Jones
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Peter G Blain
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Matthew C Wright
- Institute of Translation and Clinical Research, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom.
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14
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Lv T, Chen S, Li M, Zhang D, Kong Y, Jia J. Regional variation and temporal trend of primary biliary cholangitis epidemiology: A systematic review and meta-analysis. J Gastroenterol Hepatol 2021; 36:1423-1434. [PMID: 33141955 DOI: 10.1111/jgh.15329] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 10/12/2020] [Accepted: 10/24/2020] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIM We aimed to estimate the worldwide incidence and prevalence, with focus on the geographical differences and temporal trends. METHODS Studies on epidemiology of primary biliary cholangitis (PBC) in PubMed, Embase, and Cochrane Library were systematically retrieved from inception to October 2, 2020. Random-effect model was applied to estimate the pooled PBC incidence and prevalence rates. Subgroup analysis, meta-regression, and sensitivity analysis were conducted to find out the cause for heterogeneity. RESULTS Out of 3974 records identified through database searching, 47 population-based studies were finally included. The pooled global incidence and prevalence of PBC were 1.76 and 14.60 per 100 000 persons, respectively. Both the PBC incidence and prevalence were lower in the Asia-Pacific region (0.84, 9.82 per 100 000 persons) than that in North America (2.75, 21.81 per 100 000 persons) and Europe (1.86, 14.59 per 100 000 persons) (P < 0.05). The incidence and prevalence showed an increasing tendency in all three regions, with the fastest growth of prevalence in North America (P < 0.05). We found a similar incidence and a lower prevalence of PBC in Northern Europe than that in Southern Europe. A higher incidence and prevalence were observed in female individuals and in the elderly (60-79). CONCLUSION The PBC incidence and prevalence varied widely across regions, with North America being the highest, followed by Europe, and the lowest in the Asia-Pacific region. Both the incidence and prevalence showed an increasing tendency worldwide, especially in North America.
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Affiliation(s)
- Tingting Lv
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Disease, Beijing, China
| | - Sha Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Disease, Beijing, China
| | - Min Li
- Clinical Epidemiology and EBM Unit, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Dong Zhang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Clinical Research Institute; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Disease, Beijing, China
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15
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French J, Simpson-Yap S, van der Mei I, Ng J, Angus P, Gow PJ. Identification of a Latitude Gradient in the Prevalence of Primary Biliary Cholangitis. Clin Transl Gastroenterol 2021; 12:e00357. [PMID: 34003806 PMCID: PMC8345914 DOI: 10.14309/ctg.0000000000000357] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 04/05/2021] [Indexed: 12/03/2022] Open
Abstract
INTRODUCTION The prevalence of primary biliary cholangitis (PBC) reported in different countries varies significantly and seems to have a latitudinal gradient with the highest prevalence reported in higher latitudes, as has been observed with other autoimmune diseases. This study aimed to determine whether there is a latitudinal gradient of PBC prevalence in Australia using 2 methods of case ascertainment. METHODS We investigated the latitudinal variation of PBC prevalence across the states and territories of Australia (latitudinal range 18.0°-42.7°S) using pathology-based (private pathology antimitochondrial antibody results and PBC-specific prescription databases (prescriptions for ursodeoxycholic acid, the only publicly subsidized treatment for this disease). RESULTS PBC prevalence was significantly positively associated with latitude, and the postcodes in the highest quintile of latitude (encompassing the south coastal areas of the Australian mainland and Tasmania; latitude range -37.75° to -42.72°) had a prevalence estimate that was 1.78 times higher using the pathology-based prevalence estimation than those in the lowest quintile (encompassing tropical and southern Queensland; latitude range -18.02° to -27.59°). Comparing prevalence estimates between states/territories, the result was 2.53 and 2.21 times higher in Tasmania compared with Queensland when using the pathology-based and prescription-based methods, respectively. DISCUSSION Using 2 different case-ascertainment methods, we have demonstrated that prevalence estimates of PBC vary significantly with latitude in Australia. Further studies are needed to determine whether factors such as variations in ultraviolet radiation exposure and/or vitamin D levels are responsible for this observation and to investigate the latitudinal prevalence of PBC in other populations.
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Affiliation(s)
- Janine French
- Department of Gastroenterology, Austin Hospital, Heidelberg, Australia
| | - Steve Simpson-Yap
- Department of Biostatistics and Epidemiology, Melbourne School of Population and Global Health, University of Melbourne, Carlton, Australia
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
| | - Ingrid van der Mei
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
| | - Justin Ng
- Department of Gastroenterology, Austin Hospital, Heidelberg, Australia
| | - Peter Angus
- Department of Gastroenterology, Austin Hospital, Heidelberg, Australia
| | - Paul J. Gow
- Department of Gastroenterology, Austin Hospital, Heidelberg, Australia
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16
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Abstract
Primary biliary cholangitis (PBC) causes chronic and persistent cholestasis in the liver, eventually resulting in cirrhosis and hepatic failure without appropriate treatment. PBC mainly develops in middle-aged women, but it is also common in young women and men. PBC is considered a model of autoimmune disease because of the presence of disease-specific autoantibodies, that is, antimitochondrial antibodies (AMAs), intense infiltration of mononuclear cells into the bile ducts, and a high prevalence of autoimmune diseases such as comorbidities. Histologically, PBC is characterized by degeneration and necrosis of intrahepatic biliary epithelial cells surrounded by a dense infiltration of mononuclear cells, coined as chronic non-suppurative destructive cholangitis, which leads to destructive changes and the disappearance of small- or medium-sized bile ducts. Since 1990, early diagnosis with the detection of AMAs and introduction of ursodeoxycholic acid as first-line treatment has greatly altered the clinical course of PBC, and liver transplantation-free survival of patients with PBC is now comparable to that of the general population.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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17
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Dyson JK, Blain A, Foster Shirley MD, Hudson M, Rushton S, Jeffreys Jones DE. Geo-epidemiology and environmental co-variate mapping of primary biliary cholangitis and primary sclerosing cholangitis. JHEP Rep 2020; 3:100202. [PMID: 33474546 PMCID: PMC7803647 DOI: 10.1016/j.jhepr.2020.100202] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/14/2020] [Accepted: 10/09/2020] [Indexed: 02/07/2023] Open
Abstract
Background & Aims Autoimmune liver disease (AILD) is thought to result from a complex interplay between genetics and the environment. Studies to date have focussed on primary biliary cholangitis (PBC) and demonstrated higher disease prevalence in more urban, polluted, and socially deprived areas. This study utilises a large cohort of patients with PBC and primary sclerosing cholangitis (PSC) to investigate potential environmental contributors to disease and to explore whether the geo-epidemiology of PBC and PSC are disease-specific or pertain to cholestatic AILD in general. Methods All adult patients with PBC and PSC in a tightly defined geographical area within the UK were identified. Point- and area-based analyses and structural equation modelling (SEM) were used to investigate for disease clustering and examine for relationships between prevalence, distribution of environmental contaminants, and socio-economic status. Results We identified 2,150 patients with PBC and 472 with PSC. Significant spatial clustering was seen for each disease. A high prevalence of PBC was found in urban, post-industrial areas with a strong coal-mining heritage and increased environmental cadmium levels, whereas a high PSC prevalence was found in rural areas and inversely associated with social deprivation. Conclusions This study demonstrates spatial clustering of PBC and PSC and adds to our understanding of potential environmental co-variates for both diseases. Disease clustering, within the same geographical area but over different scales, is confirmed for each disease with distinct risk profiles identified and associations with separate putative environmental factors and socio-economic status. This suggests that different triggers and alternative pathways determine phenotypic expression of autoimmunity in the affected population. Co-variate analysis points towards the existence of specific disease triggers. Lay summary This study looked for potential environmental triggers in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) living in the north-east of England and north Cumbria. We found that PBC was more common in urban areas with a history of coal mining and high levels of cadmium whereas PSC was more common in rural areas with lower levels of social deprivation.
Clustering of PBC and PSC patients occurs with notable geographical differences. A high prevalence of PBC is seen in urban, post-industrial areas. PSC is more common in rural areas and inversely associated with social deprivation. PBC risk is associated with proximity to coal mines and environmental cadmium levels. Comprehensive epidemiological study can increase understanding of disease aetiology.
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Key Words
- AHSN NENC, Academic Health Science Network for the North East and North Cumbria
- AIH, autoimmune hepatitis
- AILD, autoimmune liver disease
- Autoimmune hepatitis
- BECs, biliary epithelial cells
- CFI, comparative fit index
- Cadmium
- DIC, deviance information criterion
- Geo-epidemiology
- IMD, Index of Multiple Deprivation
- PBC, primary biliary cholangitis
- PSC, primary sclerosing cholangitis
- Primary biliary cholangitis
- Primary sclerosing cholangitis
- RMSEA, root mean square error of association
- Rural
- SEM, structural equation modelling
- SFS, superfund toxic waste site
- Socio-economic status
- Urban
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Affiliation(s)
- Jessica Katharine Dyson
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK.,Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK
| | - Alasdair Blain
- Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle-upon-Tyne, UK
| | | | - Mark Hudson
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK.,Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK
| | - Steven Rushton
- School of Natural and Environmental Sciences, Newcastle University, Newcastle-upon-Tyne, UK
| | - David Emrys Jeffreys Jones
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK.,Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK
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18
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Abdelghany TM, Leitch AC, Nevjestić I, Ibrahim I, Miwa S, Wilson C, Heutz S, Wright MC. Emerging risk from "environmentally-friendly" solvents: Interaction of methylimidazolium ionic liquids with the mitochondrial electron transport chain is a key initiation event in their mammalian toxicity. Food Chem Toxicol 2020; 145:111593. [PMID: 32777338 DOI: 10.1016/j.fct.2020.111593] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 06/12/2020] [Accepted: 07/08/2020] [Indexed: 12/17/2022]
Abstract
Recent studies have identified the 8C alkyl chain methylimidazolium ionic liquid 1-octyl-3-methylimidazolium in the environment and its potential to trigger the auto-immune liver disease primary biliary cholangitis. The toxicity of a range of methylimidazolium ionic liquids were therefore examined. Oxygen consumption was rapidly inhibited, with potency increasing with alkyl chain length. This preceded caspase 3/7 induction and DNA fragmentation. Time- and dose-dependent loss of dye reduction capacities reflected these effects, with a >700 fold difference in potency between 2C and 10C alkyl chain liquids. None of the ionic liquids directly inhibited mitochondrial complexes I-IV or complex V (F0F1-ATPase). However, dithionite reduction and ESR spectroscopy studies indicate a one electron reduction of oxygen in the presence of a methylimidazolium ionic liquid, suggesting methylimidazolium ionic liquids function as mitochondrial electron acceptors. However, only longer chain ionic liquids form a non-aqueous phase or micelle under aqueous physiological conditions and lead to increases in reactive oxygen species in intact cells. These data therefore suggest that the longer chain methylimidazolium liquids are toxic in sensitive liver progenitor cells because they both readily integrate within the inner mitochondrial membrane and accept electrons from the electron chain, leading to oxidative stress.
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Affiliation(s)
- Tarek M Abdelghany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt; Bioscience Institute, Cookson Building, Newcastle University, Newcastle Upon Tyne, NE24HH, United Kingdom
| | - Alistair C Leitch
- Health Protection Research Unit, Wolfson Building, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Translational and Clinical Research, Level 4 Leech, Newcastle University, Newcastle Upon Tyne, NE24HH, United Kingdom
| | - Irena Nevjestić
- Department of Materials, Faculty of Engineering, Imperial College, London, SW7 2AZ, United Kingdom
| | - Ibrahim Ibrahim
- Translational and Clinical Research, Level 4 Leech, Newcastle University, Newcastle Upon Tyne, NE24HH, United Kingdom; Freeman Hospital, Newcastle Upon Tyne, United Kingdom
| | - Satomi Miwa
- Bioscience Institute, Cookson Building, Newcastle University, Newcastle Upon Tyne, NE24HH, United Kingdom
| | - Colin Wilson
- Translational and Clinical Research, Level 4 Leech, Newcastle University, Newcastle Upon Tyne, NE24HH, United Kingdom; Freeman Hospital, Newcastle Upon Tyne, United Kingdom
| | - Sandrine Heutz
- Department of Materials, Faculty of Engineering, Imperial College, London, SW7 2AZ, United Kingdom
| | - Matthew C Wright
- Health Protection Research Unit, Wolfson Building, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Translational and Clinical Research, Level 4 Leech, Newcastle University, Newcastle Upon Tyne, NE24HH, United Kingdom.
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19
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Young GR, Abdelghany TM, Leitch AC, Dunn MP, Blain PG, Lanyon C, Wright MC. Changes in the gut microbiota of mice orally exposed to methylimidazolium ionic liquids. PLoS One 2020; 15:e0229745. [PMID: 32163446 PMCID: PMC7067480 DOI: 10.1371/journal.pone.0229745] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 02/13/2020] [Indexed: 12/12/2022] Open
Abstract
Ionic liquids are salts used in a variety of industrial processes, and being relatively non-volatile, are proposed as environmentally-friendly replacements for existing volatile liquids. Methylimidazolium ionic liquids resist complete degradation in the environment, likely because the imidazolium moiety does not exist naturally in biological systems. However, there is limited data available regarding their mammalian effects in vivo. This study aimed to examine the effects of exposing mice separately to 2 different methylimidazolium ionic liquids (BMI and M8OI) through their addition to drinking water. Potential effects on key target organs-the liver and kidney-were examined, as well as the gut microbiome. Adult male mice were exposed to drinking water containing ionic liquids at a concentration of 440 mg/L for 18 weeks prior to examination of tissues, serum, urine and the gut microbiome. Histopathology was performed on tissues and clinical chemistry on serum for biomarkers of hepatic and renal injury. Bacterial DNA was isolated from the gut contents and subjected to targeted 16S rRNA sequencing. Mild hepatic and renal effects were limited to glycogen depletion and mild degenerative changes respectively. No hepatic or renal adverse effects were observed. In contrast, ionic liquid exposure altered gut microbial composition but not overall alpha diversity. Proportional abundance of Lachnospiraceae, Clostridia and Coriobacteriaceae spp. were significantly greater in ionic liquid-exposed mice, as were predicted KEGG functional pathways associated with xenobiotic and amino acid metabolism. Exposure to ionic liquids via drinking water therefore resulted in marked changes in the gut microbiome in mice prior to any overt pathological effects in target organs. Ionic liquids may be an emerging risk to health through their potential effects on the gut microbiome, which is implicated in the causes and/or severity of an array of chronic disease in humans.
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Affiliation(s)
- Gregory R. Young
- Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, England, United Kingdom
| | - Tarek M. Abdelghany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
- Health Protection Research Unit, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, England, United Kingdom
| | - Alistair C. Leitch
- Health Protection Research Unit, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, England, United Kingdom
| | - Michael P. Dunn
- Health Protection Research Unit, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, England, United Kingdom
| | - Peter G. Blain
- Health Protection Research Unit, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, England, United Kingdom
| | - Clare Lanyon
- Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, England, United Kingdom
| | - Matthew C. Wright
- Health Protection Research Unit, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, England, United Kingdom
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20
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Leitch AC, Abdelghany TM, Probert PM, Dunn MP, Meyer SK, Palmer JM, Cooke MP, Blake LI, Morse K, Rosenmai AK, Oskarsson A, Bates L, Figueiredo RS, Ibrahim I, Wilson C, Abdelkader NF, Jones DE, Blain PG, Wright MC. The toxicity of the methylimidazolium ionic liquids, with a focus on M8OI and hepatic effects. Food Chem Toxicol 2020; 136:111069. [PMID: 31883992 PMCID: PMC6996134 DOI: 10.1016/j.fct.2019.111069] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 12/02/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023]
Abstract
Ionic liquids are a diverse range of charged chemicals with low volatility and often liquids at ambient temperatures. This characteristic has in part lead to them being considered environmentally-friendly replacements for existing volatile solvents. However, methylimidazolium ionic liquids are slow to break down in the environment and a recent study at Newcastle detected 1 octyl 3 methylimidazolium (M8OI) - an 8 carbon variant methylimidazolium ionic liquid - in soils in close proximity to a landfill site. The current M8OI toxicity database in cultured mammalian cells, in experimental animal studies and in model indicators of environmental impact are reviewed. Selected analytical data from the Newcastle study suggest the soils in close proximity to the landfill site, an urban soil lacking overt contamination, had variable levels of M8OI. The potential for M8OI - or a structurally related ionic liquid - to trigger primary biliary cholangitis (PBC), an autoimmune liver disease thought to be triggered by an unknown agent(s) in the environment, is reviewed.
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Affiliation(s)
- Alistair C Leitch
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Tarek M Abdelghany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt; Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Philip M Probert
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Michael P Dunn
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Stephanie K Meyer
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Jeremy M Palmer
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Martin P Cooke
- School of Civil Engineering and Geosciences, Drummond Building, Newcastle University, Newcastle Upon Tyne, NE1 7RU, United Kingdom
| | - Lynsay I Blake
- Department of Biosciences, Durham University, Durham, DH1 3LE, United Kingdom
| | - Katie Morse
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Anna K Rosenmai
- Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Agneta Oskarsson
- Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Lucy Bates
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | | | - Ibrahim Ibrahim
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Freeman Hospital, Newcastle Upon Tyne, Tyne and Wear, NE7 7DN, United Kingdom
| | - Colin Wilson
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom; Freeman Hospital, Newcastle Upon Tyne, Tyne and Wear, NE7 7DN, United Kingdom
| | - Noha F Abdelkader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt
| | - David E Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Peter G Blain
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom
| | - Matthew C Wright
- Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, NE2 4AA, United Kingdom.
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21
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Johnson O, Diggle P, Giorgi E. A spatially discrete approximation to log-Gaussian Cox processes for modelling aggregated disease count data. Stat Med 2019; 38:4871-4887. [PMID: 31452235 DOI: 10.1002/sim.8339] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 07/16/2019] [Accepted: 07/18/2019] [Indexed: 11/08/2022]
Abstract
In this paper, we develop a computationally efficient discrete approximation to log-Gaussian Cox process (LGCP) models for the analysis of spatially aggregated disease count data. Our approach overcomes an inherent limitation of spatial models based on Markov structures, namely, that each such model is tied to a specific partition of the study area, and allows for spatially continuous prediction. We compare the predictive performance of our modelling approach with LGCP through a simulation study and an application to primary biliary cirrhosis incidence data in Newcastle upon Tyne, UK. Our results suggest that, when disease risk is assumed to be a spatially continuous process, the proposed approximation to LGCP provides reliable estimates of disease risk both on spatially continuous and aggregated scales. The proposed methodology is implemented in the open-source R package SDALGCP.
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Affiliation(s)
- Olatunji Johnson
- CHICAS, Lancaster Medical School, Lancaster University, Lancaster, UK
| | - Peter Diggle
- CHICAS, Lancaster Medical School, Lancaster University, Lancaster, UK
| | - Emanuele Giorgi
- CHICAS, Lancaster Medical School, Lancaster University, Lancaster, UK
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22
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Examining the role of a retail density ordinance in reducing concentration of tobacco retailers. Spat Spatiotemporal Epidemiol 2019; 32:100307. [PMID: 32007281 DOI: 10.1016/j.sste.2019.100307] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 09/24/2019] [Indexed: 11/21/2022]
Abstract
Neighborhood characteristics and the built environment are important determinants in shaping health inequalities. We evaluate the role of a retail density ordinance in reducing concentration of tobacco stores based on neighborhood characteristics and land use pattern in San Francisco. The study evaluated the spatial distribution of tobacco retailers before and after the ordinance to identify geographic pockets where the most significant reduction had occurred. A generalized additive model was applied to assess the association between the location of the closure of tobacco retailer and socio-demographic characteristics and land use pattern. We did not find a meaningful change in the overall concentration of retailers based on neighborhood income and ethnicity but found a significant association based on patterns of land use. Our findings suggest that future polices must account for the differential distribution of retailers based on land use mix to lower concentration in areas where it is needed the most.
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23
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Elson R, Davies TM, Jenkins C, Vivancos R, O'Brien SJ, Lake IR. Application of kernel smoothing to estimate the spatio-temporal variation in risk of STEC O157 in England. Spat Spatiotemporal Epidemiol 2019; 32:100305. [PMID: 32007279 DOI: 10.1016/j.sste.2019.100305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 09/10/2019] [Accepted: 09/16/2019] [Indexed: 01/27/2023]
Abstract
Identifying geographical areas with significantly higher or lower rates of infectious diseases can provide important aetiological clues to inform the development of public health policy and interventions designed to reduce morbidity. We applied kernel smoothing to estimate the spatial and spatio-temporal variation in risk of STEC O157 infection in England between 2009 and 2015, and to explore differences between the residential locations of cases reporting travel and those not reporting travel. We provide evidence that the distribution of STEC O157 infection in England is non-uniform with respect to the distribution of the at-risk population; that the spatial distribution of the three main genetic lineages infecting humans (I, II and I/II) differs significantly and that the spatio-temporal risk is highly dynamic. Our results also indicate that cases of STEC O157 reporting travel within or outside the UK are more likely to live in the south/south-east of the country, meaning that their residential location may not reflect the location of exposure that led to their infection. We suggest that the observed variation in risk reflects exposure to sources of STEC O157 that are geographically prescribed. These differences may be related to a combination of changes in the strains circulating in the ruminant reservoir, animal movements (livestock, birds or wildlife) or the behavior of individuals prior to infection. Further work to identify the importance of behaviours and exposures reported by cases relative to residential location is needed.
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Affiliation(s)
- Richard Elson
- National Infection Service, Public Health England, 61 Colindale Avenue, London NW9 5EQ, United Kingdom; National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Gastrointestinal Infections, United Kingdom; School of Environmental Sciences, University of East Anglia, United Kingdom.
| | - Tilman M Davies
- Department of Mathematics & Statistics, University of Otago, Dunedin, New Zealand
| | - Claire Jenkins
- National Infection Service, Public Health England, 61 Colindale Avenue, London NW9 5EQ, United Kingdom; National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Gastrointestinal Infections, United Kingdom
| | - Roberto Vivancos
- National Infection Service, Public Health England, 61 Colindale Avenue, London NW9 5EQ, United Kingdom; National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Gastrointestinal Infections, United Kingdom; National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections, United Kingdom
| | - Sarah J O'Brien
- National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Gastrointestinal Infections, United Kingdom; Institute of Population Health Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Iain R Lake
- National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Gastrointestinal Infections, United Kingdom; School of Environmental Sciences, University of East Anglia, United Kingdom
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24
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Tanaka A, Leung PSC, Gershwin ME. Pathogen infections and primary biliary cholangitis. Clin Exp Immunol 2019; 195:25-34. [PMID: 30099750 PMCID: PMC6300644 DOI: 10.1111/cei.13198] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 08/02/2018] [Accepted: 08/03/2018] [Indexed: 12/14/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a multi-factorial disease caused by the interaction of both genetic predisposition and environmental triggers. Bacterial infection has been investigated most intensively, both epidemiologically and experimentally, as a prime environmental aetiology in PBC. The association of recurrent history of urinary tract infection (UTI) with PBC has been frequently confirmed by several large-scale, case-control studies, despite variation in geographic area or case-finding methods. Escherichia coli is a predominant pathogen in most cases with UTI. Animal studies and molecular mimicry analysis between the human and E. coli E2 subunit of the 2-oxo-acid dehydrogenase complexes demonstrated that E. coli infection is a key factor in breaking immunological tolerance against the mitochondria, resulting in the production of anti-mitochondrial autoantibodies (AMA), the disease-specific autoantibodies of PBC. Novosphingobium aromaticivorans, a ubiquitous xenobiotic-metabolizing bacterium, is another candidate which may be involved in the aetiology of PBC. Meanwhile, improved environmental hygiene and increased prevalence of PBC, especially in males, may argue against the aetiological role of bacterial infection in PBC. Multiple mechanisms can result in the loss of tolerance to mitochondrial autoantigens in PBC; nonetheless, bacterial infection is probably one of the dominant pathways, especially in female patients. Notably, there is a rising prevalence of male patients with PBC. With increasing exposure to environmental xenobiotics in both genders, studies directed towards identifying the environmental culprit with systematically designed case-control studies are much needed to further determine the environmental factors and role of bacterial infections in PBC.
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Affiliation(s)
- A. Tanaka
- Department of MedicineTeikyo University School of MedicineTokyoJapan
| | - P. S. C. Leung
- Division of Rheumatology Allergy and Clinical ImmunologyUniversity of California School of MedicineDavisCAUSA
| | - M. E. Gershwin
- Division of Rheumatology Allergy and Clinical ImmunologyUniversity of California School of MedicineDavisCAUSA
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25
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Probert PM, Leitch AC, Dunn MP, Meyer SK, Palmer JM, Abdelghany TM, Lakey AF, Cooke MP, Talbot H, Wills C, McFarlane W, Blake LI, Rosenmai AK, Oskarsson A, Figueiredo R, Wilson C, Kass GE, Jones DE, Blain PG, Wright MC. Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis. J Hepatol 2018; 69:1123-1135. [PMID: 30006067 PMCID: PMC6192827 DOI: 10.1016/j.jhep.2018.06.027] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 06/24/2018] [Accepted: 06/26/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors, such as exposure to xenobiotics, which leads to a loss of tolerance to the lipoic acid-conjugated regions of the mitochondrial pyruvate dehydrogenase complex, typically to the E2 component. We aimed to identify xenobiotics that might be involved in the environmental triggering of PBC. METHODS Urban landfill and control soil samples from a region with high PBC incidence were screened for xenobiotic activities using analytical, cell-based xenobiotic receptor activation assays and toxicity screens. RESULTS A variety of potential xenobiotic classes were ubiquitously present, as identified by their interaction with xenobiotic receptors - aryl hydrocarbon receptor, androgen receptor and peroxisome proliferator activated receptor alpha - in cell-based screens. In contrast, xenoestrogens were present at higher levels in soil extracts from around an urban landfill. Furthermore, two landfill sampling sites contained a chemical(s) that inhibited mitochondrial oxidative phosphorylation and induced the apoptosis of a hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from three separate donors. The chemical was identified as the ionic liquid [3-methyl-1-octyl-1H-imidazol-3-ium]+ (M8OI) and the toxic effects were recapitulated using authentic pure chemical. A carboxylate-containing human hepatocyte metabolite of M8OI, bearing structural similarity to lipoic acid, was also enzymatically incorporated into the E2 component of the pyruvate dehydrogenase complex via the exogenous lipoylation pathway in vitro. CONCLUSIONS These results identify, for the first time, a xenobiotic in the environment that may be related to and/or be a component of an environmental trigger for PBC. Therefore, further study in experimental animal models is warranted, to determine the risk of exposure to these ionic liquids. LAY SUMMARY Primary biliary cholangitis is a liver disease in which most patients have antibodies to mitochondrial proteins containing lipoic acid binding site(s). This paper identified a man-made chemical present in soils around a waste site. It was then shown that this chemical was metabolized into a product with structural similarity to lipoic acid, which was capable of replacing lipoic acid in mitochondrial proteins.
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Affiliation(s)
- Philip M Probert
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Alistair C Leitch
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Michael P Dunn
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Stephanie K Meyer
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Jeremy M Palmer
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Tarek M Abdelghany
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt
| | - Anne F Lakey
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Martin P Cooke
- School of Civil Engineering and Geosciences, Drummond Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom
| | - Helen Talbot
- School of Civil Engineering and Geosciences, Drummond Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom
| | - Corinne Wills
- School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom
| | - William McFarlane
- School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom
| | - Lynsay I Blake
- Institute for Sustainability, The Key Building, Newcastle University, Newcastle upon Tyne NE4 5TQ, United Kingdom
| | - Anna K Rosenmai
- Swedish University of Agricultural Sciences, Uppsala, Sweden
| | | | - Rodrigo Figueiredo
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom; Freeman Hospital, Newcastle upon Tyne, Tyne and Wear NE7 7DN, United Kingdom
| | - Colin Wilson
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom; Freeman Hospital, Newcastle upon Tyne, Tyne and Wear NE7 7DN, United Kingdom
| | - George E Kass
- European Food Safety Authority, Via Carlo Magno 1A, 43126 Parma, Italy
| | - David E Jones
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Peter G Blain
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom
| | - Matthew C Wright
- Health Protection Research Unit, Wolfson Building, Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4AA, United Kingdom.
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26
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Hirschfield GM, Dyson JK, Alexander GJM, Chapman MH, Collier J, Hübscher S, Patanwala I, Pereira SP, Thain C, Thorburn D, Tiniakos D, Walmsley M, Webster G, Jones DEJ. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut 2018; 67:1568-1594. [PMID: 29593060 PMCID: PMC6109281 DOI: 10.1136/gutjnl-2017-315259] [Citation(s) in RCA: 213] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 01/22/2018] [Accepted: 01/23/2018] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.
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Affiliation(s)
- Gideon M Hirschfield
- NIHR Birmingham Biomedical Research Centre, Birmingham, UK
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Jessica K Dyson
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom
| | - Graeme J M Alexander
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
| | - Michael H Chapman
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Jane Collier
- Translational Gastroenterology Unit, Oxford University Hospitals, University of Oxford, Oxford, UK
| | - Stefan Hübscher
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Imran Patanwala
- Department of Gastroenterology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
- University of Liverpool, Liverpool, UK
| | - Stephen P Pereira
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | | | - Douglas Thorburn
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
| | - Dina Tiniakos
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | | | - George Webster
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | - David E J Jones
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom
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27
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Terziroli Beretta-Piccoli B, Stirnimann G, Cerny A, Semela D, Hessler R, Helbling B, Stickel F, Kalid-de Bakker C, Bihl F, Giostra E, Filipowicz Sinnreich M, Oneta C, Baserga A, Invernizzi P, Carbone M, Mertens J. Geoepidemiology of Primary Biliary Cholangitis: Lessons from Switzerland. Clin Rev Allergy Immunol 2018; 54:295-306. [PMID: 29181702 DOI: 10.1007/s12016-017-8656-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
No data on primary biliary cholangitis (PBC) are available in Switzerland. We established a national patient cohort to obtain information on PBC phenotypes and disease course in Switzerland. Local databases in all university hospitals and in two large secondary centers were searched for case finding. In addition, all primary care physicians, gastroenterologists, rheumatologists, and dermatologists were invited to contribute patients from their own medical records. PBC diagnosis was centrally reviewed. Five hundred one PBC patients were identified, 474 were included in data analysis, and 449 of them were enrolled by tertiary centers. The catchment area accounts for approximately one third of the Swiss population or approximately 2.8 million inhabitants. The median age at diagnosis was 53 years, 84% were women, and 86% were anti-mitochondrial antibody positive. The median follow-up was 5.4 years, 12.6% experienced a liver-related endpoint. Splenomegaly was present at diagnosis in one quarter of patients and in half of male patients. Approximately one third were non-responders to ursodeoxycholic acid (UDCA). The median transplant-free survival at 10 years was 85%. The following variables were independently associated with poor outcome: low platelet count at baseline (HR = 0.99, p < 0.0001), elevated alkaline phosphatase at baseline (HR = 1.36, p < 0.0001), elevated bilirubin at baseline (HR = 1.11, p = 0.001), and elevated alanine aminotransaminase (HR = 1.35, p = 0.04) after 12 months of UDCA therapy. The AUROC for the UK-PBC risk score at 5, 10, and 15 years was 0.82. The AUROC for the Globe score at 5, 10, and 15 years was 0.77. Patients included in this study are currently being enrolled in a prospective nationwide registry with biobank, taking advantage of the collaboration network generated by this study. Our study provides the first snapshot of PBC in Switzerland, describing a diagnostic delay with one quarter of patients diagnosed when already in the cirrhotic stage. We were also able to externally validate the UK-PBC risk score and the Globe score. The ongoing nationwide prospective registry will be fundamental to improve disease awareness and interdisciplinary collaborations and will serve as a platform for clinical and translational research. TRIAL REGISTRATION NUMBER clinicaltrials.gov : NCT02846896; SNCTP000001870.
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Affiliation(s)
| | - Guido Stirnimann
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Andreas Cerny
- Epatocentro Ticino, via Soldino 5, 6900, Lugano, Switzerland
| | - David Semela
- Hepatologie, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Roxane Hessler
- Department of Gastroenterology and Hepatology, Centre Hôpitalier Universitaire Vaudois, Lausanne, Switzerland
| | | | - Felix Stickel
- Hepatologie Hirslanden Bern, Bern, Switzerland.,Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | | | - Florian Bihl
- Servizio Epatologia EOC, Bellinzona, Switzerland
| | | | | | - Carl Oneta
- Medical office for Gastroenterology and Hepatology, Winterthur, Switzerland
| | - Adriana Baserga
- Epatocentro Ticino, via Soldino 5, 6900, Lugano, Switzerland
| | - Pietro Invernizzi
- Center for Autoimmune Liver Diseases, Division of Gastroenterology, University of Milan Bicocca, Milan, Italy
| | - Marco Carbone
- Center for Autoimmune Liver Diseases, Division of Gastroenterology, University of Milan Bicocca, Milan, Italy
| | - Joachim Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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28
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Leitch AC, Lakey AF, Hotham WE, Agius L, Kass GEN, Blain PG, Wright MC. The ionic liquid 1-octyl-3-methylimidazolium (M8OI) is an activator of the human estrogen receptor alpha. Biochem Biophys Res Commun 2018; 503:2167-2172. [PMID: 30086880 DOI: 10.1016/j.bbrc.2018.08.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 08/01/2018] [Indexed: 12/18/2022]
Abstract
Recent environmental sampling around a landfill site in the UK demonstrated that unidentified xenoestrogens were present at higher levels than control sites; that these xenoestrogens were capable of super-activating (resisting ligand-dependent antagonism) the murine variant 2 ERβ and that the ionic liquid 1-octyl-3-methylimidazolium chloride (M8OI) was present in some samples. To determine whether M8OI was a contributor to the xenoestrogen pool in the soils, activation of human estrogen receptors by M8OI was examined. M8OI activated the human ERα in MCF7 cells in a dose-response manner. These effects were inhibited by the ER antagonist ICI182780; occurred in the absence of any metabolism of M8OI and were confirmed on examination of ER-dependent induction of trefoil factor 1 mRNA in MCF7 cells. M8OI also super-activated the murine variant 2 ERβ in a murine hepatopancreatobiliary cell line. The human ERβ was not activated by M8OI when expressed in HEK293 cells. These data demonstrate that M8OI is a xenoestrogen capable of activating the human ERα and super-activating the murine variant 2 ERβ.
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Affiliation(s)
- Alistair C Leitch
- Institute Cellular Medicine, Health Protection Research Unit, Newcastle University, Level 4 Leech, Newcastle Upon Tyne, NE24HH, United Kingdom.
| | - Anne F Lakey
- Institute Cellular Medicine, Health Protection Research Unit, Newcastle University, Level 4 Leech, Newcastle Upon Tyne, NE24HH, United Kingdom.
| | - William E Hotham
- Institute Cellular Medicine, Health Protection Research Unit, Newcastle University, Level 4 Leech, Newcastle Upon Tyne, NE24HH, United Kingdom.
| | - Loranne Agius
- Institute Cellular Medicine, Health Protection Research Unit, Newcastle University, Level 4 Leech, Newcastle Upon Tyne, NE24HH, United Kingdom.
| | - George E N Kass
- European Food Safety Authority, Via Carlo Magno 1A, 43126, Parma, Italy.
| | - Peter G Blain
- Institute Cellular Medicine, Health Protection Research Unit, Newcastle University, Level 4 Leech, Newcastle Upon Tyne, NE24HH, United Kingdom.
| | - Matthew C Wright
- Institute Cellular Medicine, Health Protection Research Unit, Newcastle University, Level 4 Leech, Newcastle Upon Tyne, NE24HH, United Kingdom.
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29
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Abstract
Primary biliary cholangitis (PBC) is considered a model autoimmune disease, characterized by circulating anti-mitochondrial antibodies and a selective autoimmune destruction of intrahepatic cholangiocytes. PBC is heterogeneous in its presentation, symptomatology, disease progression, and response to therapy. The pathogenesis is still largely unknown and epidemiologic studies have facilitated the identification of risk factors and the understanding of disease prevalence, geographic variations, heterogeneity, and differences in sex ratio. Recent studies from large international cohorts have better identified prognostic factors suggesting a change in patient management based on risk-stratification tools to identify subgroups at greatest potential benefit from second-line therapies.
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Affiliation(s)
- Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Milan 20090, Italy; Liver Unit, Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano 20089, Milan, Italy.
| | - Francesca Colapietro
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Milan 20090, Italy
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30
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Tanaka A, Leung PSC, Gershwin ME. Evolution of our understanding of PBC. Best Pract Res Clin Gastroenterol 2018; 34-35:3-9. [PMID: 30343708 DOI: 10.1016/j.bpg.2018.05.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 05/10/2018] [Indexed: 01/31/2023]
Abstract
The discovery of mitochondrial autoantigens recognized by antimitochondrial antibodies (AMAs) in 1987 marked the dawn of a new era in primary biliary cholangitis (PBC) research. Since then, there has been substantial progress in our understanding of PBC partly bestowed by the development of innovative technologies in molecular biology, immunology, and genetics. Here, we review this evolutionary progress in understanding PBC. We now recognize that the epitopes of AMAs, CD4+, and CD8+ T cells are all mapped to the same region of the inner lipoyl domain of pyruvate dehydrogenase complex E2 subunit (PDC-E2), and that intrahepatic biliary epithelial cells (BECs) are exclusively targeted in PBC. BECs express PDC-E2 on apotopes in an immunologically intact form during apoptosis, but not other epithelial cells, which could explain the tissue specificity of PBC. In addition, genetic factors, environmental triggers, and epigenetic modifications play crucial roles in the development of PBC. Intact lipoylated PDC-E2, presumably after modification with xenobiotics such as 2-octynamide or 2-nonyamide that are abundantly present in the environment, is endocytosed by antigen-presenting cells and are presented to CD4+ or CD8+ T cells. An immune complex consisting of PDC-E2 and anti-PDC-E2 autoantibodies cross-present autoantigens in a more efficient manner. Finally, an adenylate uridine-rich element (ARE) Del -/- mouse model has been established, which presents a disease modeling human PBC, including female dominance as one of its most important features, and can be used to dissect the immunopathology of PBC. Expanding our knowledge of the pathology from a very early stage of the disease will provide the key to cure PBC.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
| | - Patrick S C Leung
- Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, USA.
| | - M Eric Gershwin
- Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, USA.
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31
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32
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Cholankeril G, Gonzalez HC, Satapathy SK, Gonzalez SA, Hu M, Khan MA, Yoo ER, Li AA, Kim D, Nair S, Wong RJ, Kwo PY, Harrison SA, Younossi ZM, Lindor KD, Ahmed A. Increased Waitlist Mortality and Lower Rate for Liver Transplantation in Hispanic Patients With Primary Biliary Cholangitis. Clin Gastroenterol Hepatol 2018; 16:965-973.e2. [PMID: 29427734 PMCID: PMC7331901 DOI: 10.1016/j.cgh.2017.12.017] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 12/05/2017] [Accepted: 12/10/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Data on the differences in ethnicity and race among patients with primary biliary cholangitis (PBC) awaiting liver transplantation (LT) are limited. We evaluated liver transplant waitlist trends and outcomes based on ethnicity and race in patients with PBC in the United States. METHODS Using the United Network for Organ Sharing (UNOS) registry, we collected data on patients with PBC on the liver transplant waitlist, and performed analysis with a focus on ethnicity and race-based variations clinical manifestations, waitlist mortality and LT rates from 2000 to 2014. Outcomes were adjusted for demographics, complications of portal hypertension, and Model for End-stage Liver Disease score at time of waitlist registration. RESULTS Although the number of white PBC waitlist registrants and additions decreased from 2000 to 2014, there were no significant changes in the number of Hispanic PBC waitlist registrants and additions each year. The proportion of Hispanic patients with PBC on the liver transplant waitlist increased from 10.7% in 2000 to 19.3% in 2014. Hispanics had the highest percentage of waitlist deaths (20.8%) of any ethnicity or race evaluated. After adjusting for demographic and clinical characteristics, Hispanic patients with PBC had the lowest overall rate for undergoing LT (adjusted hazard ratio, 0.71; 95% CI, 0. 60-0.83; P < .001) and a significantly higher risk of death while on the waitlist, compared to whites (adjusted hazard ratio, 1.41; 95% CI, 1.15-1.74; P < .001). Furthermore, Hispanic patients with PBC had the highest proportion of waitlist removals due to clinical deterioration. CONCLUSIONS In an analysis of data from UNOS registry focusing on outcomes, we observed differences in rates of LT and liver transplant waitlist mortality of Hispanic patients compared with white patients with PBC. Further studies are needed to improve our understanding of ethnicity and race-based differences in progression of PBC.
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Affiliation(s)
- George Cholankeril
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California
| | - Humberto C Gonzalez
- Department of Transplant Surgery, Methodist University Hospital, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Sanjaya K Satapathy
- Department of Transplant Surgery, Methodist University Hospital, University of Tennessee Health Science Center, Memphis, Tennessee
| | | | - Menghan Hu
- Department of Biostatistics, Brown University School of Public Health, Providence, Rhode Island
| | - Mohammad Ali Khan
- Department of Transplant Surgery, Methodist University Hospital, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Eric R Yoo
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California
| | - Andrew A Li
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California
| | - Satheesh Nair
- Department of Transplant Surgery, Methodist University Hospital, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Robert J Wong
- Division of Gastroenterology and Hepatology, Alameda Health System, Highland Hospital, Oakland, California
| | - Paul Y Kwo
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California
| | - Stephen A Harrison
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Zobair M Younossi
- Department of Medicine, Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Arizona State University, Phoenix, Arizona
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California.
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Meyer SK, Probert PME, Lakey AK, Leitch AC, Blake LI, Jowsey PA, Cooke MP, Blain PG, Wright MC. Environmental Xenoestrogens Super-Activate a Variant Murine ER Beta in Cholangiocytes. Toxicol Sci 2018; 156:54-71. [PMID: 28013213 PMCID: PMC5356623 DOI: 10.1093/toxsci/kfw234] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
High systemic levels of oestrogens are cholestatic and primary biliary cholangitis (PBC)-which is characterized by hepatic ductular inflammation-is thought to be triggered by exposure to xenobiotics such as those around landfill sites. Xenoestrogens may be a component of this chemical trigger. We therefore hypothesized that xenoestrogens are present at higher levels in the proximity of landfill sites. To test this hypothesis, soil samples were collected, extracts prepared and biological oestrogenic activity examined using cell-based reporter gene assays. Extracts from several sample sites around a landfill site contained a chemical(s) which activated the human ERα in a dose-dependent manner. Extracts from 3 separate control sampling sites were absent of any detectable activity. The mouse ERα and 2 variant mouse ERβ cDNAs were cloned and extracts from sample sites around a landfill site also activated these receptors. One variant murine ERβ was constitutively active when expressed in cholangiocytes, was readily inactivated by ICI182780 and activated in a dose-responsive, ICI182780-inhibitable manner by oestrogen. However, when this receptor was activated by extracts from landfill site soils, ICI182780 failed to antagonize activation. ERβ was readily detectable in murine cholangiocytes and exposing mice acutely to a pooled ER activating soil extracts also gave rise to a mild cholestatic injury. These data indicate that the environment around landfill sites may contain higher levels of xenoestrogens; that these chemicals have "super-activating" characteristics with a variant ERβ and therefore these chemicals could be a component of a xenobiotic insult that triggers PBC.
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Affiliation(s)
- Stephanie K Meyer
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK
| | - Philip M E Probert
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK.,Health Protection Research Unit, Wolfson Building, Newcastle University, Newcastle Upon Tyne NE2 4AA, UK
| | - Anne K Lakey
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK
| | - Alastair C Leitch
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK
| | - Lynsay I Blake
- Institute for Sustainability, The Key Building, Newcastle University, Newcastle upon Tyne NE4 5TQ, UK
| | - Paul A Jowsey
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK
| | - Martin P Cooke
- School of Civil Engineering and Geosciences, Drummond Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Peter G Blain
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK.,Health Protection Research Unit, Wolfson Building, Newcastle University, Newcastle Upon Tyne NE2 4AA, UK
| | - Matthew C Wright
- Institute Cellular Medicine, Level 4 Leech, Newcastle University, Newcastle Upon Tyne NE24HH, UK.,Health Protection Research Unit, Wolfson Building, Newcastle University, Newcastle Upon Tyne NE2 4AA, UK
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Tanaka A, Leung PS, Gershwin ME. Environmental basis of primary biliary cholangitis. Exp Biol Med (Maywood) 2018; 243:184-189. [PMID: 29307284 DOI: 10.1177/1535370217748893] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Autoimmunity is a consequence of both genetic and environmental factors, occurring in genetically susceptible hosts with environmental triggers. While genome-wide association studies have revealed a number of susceptible genes contributing to etiology, the environmental triggers remain poorly understood. Primary biliary cholangitis, formally known as primary biliary cirrhosis, is considered a model autoimmune disease for which our group has extensively evaluated environmental factors involved in its etiology. Bacterial infection and xenobiotics have been proposed as candidate environmental factors that may explain tolerance breakdown and production of primary biliary cholangitis-specific antimitochondrial autoantibodies. Large-scale case-control studies have consistently detected an association of primary biliary cholangitis with urinary tract infections caused by Escherichia coli, as E. coli PDC-E2 is molecularly similar to human PDC-E2, the immunodominant target of AMAs. Another bacterium of interest is Novosphingobium aromaticivorans, a ubiquitous xenobiotic-metabolizing bacterium that produces lipoylated proteins, which are highly reactive with sera from primary biliary cholangitis patients. Regarding xenobiotics, case-control studies have suggested that frequent use of nail polish is associated with an increased susceptibility to primary biliary cholangitis. We found that 2-octynamide, the conjugate derived from 2-octynoic acid present in cosmetics, lipsticks, and some chewing gums, was unique in both its quantitative structure-activity relationship analysis and reactivity with primary biliary cholangitis sera. 2-nonyamide is another xenobiotic that also has the optimal chemical structure for xenobiotic modification of the PDC-E2 epitope, as demonstrated by the enhanced epitope recognition with AMA-positive PBC sera. Moreover, we found that C57BL/6 mice immunized with 2-octynoic acid-BSA possess many of the features characteristic to primary biliary cholangitis. Impact statement Autoimmunity is believed to develop in genetically susceptible hosts with triggers from the environment. Researchers have recently demonstrated that bacteria and xenobiotics commonly present in our environment are potential triggers of tolerance breakdown against autoantigens and autoimmunity, particularly in primary biliary cholangitis (PBC). The link between xenobiotics and PBC has been further confirmed with the establishment of PBC model mice by immunizing mice with xenobiotics.
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Affiliation(s)
- Atsushi Tanaka
- 1 Department of Medicine, School of Medicine, Teikyo University, Tokyo 1738606, Japan
| | - Patrick Sc Leung
- 2 Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA 95616, USA
| | - M Eric Gershwin
- 2 Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA 95616, USA
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Davies TM, Marshall JC, Hazelton ML. Tutorial on kernel estimation of continuous spatial and spatiotemporal relative risk. Stat Med 2017; 37:1191-1221. [PMID: 29226352 DOI: 10.1002/sim.7577] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 11/08/2017] [Accepted: 11/08/2017] [Indexed: 01/14/2023]
Abstract
Kernel smoothing is a highly flexible and popular approach for estimation of probability density and intensity functions of continuous spatial data. In this role, it also forms an integral part of estimation of functionals such as the density-ratio or "relative risk" surface. Originally developed with the epidemiological motivation of examining fluctuations in disease risk based on samples of cases and controls collected over a given geographical region, such functions have also been successfully used across a diverse range of disciplines where a relative comparison of spatial density functions has been of interest. This versatility has demanded ongoing developments and improvements to the relevant methodology, including use spatially adaptive smoothers; tests of significantly elevated risk based on asymptotic theory; extension to the spatiotemporal domain; and novel computational methods for their evaluation. In this tutorial paper, we review the current methodology, including the most recent developments in estimation, computation, and inference. All techniques are implemented in the new software package sparr, publicly available for the R language, and we illustrate its use with a pair of epidemiological examples.
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Affiliation(s)
- Tilman M Davies
- Department of Mathematics & Statistics, University of Otago, Dunedin, New Zealand
| | - Jonathan C Marshall
- Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand
| | - Martin L Hazelton
- Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand
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36
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Lleo A, Marzorati S, Anaya JM, Gershwin ME. Primary biliary cholangitis: a comprehensive overview. Hepatol Int 2017; 11:485-499. [PMID: 29164395 DOI: 10.1007/s12072-017-9830-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 10/05/2017] [Indexed: 12/15/2022]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by biliary destruction, progressive cholestasis, and potentially liver cirrhosis. Patients develop a well-orchestrated immune reaction, both innate and adaptive, against mitochondrial antigens that specifically targets intrahepatic biliary cells. A puzzling feature of PBC is that the immune attack is predominantly organ specific, although the mitochondrial autoantigens are found in all nucleated cells. The disease results from a combination of genetic and environmental risk factors; however, the exact pathogenesis remains unclear. Serologically, PBC is characterized by presence of antimitochondrial antibodies, which are present in 90-95 % of patients and are often detectable years before clinical signs appear. Like other complex disorders, PBC is heterogeneous in its presentation, symptomatology, disease progression, and response to therapy. A significant number of patients develop end-stage liver disease and eventually require liver transplantation. Recent studies from large international cohorts have better identified prognostic factors, suggesting a change in patient management based on risk stratification. Therapeutic options are changing. In this review we discuss data on the autoimmune responses and treatment of the disease.
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Affiliation(s)
- Ana Lleo
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, MI, Italy
- Department of Biomedical Sciences, Humanitas University, Rozzano, MI, Italy
| | - Simona Marzorati
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, MI, Italy
| | - Juan-Manuel Anaya
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA.
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37
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Gatselis NK, Zachou K, Lygoura V, Azariadis K, Arvaniti P, Spyrou E, Papadamou G, Koukoulis GK, Dalekos GN, Rigopoulou EI. Geoepidemiology, clinical manifestations and outcome of primary biliary cholangitis in Greece. Eur J Intern Med 2017; 42:81-88. [PMID: 28535947 DOI: 10.1016/j.ejim.2017.05.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 04/21/2017] [Accepted: 05/07/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Primary biliary cholangitis (PBC) is a disease with rising prevalence and considerable geographical variation. To describe the prevalence, spatial and time distribution, baseline characteristics, response to treatment, outcome and the validity of GLOBE score in a large cohort of Greek PBC patients as an independent validation of this score has not been done so far. METHODS The last 16years, 482 PBC patients (86.5% females) were evaluated and analysed retrospectively, using a prospectively collected database. Special attention was paid to the assessment of treatment response according to GLOBE score. RESULTS Age at initial evaluation was 56.3±13.7years. Among 432 Thessaly residents, prevalence was 582/million (non-homogeneous distribution). Nineteen districts showed a prevalence >800/million. Symptomatic disease onset could be identified in 91 patients, with a significant peak during spring (P=0.03). At diagnosis, 43.6% were asymptomatic and 16.2% cirrhotic. Male sex (P=0.02), older age (P<0.001), alcohol consumption (P<0.01) and concomitant liver disease (P<0.001) were negative prognostic factors for cirrhosis. During a median [interquartile range, range] follow-up of 5.1 (7.8, 15.7) years, 62 patients died or underwent liver transplantation. Patients with GLOBE score>0.30 had significantly worse prognosis (P<0.001) with 5-, 10-, and 15-year survival rates of 84%, 50% and 42%. CONCLUSIONS There is increased PBC prevalence in Thessaly with remarkable geographic clustering and seasonal variability. PBC is diagnosed at early stages although males had a more advanced disease. GLOBE score applies perfectly in Greek patients and this will likely help detecting patients that may benefit from new therapies.
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Affiliation(s)
- Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - Vasiliki Lygoura
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - Kalliopi Azariadis
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - Pinelopi Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - Elias Spyrou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - Georgia Papadamou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - George K Koukoulis
- Department of Pathology, Medical School, University of Thessaly, Larissa, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece.
| | - Eirini I Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
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Abstract
The three common themes that underlie the induction and perpetuation of autoimmunity are genetic predisposition, environmental factors, and immune regulation. Environmental factors have gained much attention for their role in triggering autoimmunity, with increasing evidence of their influence as demonstrated by epidemiological studies, laboratory research, and animal studies. Environmental factors known to trigger and perpetuate autoimmunity include infections, gut microbiota, as well as physical and environmental agents. To address these issues, we will review major potential mechanisms that underlie autoimmunity including molecular mimicry, epitope spreading, bystander activation, polyclonal activation of B and T cells, infections, and autoinflammatory activation of innate immunity. The association of the gut microbiota on autoimmunity will be particularly highlighted by their interaction with pharmaceutical agents that may lead to organ-specific autoimmunity. Nonetheless, and we will emphasize this point, the precise mechanism of environmental influence on disease pathogenesis remains elusive.
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Affiliation(s)
- Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy.
| | - Patrick S C Leung
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA, USA
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Abstract
There is significant unmet need in Primary Biliary Cholangitis (PBC) in patients under-responsive to the only approved therapy Ursodeoxycholic Acid (UDCA) who are at increased risk of progressing to end-stage liver disease. Obeticholic Acid (OCA) is a farnesoid X receptor (FXR) agonist which has been evaluated as a second line therapy in PBC and has recently been licenced by the FDA. Areas covered: The pharmacology and biology of OCA as an FXR agonist and its clinical benefits. A systematic review was undertaken of published literature, meeting abstracts and trial registries using the search terms FXR, FGF-19 (& FGF-15), Obeticholic Acid and INT-747. Expert commentary: OCA reduces exposure to toxic hydrophobic bile acids through reduction in bile acid synthesis (by direct and indirect (via enterocyte-released FGF19) actions on Cyp7A1-mediated bile acid synthesis) and bile acid excretion by hepatocytes. It significantly improves liver biochemical parameters strongly associated with risk of disease progression in UDCA under-responsive patients and the key side-effect of pruritus can be reduced by optimised dosing. OCA will be the first stratified therapy introduced in PBC, however confirmatory trial and real life data are needed to confirm that suggestive biochemical improvements are matched by improvement in key clinical outcomes.
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Affiliation(s)
- David E J Jones
- a Institute of Cellular Medicine , Newcastle University , Newcastle upon Tyne , UK
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40
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Davies TM, Jones K, Hazelton ML. Symmetric adaptive smoothing regimens for estimation of the spatial relative risk function. Comput Stat Data Anal 2016. [DOI: 10.1016/j.csda.2016.02.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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41
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Risk and Surveillance of Cancers in Primary Biliary Tract Disease. Gastroenterol Res Pract 2016; 2016:3432640. [PMID: 27413366 PMCID: PMC4930812 DOI: 10.1155/2016/3432640] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 04/14/2016] [Accepted: 05/18/2016] [Indexed: 12/20/2022] Open
Abstract
Primary biliary diseases have been associated in several studies with various malignancies. Understanding the risk and optimizing surveillance strategy of these malignancies in this specific subset of patients are an important facet of clinical care. For instance, primary sclerosing cholangitis is associated with an increased risk for cholangiocarcinoma (which is very challenging to diagnose) and when IBD is present for colorectal cancer. On the other hand, primary biliary cirrhosis patients with cirrhosis or not responding to 12 months of ursodeoxycholic acid therapy are at increased risk of hepatocellular carcinoma. In this review we will discuss in detail the risks and optimal surveillance strategies for patients with primary biliary diseases.
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42
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Lleo A, Jepsen P, Morenghi E, Carbone M, Moroni L, Battezzati PM, Podda M, Mackay IR, Gershwin ME, Invernizzi P. Evolving Trends in Female to Male Incidence and Male Mortality of Primary Biliary Cholangitis. Sci Rep 2016; 6:25906. [PMID: 27192935 PMCID: PMC4872151 DOI: 10.1038/srep25906] [Citation(s) in RCA: 120] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Accepted: 03/16/2016] [Indexed: 12/13/2022] Open
Abstract
Primary biliary cholangitis (PBC) has been regarded as female-predominant without evidence of gender difference in survival. We aimed to compare the overall survival, incidence and prevalence of PBC in two well defined population-based studies over a recent decade, considering also sex ratios and mortality. We have taken advantage of population-wide records, during 2000-2009, in Lombardia, Northern Italy, and Denmark. We focused on the incident cases of PBC, including gender and outcome, among 9.7 million inhabitants of Lombardia and 5.5 million of Denmark. In Lombardia there were 2,970 PBC cases with a female:male ratio of 2.3:1. The age/sex-adjusted annual incidence of PBC was 16.7 per million. Point prevalence was 160 per million on January 1(st) 2009. In Denmark there were 722 cases of incident PBC, female:male ratio was 4.2:1, and the annual incidence was 11.4 per million, a point prevalence of 115 per million in 2009. Cox regression multivariate analysis identified male sex as an independent predictor of all-cause mortality in both Italian (HR 2.36) and Danish population (HR 3.04). Our data indicate for PBC a sex ratio significantly lower than previously cited, a reversal of the usual latitudinal difference in prevalence and a surprisingly higher overall mortality for male patients.
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Affiliation(s)
- Ana Lleo
- Liver Unit, Humanitas Clinical and Research Center, Rozzano (MI), Italy
| | - Peter Jepsen
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Emanuela Morenghi
- Biostatistic Unit, Humanitas Clinical and Research Center, Rozzano (MI), Italy
| | - Marco Carbone
- Liver Unit, Humanitas Clinical and Research Center, Rozzano (MI), Italy
| | - Luca Moroni
- Department of Internal Medicine, Policlinico IRCCS San Donato, University of Milan, San Donato Milanese, Italy
| | - Pier Maria Battezzati
- Department of Health Sciences, School of Medicine Ospedale San Paolo, Università degli Studi di Milano, Milan, Italy
| | - Mauro Podda
- Liver Unit, Humanitas Clinical and Research Center, Rozzano (MI), Italy
| | - Ian R. Mackay
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Pietro Invernizzi
- Liver Unit, Humanitas Clinical and Research Center, Rozzano (MI), Italy
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
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Dyson JK, Webb G, Hirschfield GM, Lohse A, Beuers U, Lindor K, Jones DEJ. Unmet clinical need in autoimmune liver diseases. J Hepatol 2015; 62:208-18. [PMID: 25234946 DOI: 10.1016/j.jhep.2014.09.010] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Revised: 09/04/2014] [Accepted: 09/05/2014] [Indexed: 02/08/2023]
Abstract
Despite recent advances in understanding and treatment, there remain significant areas of unmet clinical need in each of the autoimmune liver diseases (AILDs). The evolving research landscape and emerging large patient cohorts are creating unique opportunities to translate science into new therapies and care pathways, with the potential to significantly improve the lives of AILD patients. However, the areas of unmet need represent real challenges, which need to be addressed, if this vision is to be realised. This review describes the areas of unmet need in AILD in adults relating to diagnostic and prognostic assessment, primary therapy, symptom management, trial design and delivery, and structured care delivery, with the aim of focusing future research prioritisation.
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Affiliation(s)
| | - Gwilym Webb
- Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, UK
| | - Gideon M Hirschfield
- Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, UK; UK-PBC Research Consortium, UK
| | - Ansgar Lohse
- Universitat Klinikum Eppendorf, Hamburg, Germany
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology, Amsterdam Medical Centre, Amsterdam, Netherlands
| | - Keith Lindor
- Arizona State University Medical Centre, AZ, USA
| | - David E J Jones
- Liver Unit, Freeman Hospital, Newcastle-upon-Tyne, UK; UK-PBC Research Consortium, UK; Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
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Abstract
The etiology of the autoimmune liver disease primary biliary cirrhosis (PBC) remains largely unresolved, owing in large part to the complexity of interaction between environmental and genetic contributors underlying disease development. Observations of disease clustering, differences in geographical prevalence, and seasonality of diagnosis rates suggest the environmental component to PBC is strong, and epidemiological studies have consistently found cigarette smoking and history of urinary tract infection to be associated with PBC. Current evidence implicates molecular mimicry as a primary mechanism driving loss of tolerance and subsequent autoimmunity in PBC, yet other environmentally influenced disease processes are likely to be involved in pathogenesis. In this review, the authors provide an overview of current findings and touch on potential mechanisms behind the environmental component of PBC.
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Affiliation(s)
- Brian D. Juran
- Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota Semin Liver Dis 2014;34:265–272
| | - Konstantinos N. Lazaridis
- Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota Semin Liver Dis 2014;34:265–272
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45
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Koulentaki M, Mantaka A, Sifaki-Pistolla D, Thalassinos E, Tzanakis N, Kouroumalis E. Geoepidemiology and space-time analysis of Primary biliary cirrhosis in Crete, Greece. Liver Int 2014; 34:e200-7. [PMID: 24502439 DOI: 10.1111/liv.12479] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 01/31/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS The prevalence of Primary biliary cirrhosis varies in different geographical areas. This might reflect genetic or environmental risk factors. We aimed to define Primary biliary cirrhosis prevalence and incidence, describe patient's spatial distribution, generate prediction maps and detect any possible routing pattern of time-spatial appearance of the disease in Crete, Greece. METHODS From 1990-2010, 245 Primary biliary cirrhosis patients diagnosed and followed up at the Gastroenterology Department of the University Hospital and the District Hospitals of the island, were contacted and 222 were included in the time-spatial analysis. To map their spatial distribution per 5-year periods, geospatial models were applied in Gis-ArcMap 9.3 software. Kriging Interpolation methods were used to generate prediction maps for the disease in Crete. Areas of high and low probability of disease occurrence were estimated through multicriteria modelling. The disease route was defined by Gis-ArcMap's toolbox. RESULTS Prevalence was found to be 365 cases per million, with a mean incidence of 20.88 (range 3.79-35.99). Prediction map estimates from 1.22 to 11 patients per 50 km2 all over Crete. Areas of high risk of disease occurrence are located in the Eastern part, while low risk in the Western part of the island. DISCUSSION Prevalence and incidence of Primary biliary cirrhosis in Crete are among the higher published in Europe. Given the homogeneous and stable study population and the geopolitics of the island, the heterogeneity in the time-spatial distribution and the route of disease appearance strongly suggest a role for environmental causative agents.
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Affiliation(s)
- M Koulentaki
- Department of Gastroenterology & Hepatology, University Hospital of Crete, Heraklion, Crete, Greece
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Abstract
Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease characterised by a breakdown of immune tolerance to mitochondrial and nuclear antigens, causing injury to the biliary epithelial cells (BEC) lining the small intrahepatic bile ducts. This leads to bile duct injury and the retention of hydrophobic bile acids which cause further BEC injury leading to a self-sustaining cycle of bile duct injury. Initially the BEC respond to injury via a homeostatic response including through proliferation. Ultimately they become senescent; an active process with accompanying release of inflammatory cytokines ('the senescent secretome') which contributes to the process of interface hepatitis which is a feature of high-risk and treatment-unresponsive disease. This model for pathogenesis of PBC has implications for potential therapy approaches in targeting both the 'upstream' immune injury and 'downstream' BEC response to the immune injury. Fatigue is the commonest reported symptom in PBC and has a negative impact on patients' perceived quality of life, often through social isolation. It is unrelated to the severity of liver disease and appears unresponsive to current therapies, including ursodeoxycholic acid and transplantation. Fatigue in PBC is complex, with numerous associated peripheral and CNS features. Initially, cholestasis causes degenerative CNS change affecting areas of the brain regulating autonomic dysfunction and sleep, and these changes lead directly to some manifestations of fatigue and the associated cognitive impairment. In addition to this, the anti-mitochondrial antibody has direct muscle level metabolic effects leading to over-utilisation of anaerobic metabolism. Autonomic dysfunction contributes to the impact of this metabolic change by limiting the capacity of the muscle to respond through increased proton/lactate efflux from cells and outflow from tissues. The model has a number of implications for potential therapy approaches.
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Affiliation(s)
- Laura Griffiths
- Institute of Cellular Medicine, Newcastle University and Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK
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Boonstra K, Kunst AE, Stadhouders PH, Tuynman HA, Poen AC, van Nieuwkerk KMJ, Witteman EM, Hamann D, Witteman BJ, Beuers U, Ponsioen CY. Rising incidence and prevalence of primary biliary cirrhosis: a large population-based study. Liver Int 2014; 34:e31-8. [PMID: 24387641 DOI: 10.1111/liv.12434] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 12/03/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Large population-based studies are much needed to accurately establish the epidemiology of primary biliary cirrhosis (PBC). We aimed to collect all PBC patients in a geographically defined area to evaluate the epidemiology of PBC and examine the possible association of PBC with smoking, age at menarche, age at first pregnancy and number of pregnancies. METHODS All PBC patients between 2000 and 2008 were identified in a geographically defined area of the Netherlands, comprising 50% of the Dutch population. Four independent hospital databases were searched in 44 hospitals. Medical records were reviewed on site verifying diagnosis and for collection of clinical data. Age- and gender matched controls were recruited from the outpatient clinics of four participating hospitals. Patients and controls were asked to fill out a questionnaire regarding family history, previous and current smoking behaviour and fertility status. RESULTS Nine hundred and ninety-two PBC patients fulfilled all inclusion criteria, resulting in a mean incidence of 1.1 per 100 000; 0.3 in men and 1.9 in women. On January 1st 2008 the point prevalence was 13.2 per 100 000 inhabitants. Incidence and prevalence rates were increasing over time (P < 0.001). No geographical differences in disease distribution were observed. Smoking behaviour, age at menarche, age at first pregnancy, gravidity and number of children were not significantly different between cases and controls. CONCLUSION Incidence and prevalence rates of PBC are increasing over time. PBC was not found to be associated with smoking, age at menarche, age at first pregnancy or number of pregnancies.
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Affiliation(s)
- Kirsten Boonstra
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands
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Abstract
Primary biliary cirrhosis (PBC) is a chronic, autoimmune, cholestatic liver disease. It is characterized by slow destruction of small intrahepatic bile ducts, impaired biliary secretion and stasis of toxic endogenous bile acids within the liver with progression to liver fibrosis and cirrhosis. It has an increasing prevalence worldwide. It occurs more commonly in women than men at a ratio of 10:1. In most cases, diagnosis relies on a positive antimitochondrial antibody in the context of chronic cholestasis, without the need for a liver biopsy. Ursodeoxycholic acid improves survival even in patients with advanced liver disease. Certain findings such as fatigue, anti-nuclear antibodies, anti-centromere antibodies and the GP210 antinuclear antibody predict a poor outcome. Up to 40% of patients do not respond satisfactorily to ursodeoxycholic acid therapy and should be considered for adjunctive therapies. Several adjunctive and newer therapies are being tested and some appear promising. We provide a review of PBC with a focus on advances in therapies that may impact the management of PBC in the near future.
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McNally RJQ, James PW, Ducker S, Norman PD, James OFW. No rise in incidence but geographical heterogeneity in the occurrence of primary biliary cirrhosis in North East England. Am J Epidemiol 2014; 179:492-8. [PMID: 24401563 PMCID: PMC3908630 DOI: 10.1093/aje/kwt308] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
In this study, we examined temporal changes in the incidence of primary biliary cirrhosis (PBC) and investigated associations between PBC incidence and sociodemographic factors and spatial clustering. We included 982 patients aged ≥40 years from North East England with incident PBC diagnosed during 1987–2003. Age-standardized incidence rates with 95% confidence intervals were calculated. Negative binomial regression was used to analyze incidence and socioeconomic deprivation. Clustering analysis was performed using point process methods, testing the null hypothesis that disease risk does not vary spatially and that PBC cases occur independently. The age-standardized incidence rate was 53.50 per million persons per year (95% confidence interval: 48.65, 58.35) in 1987–1994 and 45.09 per million persons per year (95% confidence interval: 41.10, 49.07) in 1995–2003. Risk of PBC increased in areas with higher levels of socioeconomic deprivation (P = 0.035). More specifically, risk increased in areas with higher levels of overcrowded homes (P = 0.040), higher levels of households without cars (P < 0.001), and higher levels of non-owner-occupied homes (P < 0.001). Overall, there was evidence of spatial clustering (P = 0.001). The findings confirm that overall incidence of PBC did not rise over time, but sociodemographic variations suggest that certain aspects of deprivation are involved in its etiology.
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Affiliation(s)
- Richard J. Q. McNally
- Correspondence to Dr. Richard J. Q. McNally, Institute of Health and Society, Newcastle University, Sir James Spence Institute, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United Kingdom (e-mail: )
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Sarojinie Fernando WTP, Hazelton ML. Generalizing the spatial relative risk function. Spat Spatiotemporal Epidemiol 2014; 8:1-10. [PMID: 24606990 DOI: 10.1016/j.sste.2013.12.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2013] [Revised: 12/24/2013] [Accepted: 12/26/2013] [Indexed: 12/23/2022]
Abstract
The spatial relative risk function is defined as the ratio of densities describing respectively the spatial distribution of cases and controls. It has proven to be an effective tool for visualizing spatial variation in risk in many epidemiological applications over the past 20 years. We discuss the generalization of this function to spatio-temporal case-control data, and also to situations where there are covariates available that may affect the spatial patterns of disease. We examine estimation of the generalized relative risk functions using kernel smoothing, including asymptotic theory and data-driven bandwidth selection. We also consider construction of tolerance contours. Our methods are illustrated on spatio-temporal data describing the 2001 outbreak of foot-and-mouth disease in the United Kingdom, with farm size as a covariate.
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Affiliation(s)
| | - Martin L Hazelton
- Institute of Fundamental Sciences, Massey University, New Zealand; Infectious Disease Research Centre, Massey University, New Zealand.
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