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Vorasittha A, Sakamoto S, Yanagi Y, Degawa K, Kato H, Kodama T, Komine R, Yamada M, Uchida H, Fukuda A, Haga C, Yoshioka T, Kasahara M. Recurrence of Primary Sclerosing Cholangitis After Pediatric Liver Transplantation: A Single-Center, Retrospective Study in Japan. Pediatr Transplant 2025; 29:e70078. [PMID: 40217566 DOI: 10.1111/petr.70078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 03/23/2025] [Accepted: 03/31/2025] [Indexed: 04/14/2025]
Abstract
AIM Liver transplantation (LT) is a well-accepted treatment for primary sclerosing cholangitis (PSC) with generally good outcomes, although recurrent PSC (rPSC) poses significant challenges. This study aimed to describe patient characteristics and identify potential risk factors of rPSC in pediatric LT recipients. METHODS This retrospective study analyzed 13 pediatric patients who underwent LT for PSC at a single center. Patient characteristics, risk factors, and outcomes were compared between those with and without rPSC. RESULTS The median age at PSC diagnosis was 5.2 years and at LT, 15.4 years. Inflammatory bowel disease (IBD) was present in 12 patients (92.3%), and four (30.7%) had overlapping autoimmune hepatitis (AIH) before LT. Two patients received grafts from living-related donors, and 11 from deceased donors. During a median follow-up of 53 months, 4 of the 13 patients (30.7%) developed rPSC at a median of 48.9 months post-LT. Patients with rPSC tend to be younger at PSC diagnosis. All rPSC cases were associated with IBD, and half had AIH overlap, though the frequency difference was not significant. Acute cellular rejection (ACR) was universal in rPSC patients (100%) compared to nonrecurrent cases (33.3%, p = 0.07). One case of rPSC developed pulmonary hypertension following rPSC and succumbed to PH crisis, resulting in a 5-year patient survival rate of 82%. CONCLUSIONS The recurrence rate was high in pediatric patients with PSC. The observed association with immune-activating conditions raises the possibility of utilizing immunologic interventions to prevent rPSC, although further prospective studies are warranted to clarify the underlying mechanisms.
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Affiliation(s)
- Athaya Vorasittha
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Seisuke Sakamoto
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Yusuke Yanagi
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Kazuki Degawa
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Hirotaka Kato
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Tasuku Kodama
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Ryuji Komine
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Masaki Yamada
- Division for Advanced Medicine for Viral Infection, National Center for Child Health and Development, Tokyo, Japan
| | - Hajime Uchida
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Akinari Fukuda
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Chiduko Haga
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan
| | - Takako Yoshioka
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
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Ronca V, Gerussi A, Collins P, Parente A, Oo YH, Invernizzi P. The liver as a central "hub" of the immune system: pathophysiological implications. Physiol Rev 2025; 105:493-539. [PMID: 39297676 DOI: 10.1152/physrev.00004.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 09/05/2024] [Accepted: 09/08/2024] [Indexed: 01/16/2025] Open
Abstract
The purpose of this review is to describe the immune function of the liver, guiding the reader from the homeostatic tolerogenic status to the aberrant activation demonstrated in chronic liver disease. An extensive description of the pathways behind the inflammatory modulation of the healthy liver will be provided focusing on the complex immune cell network residing within the liver. The limit of tolerance will be presented in the context of organ transplantation, seizing the limits of homeostatic mechanisms that fail in accepting the graft, progressing eventually toward rejection. The triggers and mechanisms behind chronic activation in metabolic liver conditions and viral hepatitis will be discussed. The last part of the review will be dedicated to one of the greatest paradoxes for a tolerogenic organ, developing autoimmunity. Through the description of the three most common autoimmune liver diseases, the autoimmune reaction against hepatocytes and biliary epithelial cells will be dissected.
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Affiliation(s)
- Vincenzo Ronca
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
| | - Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Paul Collins
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
| | - Alessandro Parente
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom
| | - Ye Htun Oo
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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3
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Zheng D, Xu Q, Wu J, Gu Z, Chen J, Liu Y. Prevalence and bidirectional association between primary sclerosing cholangitis and Crohn's disease: A systematic review and meta-analysis. GASTROENTEROLOGIA Y HEPATOLOGIA 2025:502346. [PMID: 39832533 DOI: 10.1016/j.gastrohep.2025.502346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/05/2025] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
PURPOSE This meta-analysis aimed to evaluating the prevalence of Crohn's disease in primary sclerosing cholangitis (PSC) and the incidence of primary sclerosing cholangitis in Crohn's disease (CD), along with their interrelation. METHODS An extensive search was conducted in the PubMed and Embase to identify available publications up to December 2023. Studies were included if they reported the prevalence of CD in PSC patients, or vice versa. Proportions were assessed using the DerSimonian and Laird method, followed by transformation via the Freeman-Tukey double inverse sine transformation. The quality of the included studies utilizing the Joanna Briggs Institute Critical Appraisal Checklist. RESULTS Based on quantitative analysis of 61 studies, the prevalence of PSC in patients with CD was 0.88% (95% CI: 0.53-1.30%). The prevalence of PSC in male CD patients was 0.45% (95% CI: 0.03-1.16%). In female CD patients, the prevalence was 0.51% (95% CI: 0.09-1.14%). The prevalence of CD with PSC was 11.27% (95% CI: 9.56-13.10%). The prevalence of CD in male PSC patients was 10.71% (95% CI: 7.42-14.50%). Among female PSC patients, the pooled prevalence of CD was 13.05% (95% CI: 11.05-15.19%). CONCLUSIONS We found a significant bidirectional association between PSC and CD, with a higher prevalence of CD in female with PSC compared to male. These findings provide important epidemiological data for clinical practice.
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Affiliation(s)
- Dongyuan Zheng
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qinke Xu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jin Wu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhouyue Gu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jieya Chen
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yingchao Liu
- The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
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Evans S, Hofmann A. Autoimmune Biliary Diseases: A Review of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis, Immunoglobulin G4-Related Sclerosing Cholangitis, and Autoimmune Hepatitis. Surg Clin North Am 2024; 104:1249-1261. [PMID: 39448126 DOI: 10.1016/j.suc.2024.04.010] [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] [Indexed: 10/26/2024]
Abstract
Autoimmune and immune-mediated biliary diseases represent a small proportion of biliary disorders, but owing to their progressive nature, lead to end-stage liver disease, necessitating liver transplantation for definitive management.
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Affiliation(s)
- Suzanne Evans
- Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, C3.163, Cincinnati, OH 45229, USA.
| | - Alana Hofmann
- Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, MSB 1464, Cincinnati, OH 45267, USA
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Al-Obaidi H, Al-Obaidi M, Moliya P, Harb H, Nawras Y, Merza N. The Association Between Primary Sclerosing Cholangitis and Microscopic Colitis: A Systematic Review. Cureus 2024; 16:e75587. [PMID: 39803165 PMCID: PMC11724646 DOI: 10.7759/cureus.75587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2024] [Indexed: 01/16/2025] Open
Abstract
The association between primary sclerosing cholangitis (PSC) and microscopic colitis (MC) has been explored in limited studies, suggesting potential shared pathophysiological mechanisms. This systematic review aimed to investigate this relationship by analyzing studies identified through comprehensive searches in PubMed, Embase, and the Cochrane Library. Two studies met the inclusion criteria: a case series of 12 patients and a case report, collectively analyzing 13 cases. The case series revealed that 75% of MC diagnoses occurred after PSC, with many cases being asymptomatic, suggesting potential underdiagnosis. The case report described a patient with collagenous colitis who developed severe PSC complications, underscoring the bidirectional relationship and clinical impact of these conditions. Both studies highlighted immune dysregulation, genetic predisposition (HLA-DR3, HLA-DRw52a), and alterations in gut flora as shared mechanisms. These findings emphasize the importance of increased clinical vigilance, early diagnosis, and management of MC in PSC patients. Further research is needed to validate these associations, evaluate routine screening, and explore therapeutic approaches.
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Affiliation(s)
- Hasan Al-Obaidi
- Internal Medicine, Jamaica Hospital Medical Center, New York, USA
| | | | - Pratiksha Moliya
- Graduate Medical Education, Shri MP Shah Medical College, Jamnagar, IND
| | - Hussein Harb
- Basic Sciences, Ross University School of Medicine, Bridgetown, BRB
| | - Yusuf Nawras
- Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, USA
| | - Nooraldin Merza
- Internal Medicine, Wayne State University School of Medicine, Dearborn, USA
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Bergquist A, Ekstedt M, Hagström H, Järnerot G, Lindgren S, Nilsson E, Nyhlin N, Rorsman F, Stål P, Werner M, Kechagias S. Forty years of successful national research collaboration in liver disease - the Swedish experience. Scand J Gastroenterol 2024; 59:1314-1321. [PMID: 39485016 DOI: 10.1080/00365521.2024.2421824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/22/2024] [Accepted: 10/22/2024] [Indexed: 11/03/2024]
Abstract
AIM Sweden has historically provided a fruitful arena for research in clinical medicine. We here share 40 years of experience of collaboration in the Swedish hepatology research group (SWEHEP) (https://www.swehep.se). METHODS We describe the way the Swedish hepatology pioneers started the group and how the network continuously developed over the years. Successful projects such as thorough studies of natural history and various clinical aspects of autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and steatosis are described. RESULTS Over the years, more than 80 publications have been published by the group. A summary of new and ongoing research programs includes the randomized placebo-controlled trial of simvastatin in PSC (PiSCATIN), the prospective BIGMAP (Biochemical and genetic markers for the assessment and prognostication of liver cirrhosis) initiative in patients with liver cirrhosis, and the DETECT-HCC, a prospective multicenter cohort study comparing abbreviated MRI and ultrasound for surveillance of hepatocellular carcinoma every six months over two years. The group philosophy, success factors for the longstanding collaboration as well as experience of failures are shared. CONCLUSION The success of hepatology research in Sweden is based on longstanding collaboration over generations of hepatologists, where everyone contributes, regular research meetings, mutual trust, and perseverance.
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Affiliation(s)
- Annika Bergquist
- Division of Hepatology, Department of Upper Gastrointestinal Disease, Karolinska University Hospital, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Mattias Ekstedt
- Department of Health, Medicine, and Caring Sciences, Linköping University and Department of Gastroenterology and Hepatology, University Hospital, Linköping, Sweden
| | - Hannes Hagström
- Division of Hepatology, Department of Upper Gastrointestinal Disease, Karolinska University Hospital, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Gunnar Järnerot
- Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro
| | - Stefan Lindgren
- Lund University, Department of Gastroenterology, Skane University Hospital, Sweden
| | - Emma Nilsson
- Lund University, Department of Gastroenterology, Skane University Hospital, Sweden
| | - Nils Nyhlin
- Division of Gastroenterology, Department of Medicine, Örebro University Hospital, Örebro
| | - Fredrik Rorsman
- Department of Gastroenterology and Hepatology, Uppsala University Hospital, Sweden
| | - Per Stål
- Division of Hepatology, Department of Upper Gastrointestinal Disease, Karolinska University Hospital, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Mårten Werner
- Department of Public Health and Clinical Medicine, Umeå University, Sweden
| | - Stergios Kechagias
- Department of Health, Medicine, and Caring Sciences, Linköping University and Department of Gastroenterology and Hepatology, University Hospital, Linköping, Sweden
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7
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Lundberg Båve A, von Seth E, Ingre M, Nordenvall C, Bergquist A. Autoimmune diseases in primary sclerosing cholangitis and their first-degree relatives. Hepatology 2024; 80:527-535. [PMID: 38441983 DOI: 10.1097/hep.0000000000000823] [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] [Received: 11/11/2023] [Accepted: 02/14/2024] [Indexed: 03/07/2024]
Abstract
BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel disease (IBD). However, there is limited overlap between IBD and PSC risk genes, but a stronger association between PSC and other autoimmune conditions. We aimed to assess the coexistence and familial association of autoimmune disorders in PSC, and the influence of autoimmune comorbidity on severe outcomes. APPROACH AND RESULTS In a matched cohort study, 1378 individuals with PSC and 13,549 general population comparators and their first-degree relatives were evaluated. National registries provided data on diagnoses and outcomes (liver transplantation, hepatobiliary cancer, and liver-related death). The OR of autoimmune disease was estimated by logistic regression. The Fine and Gray competing risk regression estimated HRs for severe outcomes. The prevalence of non-IBD, non-autoimmune hepatitis, and autoimmune disease was 18% in PSC and 11% in comparators, OR: 1.77 (95% CI: 1.53-2.05). Highest odds were seen for celiac disease [OR: 4.36 (95% CI: 2.44-7.49)], sarcoidosis [OR: 2.74 (95% CI: 1.29-5.33)], diabetes type 1 [OR: 2.91 (95% CI: 2.05-4.05)], and autoimmune skin disease [OR: 2.15 (95% CI: 1.52-2.96)]. First-degree relatives of individuals with PSC had higher odds of developing IBD, autoimmune hepatitis, and any autoimmune disease than relatives of the comparators [OR: 3.25 (95% CI: 2.68-3.91); OR: 5.94 (95% CI: 2.82-12.02); OR: 1.34 (95% CI: 1.19-1.50)]. Autoimmune comorbidity in PSC was not associated with poorer outcomes [HR: 0.96 (95% CI: 0.71-1.28)]. CONCLUSIONS Individuals with PSC and their first-degree relatives had higher odds of autoimmune disease compared to matched comparators. This finding provides validation for prior genetic discoveries at a phenotypic level. Autoimmune comorbidity did not impact severe outcomes.
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Affiliation(s)
- Aiva Lundberg Båve
- Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Stockholm, Sweden
- Department of Upper GI Disease, Division of Hepatology, Karolinska University Hospital, Stockholm, Sweden
| | - Erik von Seth
- Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Stockholm, Sweden
- Department of Upper GI Disease, Division of Hepatology, Karolinska University Hospital, Stockholm, Sweden
| | - Michael Ingre
- Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Stockholm, Sweden
- Department of Upper GI Disease, Division of Hepatology, Karolinska University Hospital, Stockholm, Sweden
| | - Caroline Nordenvall
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Pelvic Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Annika Bergquist
- Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Stockholm, Sweden
- Department of Upper GI Disease, Division of Hepatology, Karolinska University Hospital, Stockholm, Sweden
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Trivedi PJ, Hirschfield GM, Adams DH, Vierling JM. Immunopathogenesis of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis and Autoimmune Hepatitis: Themes and Concepts. Gastroenterology 2024; 166:995-1019. [PMID: 38342195 DOI: 10.1053/j.gastro.2024.01.049] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 01/21/2024] [Accepted: 01/28/2024] [Indexed: 02/13/2024]
Abstract
Autoimmune liver diseases include primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis, a family of chronic immune-mediated disorders that target hepatocytes and cholangiocytes. Treatments remain nonspecific, variably effective, and noncurative, and the need for liver transplantation is disproportionate to their rarity. Development of effective therapies requires better knowledge of pathogenic mechanisms, including the roles of genetic risk, and how the environment and gut dysbiosis cause immune cell dysfunction and aberrant bile acid signaling. This review summarizes key etiologic and pathogenic concepts and themes relevant for clinical practice and how such learning can guide the development of new therapies for people living with autoimmune liver diseases.
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Affiliation(s)
- Palak J Trivedi
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom; Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom.
| | - Gideon M Hirschfield
- Division of Gastroenterology and Hepatology, Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | - David H Adams
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom
| | - John M Vierling
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, Texas.
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Konkwo C, Chowdhury S, Vilarinho S. Genetics of liver disease in adults. Hepatol Commun 2024; 8:e0408. [PMID: 38551385 PMCID: PMC10984672 DOI: 10.1097/hc9.0000000000000408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 01/30/2024] [Indexed: 04/02/2024] Open
Abstract
Chronic liver disease stands as a significant global health problem with an estimated 2 million annual deaths across the globe. Combining the use of next-generation sequencing technologies with evolving knowledge in the interpretation of genetic variation across the human genome is propelling our understanding, diagnosis, and management of both rare and common liver diseases. Here, we review the contribution of risk and protective alleles to common forms of liver disease, the rising number of monogenic diseases affecting the liver, and the role of somatic genetic variants in the onset and progression of oncological and non-oncological liver diseases. The incorporation of genomic information in the diagnosis and management of patients with liver disease is driving the beginning of a new era of genomics-informed clinical hepatology practice, facilitating personalized medicine, and improving patient care.
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Affiliation(s)
- Chigoziri Konkwo
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
| | - Shanin Chowdhury
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Silvia Vilarinho
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
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10
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van Munster KN, Bergquist A, Ponsioen CY. Inflammatory bowel disease and primary sclerosing cholangitis: One disease or two? J Hepatol 2024; 80:155-168. [PMID: 37940453 DOI: 10.1016/j.jhep.2023.09.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 09/01/2023] [Accepted: 09/29/2023] [Indexed: 11/10/2023]
Abstract
Primary sclerosing cholangitis (PSC) was declared one of the biggest unmet needs in hepatology during International Liver Congress 2016 in Berlin. Since then, not much has changed unfortunately, largely due to the still elusive pathophysiology of the disease. One of the most striking features of PSC is its association with inflammatory bowel disease (IBD), with the majority of patients with PSC being diagnosed with extensive colitis. This review describes the epidemiology of IBD in PSC, its specific phenotype, complications and potential pathophysiological mechanisms connecting the two diseases. Whether PSC is merely an extra-intestinal manifestation of IBD or if PSC and IBD are two distinct diseases that happen to share a common susceptibility that leads to a dual phenotype is debated. Implications for the management of the two diseases together are also discussed. Overall, this review summarises the available data in PSC-IBD and discusses whether PSC and IBD are one or two disease(s).
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Affiliation(s)
- Kim N van Munster
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Annika Bergquist
- Department of Medicine Huddinge, Division of Hepatology, Karolinska Institutet, Department of Upper GI Disease, Karolinska University Hospital, Stockholm, Sweden
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands.
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11
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Tan N, Lubel J, Kemp W, Roberts S, Majeed A. Current Therapeutics in Primary Sclerosing Cholangitis. J Clin Transl Hepatol 2023; 11:1267-1281. [PMID: 37577219 PMCID: PMC10412694 DOI: 10.14218/jcth.2022.00068s] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 01/01/2023] [Accepted: 01/20/2023] [Indexed: 07/03/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an orphan, cholestatic liver disease that is characterized by inflammatory biliary strictures with variable progression to end-stage liver disease. Its pathophysiology is poorly understood. Chronic biliary inflammation is likely driven by immune dysregulation, gut dysbiosis, and environmental exposures resulting in gut-liver crosstalk and bile acid metabolism disturbances. There is no proven medical therapy that alters disease progression in PSC, with the commonly prescribed ursodeoxycholic acid being shown to improve liver biochemistry at low-moderate doses (15-23 mg/kg/day) but not alter transplant-free survival or liver-related outcomes. Liver transplantation is the only option for patients who develop end-stage liver disease or refractory complications of PSC. Immunosuppressive and antifibrotic agents have not proven to be effective, but there is promise for manipulation of the gut microbiome with fecal microbiota transplantation and antibiotics. Bile acid manipulation via alternate synthetic bile acids such as norursodeoxycholic acid, or interaction at a transcriptional level via nuclear receptor agonists and fibrates have shown potential in phase II trials in PSC with several leading to larger phase III trials. In view of the enhanced malignancy risk, statins, and aspirin show potential for reducing the risk of colorectal cancer and cholangiocarcinoma in PSC patients. For patients who develop clinically relevant strictures with cholestatic symptoms and worsening liver function, balloon dilatation is safer compared with biliary stent insertion with equivalent clinical efficacy.
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Affiliation(s)
- Natassia Tan
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - John Lubel
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - William Kemp
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Stuart Roberts
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Ammar Majeed
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
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12
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Pratt HE, Wu T, Elhajjajy S, Zhou J, Fitzgerald K, Fazzio T, Weng Z, Pratt DS. Beyond genome-wide association studies: Investigating the role of noncoding regulatory elements in primary sclerosing cholangitis. Hepatol Commun 2023; 7:e0242. [PMID: 37756045 PMCID: PMC10531193 DOI: 10.1097/hc9.0000000000000242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/13/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND Genome-wide association studies (GWAS) have identified 30 risk loci for primary sclerosing cholangitis (PSC). Variants within these loci are found predominantly in noncoding regions of DNA making their mechanisms of conferring risk hard to define. Epigenomic studies have shown noncoding variants broadly impact regulatory element activity. The possible association of noncoding PSC variants with regulatory element activity has not been studied. We aimed to (1) determine if the noncoding risk variants in PSC impact regulatory element function and (2) if so, assess the role these regulatory elements have in explaining the genetic risk for PSC. METHODS Available epigenomic datasets were integrated to build a comprehensive atlas of cell type-specific regulatory elements, emphasizing PSC-relevant cell types. RNA-seq and ATAC-seq were performed on peripheral CD4+ T cells from 10 PSC patients and 11 healthy controls. Computational techniques were used to (1) study the enrichment of PSC-risk variants within regulatory elements, (2) correlate risk genotype with differences in regulatory element activity, and (3) identify regulatory elements differentially active and genes differentially expressed between PSC patients and controls. RESULTS Noncoding PSC-risk variants are strongly enriched within immune-specific enhancers, particularly ones involved in T-cell response to antigenic stimulation. In total, 250 genes and >10,000 regulatory elements were identified that are differentially active between patients and controls. CONCLUSIONS Mechanistic effects are proposed for variants at 6 PSC-risk loci where genotype was linked with differential T-cell regulatory element activity. Regulatory elements are shown to play a key role in PSC pathophysiology.
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Affiliation(s)
- Henry E. Pratt
- Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Tong Wu
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Shaimae Elhajjajy
- Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Jeffrey Zhou
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical, School, Worcester, Massachusetts, USA
| | - Kate Fitzgerald
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical, School, Worcester, Massachusetts, USA
| | - Tom Fazzio
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Zhiping Weng
- Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Daniel S. Pratt
- Autoimmune & Cholestatic Liver Center, GI Division, Massachusetts General Hospital, Boston, Massachusetts, USA
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13
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Váncza L, Torok NJ. Primary sclerosing cholangitis and the path to translation. J Clin Invest 2023; 133:e174218. [PMID: 37655665 PMCID: PMC10471165 DOI: 10.1172/jci174218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/02/2023] Open
Affiliation(s)
- Lóránd Váncza
- Gastroenterology and Hepatology, Stanford University, Stanford, California, USA
- VA, Palo Alto, California, USA
| | - Natalie J. Torok
- Gastroenterology and Hepatology, Stanford University, Stanford, California, USA
- VA, Palo Alto, California, USA
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14
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Martinez Lyons A, Boulter L. NOTCH signalling - a core regulator of bile duct disease? Dis Model Mech 2023; 16:dmm050231. [PMID: 37605966 PMCID: PMC10461466 DOI: 10.1242/dmm.050231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2023] Open
Abstract
The Notch signalling pathway is an evolutionarily conserved mechanism of cell-cell communication that mediates cellular proliferation, fate determination and maintenance of stem/progenitor cell populations across tissues. Although it was originally identified as a critical regulator of embryonic liver development, NOTCH signalling activation has been associated with the pathogenesis of a number of paediatric and adult liver diseases. It remains unclear, however, what role NOTCH actually plays in these pathophysiological processes and whether NOTCH activity represents the reactivation of a conserved developmental programme that is essential for adult tissue repair. In this Review, we explore the concepts that NOTCH signalling reactivation in the biliary epithelium is a reiterative and essential response to bile duct damage and that, in disease contexts in which biliary epithelial cells need to be regenerated, NOTCH signalling supports ductular regrowth. Furthermore, we evaluate the recent literature on NOTCH signalling as a critical factor in progenitor-mediated hepatocyte regeneration, which indicates that the mitogenic role for NOTCH signalling in biliary epithelial cell proliferation has also been co-opted to support other forms of epithelial regeneration in the adult liver.
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Affiliation(s)
| | - Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Cancer, Edinburgh EH4 2XU, UK
- CRUK Scottish Centre, Institute of Genetics and Cancer, Edinburgh EH4 2XU, UK
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15
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Shah YR, Nombera-Aznaran N, Guevara-Lazo D, Calderon-Martinez E, Tiwari A, Kanumilli S, Shah P, Pinnam BSM, Ali H, Dahiya DS. Liver transplant in primary sclerosing cholangitis: Current trends and future directions. World J Hepatol 2023; 15:939-953. [PMID: 37701917 PMCID: PMC10494561 DOI: 10.4254/wjh.v15.i8.939] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/23/2023] [Accepted: 08/11/2023] [Indexed: 08/22/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic and progressive immune-mediated cholangiopathy causing biliary tree inflammation and scarring, leading to liver cirrhosis and end-stage liver disease. Diagnosis of PSC is challenging due to its nonspecific symptoms and overlap with other liver diseases. Despite the rising incidence of PSC, there is no proven medical therapy that can alter the natural history of the disease. While liver transplantation (LT) is the most effective approach for managing advanced liver disease caused by PSC, post-transplantation recurrence of PSC remains a challenge. Therefore, ongoing research aims to develop better therapies for PSC, and continued efforts are necessary to improve outcomes for patients with PSC. This article provides an overview of PSC's pathogenesis, clinical presentation, and management options, including LT trends and future aspects. It also highlights the need for improved therapeutic options and ethical considerations in providing equitable access to LT for patients with PSC. Additionally, the impact of liver transplant on the quality of life and psychological outcomes of patients with PSC is discussed. Ongoing research into PSC's pathogenesis and post-transplant recurrence is crucial for improved understanding of the disease and more effective treatment options.
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Affiliation(s)
- Yash R Shah
- Department of Internal Medicine, Trinity Health Oakland, Pontiac, MI 48341, United States
| | | | - David Guevara-Lazo
- Faculty of Medicine, Universidad Peruana Cayetano Heredia, Lima 15102, Peru
| | - Ernesto Calderon-Martinez
- Department of Internal Medicine, Universidad Nacional Autonoma de Mexico, Ciudad De Mexico 04510, Mexico
| | - Angad Tiwari
- Department of Internal Medicine, Maharani Laxmi Bai Medical College, Jhansi 284001, India
| | | | - Purva Shah
- Department of Postgraduate Education, Harvard Medical School, Boston, MA 02115, United States
| | - Bhanu Siva Mohan Pinnam
- Department of Internal Medicine, John H. Stroger Hospital of Cook County, Chicago, IL 60612, United States
| | - Hassam Ali
- Department of Internal Medicine, East Carolina University/Brody School of Medicine, Greenville, NC 27858, United States
| | - Dushyant Singh Dahiya
- Division of Gastroenterology, Hepatology and Motility, The University of Kansas School of Medicine, Kansas City, KS 66160, United States.
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16
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Kim YS, Hurley EH, Park Y, Ko S. Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gut-liver axis. Exp Mol Med 2023; 55:1380-1387. [PMID: 37464092 PMCID: PMC10394020 DOI: 10.1038/s12276-023-01042-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/17/2023] [Accepted: 04/17/2023] [Indexed: 07/20/2023] Open
Abstract
The close relationship between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) provides a good opportunity to comprehend the gut-liver axis. The gut and the liver have reciprocal interactions, including how gut inflammation influences the liver through immune cells and the microbiota and how the microbiota in the gut modifies bile acids, which are produced and secreted from the liver. PSC-IBD shows distinct clinical findings from classical IBD. In addition, a distinct genetic predisposition and unique microbiota composition suggest that PSC-IBD is an independent disease entity. Understanding the pathogenesis of PSC-IBD helps to develop novel and effective therapeutic agents. Given the high risk of malignancies associated with PSC-IBD, it is critical to identify patients at high risk and implement appropriate surveillance and monitoring strategies. In this review, we provide an overview of PSC-IBD, which exemplifies the gut-liver axis.
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Affiliation(s)
- You Sun Kim
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Edward H Hurley
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Yoojeong Park
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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17
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Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez M, Sapisochin G, Shroff R, Tabibian JH, Assis DN. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023; 77:659-702. [PMID: 36083140 DOI: 10.1002/hep.32771] [Citation(s) in RCA: 139] [Impact Index Per Article: 69.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology , University of California Davis Health , Sacramento , California , USA
| | | | - Annika Bergquist
- Karolinska Institutet , Karolinska University Hospital , Stockholm , Sweden
| | - Mark Deneau
- University of Utah , Salt Lake City , Utah , USA
| | - Lisa Forman
- University of Colorado , Aurora , Colorado , USA
| | - Sumera I Ilyas
- Mayo Clinic College of Medicine and Science , Rochester , Minnesota , USA
| | - Keri E Lunsford
- Rutgers University-New Jersey Medical School , Newark , New Jersey , USA
| | - Mercedes Martinez
- Vagelos College of Physicians and Surgeons , Columbia University , New York , New York , USA
| | | | | | - James H Tabibian
- David Geffen School of Medicine at UCLA , Los Angeles , California , USA
| | - David N Assis
- Yale School of Medicine , New Haven , Connecticut , USA
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18
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Färkkilä M, Kautiainen H, Tenca A, Jokelainen K, Arola J. PNPLA3 allele frequency has no impact on biliary bile acid composition or disease course in patients with primary sclerosing cholangitis. PLoS One 2022; 17:e0277084. [PMID: 36454904 PMCID: PMC9714899 DOI: 10.1371/journal.pone.0277084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 10/19/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease that leads to bile duct strictures, cholestasis, and biliary cirrhosis. PNPLA3 (patatin-like phospholipase domain containing 3), regulates cellular lipid synthesis by converting lysophosphatidic acid into phosphatidic acid. Isoleucine mutation to methionine at position 148 (I148M) causes a loss of this function. Only two studies, with contradictory results, have evaluated the role of PNPLA3 in PSC. The rs738409(G) variant of PNPLA3 has been associated with an increased risk for transplantation in male patients with dominant strictures (DS). The study aimed to evaluate the PNPLA3 allele frequency effect on the clinical outcomes, progression, and prognosis of PSC. Furthermore, we analyzed the impact of PNPLA3 on phospholipid and bile acid composition to evaluate the effect of the PNPLA3 status on UDCA response. PATIENTS AND METHODS We recruited 560 patients prospectively and collected clinical and laboratory data as well as liver histology and imaging findings. PNPLA3 (CC, CG, GG) alleles were analyzed with TaqManTM. We also analyzed bile acids (BA), cholesterol and phospholipids and individual BA from a sample aspirated during endoscopic retrograde cholangiography (ERC). RESULTS Among the recruited patients, 58.4%, 35.7% and 5.9% had the wild (CC), heterozygous (CG) and homozygous (GG) alleles, respectively. The PNPLA3 haplotype did not impact bile composition or individual BA. In addition, we found no differences in age at diagnosis, disease progression, liver fibrosis or survival between the cohorts. CONCLUSIONS The PNPLA3 I148M variant had no significant impact on on bile composition, including UDCA content, clinical outcomes, progression of liver fibrosis, hepatobiliary cancer risk, liver transplantation, or overall survival.
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Affiliation(s)
- Martti Färkkilä
- Department of Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- * E-mail:
| | - Hannu Kautiainen
- Folkhälsan Research Center, Helsinki, Finland
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Andrea Tenca
- Department of Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Kalle Jokelainen
- Department of Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Johanna Arola
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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19
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Tan N, Ngu N, Worland T, Lee T, Abrahams T, Pandya K, Freeman E, Hannah N, Gazelakis K, Madden RG, Lynch KD, Valaydon Z, Sood S, Dev A, Bell S, Thompson A, Ding J, Nicoll AJ, Liu K, Gow P, Lubel J, Kemp W, Roberts SK, Majeed A. Epidemiology and outcomes of primary sclerosing cholangitis: an Australian multicentre retrospective cohort study. Hepatol Int 2022; 16:1094-1104. [PMID: 35657479 PMCID: PMC9525417 DOI: 10.1007/s12072-022-10356-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 05/06/2022] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND AIMS Little is known regarding the epidemiology and outcomes of patients with primary sclerosing cholangitis (PSC) in Australia. We, therefore, evaluated the epidemiology and clinical outcomes of PSC in a large cohort of Australian patients and compared these to the general population. METHODS We conducted a multicentre, retrospective cohort study of PSC patients at nine tertiary liver centers across three Australian states, including two liver transplant centers. RESULTS A total of 413 PSC patients with 3,285 person-years of follow-up were included. Three hundred and seventy-one (90%) patients had large duct PSC and 294 (71%) had associated inflammatory bowel disease. A total of 168 (41%) patients developed cirrhosis (including 34 at the time of PSC diagnosis) after a median of 15.8 (95% CI 12.4, NA) years. The composite endpoint of death or liver transplantation occurred in 49 (12%) and 78 (19%) patients, respectively, with a median transplant-free survival of 13.4 (95% CI 12.2-15) years. Compared to the general population, PSC accounted for a 240-fold increased risk of development of cholangiocarcinoma (CCA) and CCA-related death. CCA risk was increased with older age of PSC diagnosis, presence of dominant stricture and colectomy. Compared to same-aged counterparts in the general population, PSC patients who were diagnosed at an older age or with longer disease duration had reduced relative survival. CONCLUSION In this large retrospective cohort study of PSC patients in Australia, increased age and time from diagnosis was associated with increased mortality and morbidity particularly from CCA and development of cirrhosis, necessitating need for liver transplant.
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Affiliation(s)
- Natassia Tan
- Gastroenterology and Hepatology Department, The Alfred Hospital, 55 Commercial Rd, Melbourne, 3004, Australia.
- Monash University, Melbourne, Australia.
| | - N Ngu
- Monash University, Melbourne, Australia
- Gastroenterology Department, Monash Health, Melbourne, Australia
| | - T Worland
- Gastroenterology and Hepatology Department, Austin Health, Melbourne, Australia
| | - T Lee
- Gastroenterology and Hepatology Department, St Vincent's Health, Melbourne, Australia
| | - T Abrahams
- Gastroenterology and Hepatology Department, St Vincent's Health, Melbourne, Australia
| | - K Pandya
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
| | - E Freeman
- Gastroenterology and Hepatology Department, The Alfred Hospital, 55 Commercial Rd, Melbourne, 3004, Australia
| | - N Hannah
- Gastroenterology and Hepatology Department, Melbourne Health, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - K Gazelakis
- Gastroenterology and Hepatology Department, Western Health, Melbourne, Australia
| | - R G Madden
- Gastroenterology and Hepatology Department, Royal Adelaide Hospital, Adelaide, Australia
| | - K D Lynch
- Gastroenterology and Hepatology Department, Royal Adelaide Hospital, Adelaide, Australia
| | - Z Valaydon
- Gastroenterology and Hepatology Department, Western Health, Melbourne, Australia
| | - S Sood
- Gastroenterology and Hepatology Department, Melbourne Health, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - A Dev
- Monash University, Melbourne, Australia
- Gastroenterology Department, Monash Health, Melbourne, Australia
| | - S Bell
- Monash University, Melbourne, Australia
- Gastroenterology Department, Monash Health, Melbourne, Australia
| | - A Thompson
- Gastroenterology and Hepatology Department, St Vincent's Health, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - J Ding
- Gastroenterology and Hepatology Department, St Vincent's Health, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - A J Nicoll
- Monash University, Melbourne, Australia
- Gastroenterology Department, Eastern Health, Melbourne, Australia
| | - K Liu
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
| | - P Gow
- Gastroenterology and Hepatology Department, Austin Health, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - J Lubel
- Gastroenterology and Hepatology Department, The Alfred Hospital, 55 Commercial Rd, Melbourne, 3004, Australia
- Monash University, Melbourne, Australia
| | - W Kemp
- Gastroenterology and Hepatology Department, The Alfred Hospital, 55 Commercial Rd, Melbourne, 3004, Australia
- Monash University, Melbourne, Australia
| | - S K Roberts
- Gastroenterology and Hepatology Department, The Alfred Hospital, 55 Commercial Rd, Melbourne, 3004, Australia
- Monash University, Melbourne, Australia
| | - A Majeed
- Gastroenterology and Hepatology Department, The Alfred Hospital, 55 Commercial Rd, Melbourne, 3004, Australia
- Monash University, Melbourne, Australia
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20
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Zhang Y, Gao X, He Z, Jia H, Chen M, Wang X, Hong L, Cui Y, Wan J. Prevalence of inflammatory bowel disease in patients with primary sclerosing cholangitis: A systematic review and meta-analysis. Liver Int 2022; 42:1814-1822. [PMID: 35689520 DOI: 10.1111/liv.15339] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/05/2022] [Accepted: 06/08/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIM Previous studies have established an association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis (UC). The disease burden of IBD in PSC patients was not well estimated. The study aimed to quantify the pooled prevalence of IBD in PSC and to investigate whether subtypes of PSC and sex influence the prevalence of IBD. METHODS PubMed, Embase, and Web of Science were searched through November 2021 for studies reporting data on IBD among PSC patients. The outcomes were the prevalence of IBD in patients with PSC, as well as the association (odds ratio [OR]) of IBD in PSC according to subtype and sex. RESULTS Based on the analysis of 25 studies, the prevalence of IBD in patients with PSC was 71.1% (95% CI 68.2-75.1%), most commonly in UC (55.9%, 95% CI 52.5-59.3%). The pooled prevalence of IBD was 76.9% in Australia (95% CI 71.2-82.6%, 1 study), 75.9% (95% CI 69.5-82.3%, 4 studies) in North America, 70.9% (95% CI 65.8-76.0%, 17 studies) in Europe and 67.0% (95% CI 57.9-76.0%, 2 studies) in Asia. Male PSC patients had a higher prevalence of IBD (OR 1.67, 95% CI 1.52-1.83) and UC (OR 2.02, 95% CI 1.56-2.63) and a lower prevalence of CD (OR 0.77, 95% CI 0.67-0.88) than female patients. Large duct PSC patients had a higher prevalence of IBD (OR 2.57, 95% CI 2.03-3.25) and UC (OR 4.51, 95% CI 1.22-16.71) than small duct PSC patients. CONCLUSIONS The study provided the first pooled estimates of the burden of IBD in patients with PSC and could be used as the basis for risk stratification of PSC patients.
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Affiliation(s)
- Yujie Zhang
- Department of Histology and Embryology, School of Basic Medicine, Xi'an Medical University, Xi'an, China
| | - Xinbao Gao
- Medical affairs, Tigermed Consulting Co., Ltd, Hangzhou, China
| | - Zhiyi He
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research and Department of Prosthodontics, College of Stomatology, Xi'an Jiaotong University, Xi'an, China
| | - Hui Jia
- Department of gastroenterology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Min Chen
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Xuan Wang
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Liu Hong
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yuanyuan Cui
- Department of Histology and Embryology, School of Basic Medicine, Xi'an Medical University, Xi'an, China
| | - Jian Wan
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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21
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Stevens JP, Gupta NA. Recent Insights into Pediatric Primary Sclerosing Cholangitis. Clin Liver Dis 2022; 26:489-519. [PMID: 35868687 DOI: 10.1016/j.cld.2022.03.009] [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] [Indexed: 01/31/2023]
Abstract
This article reviews recent literature on the pathogenesis, presentation, diagnosis, comorbidities, natural history, and management of pediatric primary sclerosing cholangitis (PSC). The authors shed light on the role of genetic and environmental factors in PSC, although recognize the limitations in the understanding of PSC pathogenesis. They reflect on presenting disease phenotypes, including the association with inflammatory bowel disease and frequent histologic presence of autoimmune hepatitis features. The current lack of effective medications is discussed, and disease complications and prognosis are described. Finally, the authors highlight available evidence while acknowledging the paucity of prospective pediatric data.
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Affiliation(s)
- James P Stevens
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, 1760 Haygood Drive, Atlanta GA 30322, USA
| | - Nitika A Gupta
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, 1760 Haygood Drive, Atlanta GA 30322, USA.
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22
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Ellinghaus D. How genetic risk contributes to autoimmune liver disease. Semin Immunopathol 2022; 44:397-410. [PMID: 35650446 PMCID: PMC9256578 DOI: 10.1007/s00281-022-00950-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/06/2022] [Indexed: 12/16/2022]
Abstract
Genome-wide association studies (GWAS) for autoimmune hepatitis (AIH) and GWAS/genome-wide meta-analyses (GWMA) for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) have been successful over the past decade, identifying about 100 susceptibility loci in the human genome, with strong associations with the HLA locus and many susceptibility variants outside the HLA locus with relatively low risk. However, identifying causative variants and genes and determining their effects on liver cells and their immunological microenvironment is far from trivial. Polygenic risk scores (PRSs) based on current genome-wide data have limited potential to predict individual disease risk. Interestingly, results of mediated expression score regression analysis provide evidence that a substantial portion of gene expression at susceptibility loci is mediated by genetic risk variants, in contrast to many other complex diseases. Genome- and transcriptome-wide comparisons between AIH, PBC, and PSC could help to better delineate the shared inherited component of autoimmune liver diseases (AILDs), and statistical fine-mapping, chromosome X-wide association testing, and genome-wide in silico drug screening approaches recently applied to GWMA data from PBC could potentially be successfully applied to AIH and PSC. Initial successes through single-cell RNA sequencing (scRNA-seq) experiments in PBC and PSC now raise high hopes for understanding the impact of genetic risk variants in the context of liver-resident immune cells and liver cell subpopulations, and for bridging the gap between genetics and disease.
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Affiliation(s)
- David Ellinghaus
- Institute of Clinical Molecular Biology (IKMB), Kiel University and University Medical Center Schleswig-Holstein, Rosalind-Franklin-Str. 12, 24105, Kiel, Germany.
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23
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Buness JG, Ali AH, Tabibian JH, Buness CW, Cox KL, Lindor KD. Potential Association of Doxycycline With the Onset of Primary Sclerosing Cholangitis: A Case Series. Am J Ther 2022; 29:e437-e443. [PMID: 31567143 DOI: 10.1097/mjt.0000000000001065] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). Evidence suggests an association between the gut microbiome and PSC. However, the putative relationship between exposure to antibiotics and onset of PSC has never been reported. We observed 3 cases in which patients without antecedent liver or bowel issues developed symptoms leading to diagnosis of IBD and subsequently PSC after being exposed to doxycycline. We aimed to identify, through the PSC Partners national patient registry, additional cases of PSC in which there is a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. AREAS OF UNCERTAINTY The etiopathogenesis of PSC remains an enigma. DATA SOURCES We collected data from patients with PSC and PSC-IBD in which there seemed to be a temporal relationship between exposure to doxycycline and PSC. Time from doxycycline exposure to: (1) onset of PSC or PSC-IBD symptoms and (2) diagnosis of PSC were documented for each patient. Descriptive statistical analyses were performed. RESULTS We identified 6 additional patients with PSC or PSC-IBD in whom there was a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. The median age of these 9 patients was 20 years, 6 were female, and 7 had ulcerative colitis. The median time from doxycycline exposure to onset of first symptoms was 3 months, and median time from doxycycline exposure to diagnosis of PSC was 15 months. THERAPEUTIC HYPOTHESIS We describe 9 cases of PSC and PSC-IBD in which there seem to be a temporal relationship between exposure to doxycycline and onset of PSC.
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Affiliation(s)
- James Gage Buness
- Arizona College of Osteopathic Medicine, Midwestern University, Downers Grove, IL
| | - Ahmad Hassan Ali
- Division of Hepatology, Mayo Clinic, Phoenix, AZ
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Los Angeles, CA
| | - Cynthia W Buness
- National Patient Advocate Foundation, Arizona State University, Phoenix, AZ; and
| | - Kenneth L Cox
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Stanford University, Palo Alto, CA
| | - Keith D Lindor
- Arizona College of Osteopathic Medicine, Midwestern University, Downers Grove, IL
- Division of Hepatology, Mayo Clinic, Phoenix, AZ
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Park JW, Kim JH, Kim SE, Jung JH, Jang MK, Park SH, Lee MS, Kim HS, Suk KT, Kim DJ. Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics. Biomedicines 2022; 10:1288. [PMID: 35740310 PMCID: PMC9220082 DOI: 10.3390/biomedicines10061288] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/24/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023] Open
Abstract
Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments.
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Affiliation(s)
- Ji-Won Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jung-Hee Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sung-Eun Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jang Han Jung
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Myoung-Kuk Jang
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sang-Hoon Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Myung-Seok Lee
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Hyoung-Su Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Ki Tae Suk
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
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Jaffey JA. Feline cholangitis/cholangiohepatitis complex - what have we learned? J Small Anim Pract 2022; 63:573-589. [PMID: 35522164 DOI: 10.1111/jsap.13508] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 02/19/2022] [Accepted: 04/11/2022] [Indexed: 12/07/2022]
Abstract
Cholangitis/cholangiohepatitis complex in cats is commonly encountered in clinical practice worldwide. Diagnosis and management of cats with this complex is difficult because of the ambiguity of clinical signs, diagnostic test results and commonality of comorbid disorders. These impediments can delay disease identification and treatment, which can increase morbidity and mortality. In this narrative review, we aimed to provide a thorough review of the unique physioanatomic features of the biliary system as well as clinically relevant updates on cholangitis/cholangiohepatitis complex in cats.
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Affiliation(s)
- J A Jaffey
- Department of Specialty Medicine, College of Veterinary Medicine, Midwestern University, Glendale, Arizona, 85308, USA
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26
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Outcome of pregnancy in patients with primary sclerosing cholangitis. Dig Liver Dis 2022; 54:509-514. [PMID: 34518127 DOI: 10.1016/j.dld.2021.08.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 08/18/2021] [Accepted: 08/20/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Data on the clinical course of primary sclerosing cholangitis (PSC) during pregnancy remain scarce. Herein, we assessed the maternal and fetal outcomes of pregnancy in this condition. METHODS We reviewed 104 consecutive female outpatients with PSC using a structured questionnaire. The outcomes were assessed both before and after the diagnosis of PSC. RESULTS In total, 62 patients (60%) reported 126 pregnancies. Of these, 25 patients reported 44 pregnancies occurring after the diagnosis of PSC. There were two (5%) pregnancies in progress, and among the completed pregnancies there were 34 (80%) live births, six (14%) miscarriages, one (2%) stillbirth, and one (2%) termination. The median neonatal APGAR score was 10, the median body weight was 3375 g and the median body length was 55 cm. In three pregnancies, there was a flare-up of inflammatory bowel disease. In 45 patients, 82 pregnancies occurred before PSC was diagnosed with comparable maternal and fetal outcomes. Out of 42 pregnancies following PSC diagnosis, in 29 UDCA was continued. There was no difference in the fetal outcomes between the UDCA and non-UDCA groups. CONCLUSIONS Pregnancy in patients with PSC seems to be well tolerated, but should be closely monitored by an obstetrician and an experienced hepatologist.
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Di Giorgio A, Vergani D, Mieli-Vergani G. Cutting edge issues in juvenile sclerosing cholangitis. Dig Liver Dis 2022; 54:417-427. [PMID: 34289942 DOI: 10.1016/j.dld.2021.06.028] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/08/2021] [Accepted: 06/23/2021] [Indexed: 12/11/2022]
Abstract
Sclerosing cholangitis (SC) is a rare chronic disorder characterised by inflammation and progressive obliterative fibrosis of the intrahepatic and/or extrahepatic bile ducts. Diagnosis is based on cholangiogram showing bile duct dilatation, narrowing and obliteration of the biliary tree, and histologically, on the presence of inflammatory bile duct damage leading to periductal fibrosis. In children the most common SC is associated with strong autoimmune features, overlapping with those of autoimmune hepatitis (AIH); this form is known as autoimmune sclerosing cholangitis, ASC. Conversely, primary SC (PSC), a condition in which the term "primary" indicates that aetiology and pathogenesis are unknown, is rare in paediatrics. Secondary SC (SSC) defines a cholangiopathy associated with an identifiable aetiology such as immunodeficiencies, infections or haematological disorders. ASC and PSC are strongly associated with inflammatory bowel disease (IBD). ASC responds biochemically well to immunosuppressive drugs and ursodeoxycholic acid (UDCA). Primary forms are exclusively managed with oral UDCA, while in the secondary forms the medical treatment depends on the underlying aetiology. Despite treatment, SC often progresses to biliary cirrhosis and end-stage liver disease requiring liver transplantation. The disease can recur after transplant. Better understanding of pathogenic mechanisms and better treatment modalities are needed to improve the prognosis of this invalidating hepatic disorder.
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Affiliation(s)
- Angelo Di Giorgio
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Bergamo, Italy.
| | - Diego Vergani
- King's College London Faculty of Life Sciences and Medicine, Institute of Liver Studies, Mowat Labs King's College Hospital, London, United Kingdom
| | - Giorgina Mieli-Vergani
- King's College London Faculty of Life Sciences and Medicine, Institute of Liver Studies, Mowat Labs King's College Hospital, London, United Kingdom; Paediatric Liver, Gastrointestinal, and Nutrition Centre, King's College Hospital, London, United Kingdom
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28
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Nguyen CM, Kline KT, Stevenson HL, Khan K, Parupudi S. Small duct primary sclerosing cholangitis: A discrete variant or a bridge to large duct disease, a practical review. World J Hepatol 2022; 14:495-503. [PMID: 35582290 PMCID: PMC9055190 DOI: 10.4254/wjh.v14.i3.495] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/12/2021] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
The natural history, associations with inflammatory bowel disease (IBD), and long-term outcomes of large duct primary sclerosing cholangitis (ldPSC) have been well documented. Small duct primary sclerosing cholangitis (sdPSC) is a much less common and relatively more benign variant. The natural history of sdPSC has been difficult to characterize given the limited number of studies in the literature especially with regards to the subset of patients who progress to large duct involvement. It has been unclear whether sdPSC represented a subset of ldPSC, an earlier staging of ldPSC, or a completely separate and distinct entity of its own. Strong associations between sdPSC and IBD have been established with suspicion that concurrent sdPSC-IBD may be a key prognostic factor in determining which patients are at risk of progression to ldPSC. Little is known regarding the discrete circumstances that predisposes some patients with sdPSC to progress to ldPSC. It has been suspected that progression to large biliary duct involvement subjects this subset of patients to potentially developing life-threatening complications. Here the authors conducted a thorough review of the published sdPSC literature using Pubmed searches and cross-referencing to compile all accessible studies regarding cohorts of sdPSC patients in order better characterize the subset of sdPSC patients who progress to ldPSC and the associated outcomes.
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Affiliation(s)
- Christopher M Nguyen
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Kevin T Kline
- Department of Gastroenterology and Hepatology, The University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Heather L Stevenson
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Kashif Khan
- Department of Gastroenterology and Hepatology, The University of Texas Medical Branch, Galveston, TX 77555, United States
| | - Sreeram Parupudi
- Department of Gastroenterology and Hepatology, The University of Texas Medical Branch, Galveston, TX 77555, United States
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29
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Possible role of the HMGB1 and RAGE inflammatory pathway in primary sclerosing cholangitis. Clin Res Hepatol Gastroenterol 2022; 46:101791. [PMID: 34400366 DOI: 10.1016/j.clinre.2021.101791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 07/28/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Activation of the receptor for advanced glycation end products (RAGE) and its ligand High Mobility Group Box Protein 1 (HMGB1), a nuclear protein with proinflammatory properties, has been implicated in several inflammatory disorders. OBJECTIVE To analyse the influence of RAGE and HMGB1 signalling in patients with primary sclerosing cholangitis (PSC). METHODS Levels of HMGB1 and bile acid in serum and bile samples of 69 PSC patients and 32 controls were measured. Additionally, 640 patients with PSC and other liver diseases were analysed for the gain-of-function RAGE G82S SNP by PCR. Laboratory and clinical parameters were retrieved by chart review. RESULTS ELISA analysis showed significantly higher biliary HMGB1 concentrations in PSC patients (n=69, median 124,1 ng/ml) than in the control group (n=32, median 6,85 ng/ml, p<0,001). Median serum HMGB1 (n=22, median 2,4 ng/ml) was significantly lower than median biliary HMGB1 of the concomitant bile samples (n=22, median 151 ng/ml, p =0,001). There was no correlation of biliary HMGB1 levels with laboratory parameters or clinical end points. Analysis of the gain-of-function G82SSNP RAGE SNP in PSC patients showed 8 patients with heterozygote mutant alleles (8/324, 2,5%). Patients carrying the mutation developed more often dominant strictures of the large bile ducts (100.0% vs. 61.3%; p=0.04) and had reduced transplantation-free survival in the mutant allele group (p<0.001). CONCLUSIONS Biliary HMGB1 levels are elevated in PSC patients compared to controls and a gain-of-function SNP in RAGE is associated with development of dominant strictures and reduced survival in PSC patients.
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The Epidemiology of UK Autoimmune Liver Disease Varies With Geographic Latitude. Clin Gastroenterol Hepatol 2021; 19:2587-2596. [PMID: 33493696 PMCID: PMC8661127 DOI: 10.1016/j.cgh.2021.01.029] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 01/05/2021] [Accepted: 01/18/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The epidemiology of autoimmune liver disease (AILD) is challenging to study because of the diseases' rarity and because of cohort selection bias. Increased incidence farther from the Equator has been reported for multiple sclerosis, another autoimmune disease. We assessed the incidence of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) in relation to latitude. METHODS We performed a retrospective cohort study using anonymized UK primary care records from January 1, 2002, to May 10, 2016. All adults without a baseline diagnosis of AILD were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database. Latitude was measured as registered general practice rounded down to whole degrees. RESULTS The cohort included 8,590,421 records with 53.3 × 107 years of follow-up evaluation from 694 practices. There were 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34-2.60); PSC, 0.74 (95% CI, 0.67-0.82); and AIH, 1.94 (95% CI, 1.83-2.06) per 100,000 per year. PBC incidence correlated with female sex, smoking, and deprivation; PSC incidence correlated with male sex and non-smoking; AIH incidence correlated with female sex and deprivation. A more northerly latitude was associated strongly with incidence of PBC: 2.16 (95% CI, 1.79-2.60) to 4.86 (95% CI, 3.93-6.00) from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 (95% CI, 1.65-2.43) to 3.28 (95% CI, 2.53-4.24) (P = .003), but not incidence of PSC: 0.82 (95% CI, 0.60-1.11) to 1.02 (95% CI, 0.64-1.61) (P = .473). Incidence after adjustment for age, sex, smoking, and deprivation status showed similar positive correlations for PBC and AIH with latitude, but not PSC. Incident AIH cases were younger at more northerly latitude. CONCLUSIONS We describe an association in the United Kingdom between more northerly latitude and the incidence of PBC and AIH that requires both confirmation and explanation.
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Trivedi PJ, Hirschfield GM. Recent advances in clinical practice: epidemiology of autoimmune liver diseases. Gut 2021; 70:1989-2003. [PMID: 34266966 DOI: 10.1136/gutjnl-2020-322362] [Citation(s) in RCA: 129] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 06/24/2021] [Indexed: 12/13/2022]
Abstract
Autoimmune liver diseases are chronic inflammatory hepatobiliary disorders that when classically defined encompass three distinctive clinical presentations; primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). Meaningful changes in disease epidemiology are reported, with increasing incidence and prevalence of AIH and PSC in Europe, and rising prevalence of PBC across Europe, North America and the Asia-Pacific region. However, there appears to be very significant global variation with contemporary incidence rates of disease per 100 000 ranging from 0.84 to 2.75 for PBC, 0.1 to 4.39 for PSC and 0.4 to 2.39 for AIH. Prevalence corresponds, and per 100 000 estimates for PBC range from 1.91 to 40.2, for PSC between 0.78 and 31.7 and for AIH from 4.8 to 42.9. Population-based studies and multicentre observational cohort series provide improved understanding of the clinical course that patients experience, highlighting variations in presenting phenotypes geographically and temporally. Collectively, while autoimmune liver diseases are rare, the clinical burden is disproportionately high relative to population incidence and prevalence. Age, sex and race also impact clinical outcomes, and patient morbidity and mortality are reflected by high need for gastroenterology, hepatology and organ transplant services.
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Affiliation(s)
- Palak J Trivedi
- National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Centre, University of Birmingham College of Medical and Dental Sciences, Birmingham, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
- Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, UK
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada
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Ahn DW. [Novel Insights of Primary Sclerosing Cholangitis and Primary Biliary Cholangitis]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2021; 75:246-256. [PMID: 32448856 DOI: 10.4166/kjg.2020.75.5.246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 04/16/2020] [Accepted: 04/16/2020] [Indexed: 11/03/2022]
Abstract
Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are immune-mediated chronic liver diseases. PSC is a rare disorder characterized by multi-focal bile duct strictures and progressive liver diseases that ultimately results in the need for liver transplantation in most patients. Imaging studies, such as MRCP, have an essential role in the diagnosis of most cases of PSC. PSC is usually accompanied by inflammatory bowel disease, and there is a high risk of cholangiocarcinoma and colorectal cancer in PSC. No medical therapies have been proven to delay the progression of PSC. Endoscopic intervention for tissue diagnosis or biliary drainage is frequently required in cases of PSC with a dominant stricture, acute cholangitis, or clinically suspected cholangiocarcinoma. PBC is a chronic inflammatory autoimmune cholestatic liver disease, which, when untreated, will culminate in end-stage biliary cirrhosis requiring liver transplantation. A diagnosis is usually based on the presence of serum liver tests indicative of cholestatic hepatitis in association with circulating antimitochondrial antibodies. Patient presentation and course can be diverse in PBC, and risk stratification is important for ensuring that all patients receive a personalized approach to their care. Medical therapy using ursodeoxycholic acid or obeticholic acid has an important role in reducing the progression to end-stage liver disease in PBC.
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Affiliation(s)
- Dong-Won Ahn
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
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Akamatsu N, Hasegawa K, Egawa H, Ohdan H, Yoshizawa A, Kokudo N, Tazuma S, Tanaka A, Takikawa H. Donor age (≥45 years) and reduced immunosuppression are associated with the recurrent primary sclerosing cholangitis after liver transplantation - a multicenter retrospective study. Transpl Int 2021; 34:916-929. [PMID: 33629379 DOI: 10.1111/tri.13852] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 01/18/2021] [Accepted: 02/22/2021] [Indexed: 01/25/2023]
Abstract
The present study investigated the possible risk factors, including relationship/HLA matching between donor and recipient, and immunosuppressive therapies on the recurrence of primary sclerosing cholangitis (PSC) after liver transplantation (LT). Subjects were 197 recipients of LT for PSC, among whom 180 surviving more than 1 year after LT were further analyzed for risk factors of recurrence. The 5- and 10-year patient- and graft survival rates were 83% and 68%, and 71% and 62%, respectively. The overall PSC recurrence rate was 25% with a 5- and 10-year graft survival rate of 34% and 18%, which was significantly lower than the survival rate of those without recurrence (P < 0.001). Univariate analysis identified the following as risk factors for recurrence: donor age (P < 0.001), cyclosporine use (P = 0.012), mono or no immunosuppressive agent (P < 0.001), postoperative biliary complication (P < 0.001), and active intestinal bowel disease after LT (P < 0.001). Among these factors, donor age ≥45 years [hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.21-2.69; P = 0.003] and mono or no immunosuppressive agent 1-year after LT (HR, 2.38; 95% CI, 1.23-3.45; P = 0.011) were identified as independent risk factors in the final multivariate Cox regression model. The results were similar in sub-analysis for ABO-identical/compatible adult living donor LT cases.
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Affiliation(s)
- Nobuhisa Akamatsu
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroto Egawa
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Atsushi Yoshizawa
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Norihiro Kokudo
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Susumu Tazuma
- Department of General Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University Hospital, Hiroshima, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Hajime Takikawa
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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Waldthaler A, Schramm C, Bergquist A. Present and future role of endoscopic retrograde cholangiography in primary sclerosing cholangitis. Eur J Med Genet 2021; 64:104231. [PMID: 33905896 DOI: 10.1016/j.ejmg.2021.104231] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 04/20/2021] [Accepted: 04/21/2021] [Indexed: 12/12/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a rare, inflammatory cholestatic liver disease that causes biliary strictures which can lead to secondary complications. About 30-50% of PSC patients develop dominant strictures (DS) in the biliary tree, which are both the cause of jaundice and bacterial cholangitis as well as predilection spots for development of neoplastic development. Cancer is the most common cause of death in PSC. A central concern is to distinguish malignant from benign strictures, which eventually is done by invasive methods to obtain a brush cytology or biopsy sample, in most cases via endoscopic retrograde cholangiography-pancreatography (ERCP). Since medical therapies, like ursodesoxycholic acid or immunosuppressive drugs have no proven effect, therapeutic ERCP has become the primary management strategy to improve symptoms and in some patients may slow down disease progression. This article aims at outlining the current and emerging methods in ERCP in PSC patients.
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Affiliation(s)
- A Waldthaler
- Department of Medicine Huddinge, Functional Unit Endoscopy, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; European Reference Network for Hepatological Diseases (ENR RARE-LIVER), Sweden.
| | - C Schramm
- Department of Medicine and Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; European Reference Network for Hepatological Diseases (ENR RARE-LIVER), Sweden
| | - A Bergquist
- Department of Medicine Huddinge, Unit of Gastroenterology and Rheumatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; European Reference Network for Hepatological Diseases (ENR RARE-LIVER), Sweden
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Rabiee A, Silveira MG. Primary sclerosing cholangitis. Transl Gastroenterol Hepatol 2021; 6:29. [PMID: 33824933 DOI: 10.21037/tgh-20-266] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/19/2020] [Indexed: 12/15/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease characterized by inflammatory destruction of the intrahepatic and/or extrahepatic bile ducts, leading to bile stasis, fibrosis, and ultimately to cirrhosis, and often requires liver transplantation (LT). PSC occurs more commonly in men, and is typically diagnosed between the ages of 30 and 40. Most cases occur in association with inflammatory bowel disease (IBD), which often precedes the development of PSC. PSC is usually diagnosed after detection of cholestasis during health evaluation or screening of patients with IBD. When symptomatic, the most common presenting symptoms are abdominal pain, pruritus, jaundice or fatigue. The etiology of PSC is poorly understood, but an increasing body of evidence supports the concept of cholangiocyte injury as a result of environmental exposure and an abnormal immune response in genetically susceptible individuals. PSC is a progressive disease, yet no effective medical therapy for halting disease progression has been identified. Management of PSC is mainly focused on treatment of symptoms and addressing complications. PSC can be complicated by bacterial cholangitis, dominant strictures (DSs), gallbladder polyps and adenocarcinoma, cholangiocarcinoma (CCA) and, in patients with IBD, colorectal malignancy. CCA is the most common malignancy in PSC with a cumulative lifetime risk of 10-20%, and accounts for a large proportion of mortality in PSC. LT is currently the only life-extending therapeutic approach for eligible patients with end-stage PSC, ultimately required in approximately 40% of patients. LT secondary to PSC has an excellent outcome compared to other LT indications, although the disease can recur and result in morbidity post-transplant.
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Affiliation(s)
- Anahita Rabiee
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Marina G Silveira
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
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Prokopič M, Beuers U. Management of primary sclerosing cholangitis and its complications: an algorithmic approach. Hepatol Int 2020; 15:6-20. [PMID: 33377990 PMCID: PMC7886831 DOI: 10.1007/s12072-020-10118-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 11/25/2020] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease, characterized by multiple strictures and dilatations of the intra- and extrahepatic bile ducts, leading to progressive liver fibrosis, in 10–15% cholangiocarcinoma, and ultimately end-stage liver disease. The pathogenesis is poorly understood, but (epi-)genetic factors, mechanisms of innate and adaptive immunity, toxic effects of hydrophobic bile acids, and possibly intestinal dysbiosis appear to be involved. The strong link with inflammatory bowel disease (IBD) is associated with a markedly enhanced risk of colorectal cancer which next to cholangiocarcinoma represents the most serious diagnostic challenge in long-term PSC management. Despite extensive research, no medical treatment has been proven so far to prolong the time to liver transplantation (LTx), which remains the effective treatment in late-stage disease. Recurrence of PSC after LTx is observed in up to 20% of patients. Here, we briefly summarize actual views on PSC pathogenesis and provide an algorithmic approach to diagnostic procedures and recommendations for the management of PSC and its complications. We describe promising treatment options subject to current clinical trials.
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Affiliation(s)
- Michal Prokopič
- Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Location AMC, AGEM, C2-327, Meibergdreef 9, 1100 DE, Amsterdam, The Netherlands.,Department of Gastroenterology, Comenius University Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Location AMC, AGEM, C2-327, Meibergdreef 9, 1100 DE, Amsterdam, The Netherlands.
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37
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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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Chen QL, Zhong R, Zhang XX, Feng LN, Wen XY, Jin QL. Primary sclerosing cholangitis with increased immunoglobulin G4 levels: A case report. Medicine (Baltimore) 2019; 98:e18411. [PMID: 31852163 PMCID: PMC6922380 DOI: 10.1097/md.0000000000018411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
RATIONALE Primary sclerosing cholangitis (PSC) is recognized as an autoimmune-mediated liver disease characterized by progressive biliary inflammation and fibrosis. Some PSC cases with elevated immunoglobulin G4 (IgG4) levels are likely to be misdiagnosed with immunoglobulin G4-related sclerosing cholangitis (IgG4-SC). Thus, distinguishing these 2 diseases is particularly important. PATIENT CONCERNS A 34-year-old male presented with right hypochondrium abdominal intermittent pain and jaundice lasting for 1 month. Here, we present a case of PSC with increased IgG4 levels with improvement of quality of life upon liver transplantation (LT). DIAGNOSIS The diagnosis of PSC was confirmed based on clinical symptoms, laboratory test results, imaging findings, pathologic results and a lack of response to steroid therapy. INTERVENTIONS LT surgery was performed successfully when his vital parameters were stabilized. Immunosuppressive agents were routinely used after LT. OUTCOMES Three years after LT, liver function values show that alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were in the normal range. An abdominal ultrasonography showed no obvious abnormalities. LESSONS There are similar biochemical characteristics and cholangiographic findings between PSC and IgG4-SC. Therefore, distinguishing these 2 diseases is particularly important. LT remains the only option for end-stage PSC. Early diagnosis and effective treatment can achieve a good prognosis.
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Affiliation(s)
| | - Rui Zhong
- Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin, China
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Liao L, Schneider KM, Galvez EJC, Frissen M, Marschall HU, Su H, Hatting M, Wahlström A, Haybaeck J, Puchas P, Mohs A, Peng J, Bergheim I, Nier A, Hennings J, Reißing J, Zimmermann HW, Longerich T, Strowig T, Liedtke C, Cubero FJ, Trautwein C. Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis. Gut 2019; 68:1477-1492. [PMID: 30872395 DOI: 10.1136/gutjnl-2018-316670] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 02/06/2019] [Accepted: 02/10/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVE There is a striking association between human cholestatic liver disease (CLD) and inflammatory bowel disease. However, the functional implications for intestinal microbiota and inflammasome-mediated innate immune response in CLD remain elusive. Here we investigated the functional role of gut-liver crosstalk for CLD in the murine Mdr2 knockout (Mdr2-/-) model resembling human primary sclerosing cholangitis (PSC). DESIGN Male Mdr2-/-, Mdr2-/- crossed with hepatocyte-specific deletion of caspase-8 (Mdr2-/- /Casp8∆hepa) and wild-type (WT) control mice were housed for 8 or 52 weeks, respectively, to characterise the impact of Mdr2 deletion on liver and gut including bile acid and microbiota profiling. To block caspase activation, a pan-caspase inhibitor (IDN-7314) was administered. Finally, the functional role of Mdr2-/- -associated intestinal dysbiosis was studied by microbiota transfer experiments. RESULTS Mdr2-/- mice displayed an unfavourable intestinal microbiota signature and pronounced NLRP3 inflammasome activation within the gut-liver axis. Intestinal dysbiosis in Mdr2-/- mice prompted intestinal barrier dysfunction and increased bacterial translocation amplifying the hepatic NLRP3-mediated innate immune response. Transfer of Mdr2-/- microbiota into healthy WT control mice induced significant liver injury in recipient mice, highlighting the causal role of intestinal dysbiosis for disease progression. Strikingly, IDN-7314 dampened inflammasome activation, ameliorated liver injury, reversed serum bile acid profile and cholestasis-associated microbiota signature. CONCLUSIONS MDR2-associated cholestasis triggers intestinal dysbiosis. In turn, translocation of endotoxin into the portal vein and subsequent NLRP3 inflammasome activation contribute to higher liver injury. This process does not essentially depend on caspase-8 in hepatocytes, but can be blocked by IDN-7314.
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Affiliation(s)
- Lijun Liao
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
- Department of Anesthesiology and Pain Management, Tongji University, Shanghai, Shanghai, China
| | | | - Eric J C Galvez
- Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Mick Frissen
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Hanns-Ulrich Marschall
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Gothenburg, Sweden
| | - Huan Su
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Maximilian Hatting
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Annika Wahlström
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Johannes Haybaeck
- Department of Pathology, Otto von Guericke University of Magdeburg, Magdeburg, Germany
- Medical University of Graz, Institute of Pathology, Graz, Austria
| | - Philip Puchas
- Institute of Pathology, Medizinische Universitat Graz, Graz, Steiermark, Azerbaijan
| | - Antje Mohs
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Jin Peng
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ina Bergheim
- Molecular Nutritional Science Division, Department of Nutritional Sciences, University of Vienna, Vienna, Austria
| | - Anika Nier
- Molecular Nutritional Science Division, Department of Nutritional Sciences, University of Vienna, Vienna, Austria
| | - Julia Hennings
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Johanna Reißing
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | | | - Thomas Longerich
- Institute of Pathology, UniversitatsKlinikum Heidelberg, Heidelberg, Germany
| | - Till Strowig
- Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Christian Liedtke
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Francisco J Cubero
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
- Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), Madrid, Spain
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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Suri J, Patwardhan V, Bonder A. Pharmacologic management of primary sclerosing cholangitis: what's in the pipeline? Expert Rev Gastroenterol Hepatol 2019; 13:723-729. [PMID: 31257956 DOI: 10.1080/17474124.2019.1636647] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Introduction: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by biliary inflammation, fibrosis, and stricturing. Although considered progressive, its course is difficult to predict, and there is currently no definitive therapy shown to alter disease course and prevent death or the need for liver transplantation. Areas covered: There are multiple agents in the pipeline targeting various pathways hypothesized to lead to and drive this disease. Some are already used for other treatment indications, including antibiotics such as oral vancomycin, metronidazole, and minocycline. Other agents including obeticholic acid, nor-ursodeoxycholic acid, and monoclonal antibodies are also under investigation. This narrative review focuses on the most recent published clinical trials available for discussion. We attempt to summarize the data on current and future treatment options. Expert opinion: The rarity of this condition and poor understanding of its pathophysiology have created a void for safe and effective treatment options to alter mortality or transplant free survival. Nevertheless, some agents currently being tested have demonstrated therapeutic potential. We await validation and prospective data on these agents in hopes of modifying the disease course for patients in the future.
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Affiliation(s)
- Jaspreet Suri
- a Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA
| | - Vilas Patwardhan
- a Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA
| | - Alan Bonder
- a Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA
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Abstract
Hepatobiliary disorders are commonly encountered in patients with inflammatory bowel disease (IBD). Although primary sclerosing cholangitis is the stereotypical hepatobiliary disorder associated with IBD, other diseases, including autoimmune hepatitis and nonalcoholic fatty liver disease, also are encountered in this population. Several agents used for treatment of IBD may cause drug-induced liver injury, although severe hepatotoxicity occurs infrequently. Furthermore, reactivation of hepatitis B virus infection may occur in patients with IBD treated with systemic corticosteroids and biologic agents.
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Affiliation(s)
- Mahmoud Mahfouz
- Department of Internal Medicine, Mount Sinai Medical Center, 4300 Alton Road, Suite 301, Miami Beach, FL 33140, USA
| | - Paul Martin
- Division of Gastroenterology and Hepatology, University of Miami Miller School of Medicine, 1120 Northwest 14 Street #1115, Miami, FL 33136, USA.
| | - Andres F Carrion
- Division of Gastroenterology and Hepatology, University of Miami Miller School of Medicine, 1120 Northwest 14 Street #1115, Miami, FL 33136, USA
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43
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[Immune-mediated cholangiopathies : Diagnostic and therapeutic challenges]. Radiologe 2019; 59:348-356. [PMID: 30874827 DOI: 10.1007/s00117-019-0513-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
BACKGROUND Immune-mediated cholangiopathies comprise primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and IgG4-associated cholangitis (IAC). A common feature is the progressive destruction of bile ducts leading to cholestasis with fibrosis and cirrhosis of the liver over time. The diseases are mostly identified during routine laboratory testing. Clinical signs and symptoms such as pruritus, fatigue or jaundice are infrequent in the early stage. DIAGNOSIS The diagnostic work-up involves the patient's history, physical examination, serological tests, abdominal ultrasonography, magnetic resonance cholangiopancreatography (MRCP) and, where necessary, liver biopsy and genetic testing. THERAPY Ursodeoxycholic acid (UDCA) is an effective treatment of PBC. Second-line therapies in addition to UDCA for incomplete UDCA responders are obeticholic acid (OCA) and bezafibrate, whereby only OCA has received approval for this indication from American (Federal Drug Administration) and European (European Medicines Agency) authorities. In PSC, UDCA improves prognostic markers; dominant bile duct strictures are treated with endoscopic balloon dilatation. Despite therapy, liver transplantation is frequently necessary for PSC. The risk of developing cholangiocarcinoma, colon cancer, and gallbladder cancer is increased for patients with PSC. In contrast to PBC and PSC, IAC responds well to corticosteroids. Disease relapse, however, is common, making long-term treatment with low-dose prednisolone or azathioprine necessary.
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Isayama H, Tazuma S, Kokudo N, Tanaka A, Tsuyuguchi T, Nakazawa T, Notohara K, Mizuno S, Akamatsu N, Serikawa M, Naitoh I, Hirooka Y, Wakai T, Itoi T, Ebata T, Okaniwa S, Kamisawa T, Kawashima H, Kanno A, Kubota K, Tabata M, Unno M, Takikawa H. Clinical guidelines for primary sclerosing cholangitis 2017. J Gastroenterol 2018; 53:1006-1034. [PMID: 29951926 PMCID: PMC8930933 DOI: 10.1007/s00535-018-1484-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 06/11/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is relatively rare disease and pathogenesis and methods of treatments were still not established. Then, we had conducted the making clinical guidelines to manage patients with PSC based on the literature review and expert opinions. These clinical guidelines were made for the medical doctors on the management of PSC, except child case of PSC. METHODS We had employed modified Delphi method. The production committee decided guidelines, strength of recommendations and evidence level after reviewed literatures systematically, and The Expert panel evaluated those. The Scientific Committee of the Japan Biliary Association (JBA) evaluated revised guidelines, and the Public comments were collected on web site of JBA. RESULTS We had made 16 guidelines about epidemiology/pathophysiology, diagnostics, therapy and prognosis. Also, we had made both diagnostic and therapeutic flow chart. CONCLUSIONS We hope that these guidelines will contribute to the improvement and development of the medical care of PSC.
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Affiliation(s)
- Hiroyuki Isayama
- Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Susumu Tazuma
- Department of General Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Norihiro Kokudo
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Toshio Tsuyuguchi
- Department of Medicine and Gastroenterology, Chiba University, Chiba, Japan
| | - Takahiro Nakazawa
- Department of Gastroenterology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan
| | - Kenji Notohara
- Department of Anatomic Pathology, Kurashiki Central Hospital, Kurashiki, Japan
| | - Suguru Mizuno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nobuhisa Akamatsu
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masahiro Serikawa
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Itaru Naitoh
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Yoshiki Hirooka
- Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takao Itoi
- Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan
| | - Tomoki Ebata
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shinji Okaniwa
- Department of Gastroenterology, Iida Municipal Hospital, Nagano, Japan
| | - Terumi Kamisawa
- Department of Internal Medicine, Tokyo Komagome Metropolitan Hospital, Tokyo, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Atsushi Kanno
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Keiichi Kubota
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Masami Tabata
- Department of Surgery, Matsusaka Central General Hospital, Matsusaka, Mie, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Hajime Takikawa
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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Alberts R, de Vries EMG, Goode EC, Jiang X, Sampaziotis F, Rombouts K, Böttcher K, Folseraas T, Weismüller TJ, Mason AL, Wang W, Alexander G, Alvaro D, Bergquist A, Björkström NK, Beuers U, Björnsson E, Boberg KM, Bowlus CL, Bragazzi MC, Carbone M, Chazouillères O, Cheung A, Dalekos G, Eaton J, Eksteen B, Ellinghaus D, Färkkilä M, Festen EAM, Floreani A, Franceschet I, Gotthardt DN, Hirschfield GM, van Hoek B, Holm K, Hohenester S, Hov JR, Imhann F, Invernizzi P, Juran BD, Lenzen H, Lieb W, Liu JZ, Marschall HU, Marzioni M, Melum E, Milkiewicz P, Müller T, Pares A, Rupp C, Rust C, Sandford RN, Schramm C, Schreiber S, Schrumpf E, Silverberg MS, Srivastava B, Sterneck M, Teufel A, Vallier L, Verheij J, Vila AV, de Vries B, Zachou K, The International PSC Study Group, The UK PSC Consortium, Chapman RW, Manns MP, Pinzani M, Rushbrook SM, Lazaridis KN, Franke A, Anderson CA, Karlsen TH, Ponsioen CY, Weersma RK. Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis. Gut 2018; 67:1517-1524. [PMID: 28779025 PMCID: PMC5797498 DOI: 10.1136/gutjnl-2016-313598] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 04/28/2017] [Accepted: 05/19/2017] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. DESIGN We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. RESULTS We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10-9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. CONCLUSION We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.
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Affiliation(s)
- Rudi Alberts
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Elisabeth M G de Vries
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Elizabeth C Goode
- Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK,Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Xiaojun Jiang
- Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway,Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Fotis Sampaziotis
- Department of Surgery, Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge, UK,Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Krista Rombouts
- Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK
| | - Katrin Böttcher
- Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK
| | - Trine Folseraas
- Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway,Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Tobias J Weismüller
- Department of Gastroenterology Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,Integrated Research and Treatment Center-Transplantation (IFB-tx) Hannover Medical School, Hannover, Germany
| | - Andrew L Mason
- Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada
| | - Weiwei Wang
- Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada
| | - Graeme Alexander
- Department of Medicine, Division of Hepatology, University of Cambridge, Cambridge, UK
| | - Domenico Alvaro
- Department of Clinical Medicine, Division of Gastroenterology, Sapienza University of Rome, Rome, Italy
| | - Annika Bergquist
- Center for Digestive Diseases, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Niklas K Björkström
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Einar Björnsson
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Landspitali University Hospital, Reykjavik, Iceland
| | - Kirsten Muri Boberg
- Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway,K G Jebsen Inflammation Research Centre and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis, Davis, California, USA
| | - Maria C Bragazzi
- Sapienza University of Rome, Medico-Surgical Sciences and Biotechnologies, Rome, Italy
| | - Marco Carbone
- Department of Medicine and Surgery, Program for Autoimmune Liver Diseases, International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy
| | | | - Angela Cheung
- General Internal Medicine, University Health Network, Toronto General Hospital, Toronto, Canada
| | - Georgios Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - John Eaton
- Division of Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota, USA
| | - Bertus Eksteen
- Department of Medicine, Snyder Institute of Chronic Diseases, University of Calgary, Calgary, Canada
| | - David Ellinghaus
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Martti Färkkilä
- Department of Medicine, Division of Gastroenterology, Helsinki University Hospital, Helsinki, Finland
| | - Eleonora A M Festen
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Annarosa Floreani
- Department of Surgical Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Irene Franceschet
- Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy
| | | | - Gideon M Hirschfield
- Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Kristian Holm
- Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway,Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Simon Hohenester
- Department of Medicine II, Liver Center Munich, University of Munich, Munich, Germany
| | - Johannes Roksund Hov
- Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway,Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Floris Imhann
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Pietro Invernizzi
- Department of Medicine and Surgery, Program for Autoimmune Liver Diseases, International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy
| | - Brian D Juran
- Division of Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota, USA
| | - Henrike Lenzen
- Department of Gastroenterology Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Wolfgang Lieb
- Popgen Biobank, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany,Institute for Epidemiology, Christian-Albrechts University, Kiel, Germany
| | - Jimmy Z Liu
- Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Cambridge, UK
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Gothenburg, Sweden
| | - Marco Marzioni
- Department of Gastroenterology, Università Politecnica delle Marche, Ospedali Riuniti University Hospital, Ancona, Italy
| | - Espen Melum
- Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway,Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
| | - Tobias Müller
- Department of Internal Medicine Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Albert Pares
- Liver Unit Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | - Christian Rupp
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany
| | - Christian Rust
- Department of Medicine I, Krankenhaus Barmherzige Brüder, Munich, Germany
| | - Richard N Sandford
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Christoph Schramm
- 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany,Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
| | - Erik Schrumpf
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway,Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Mark S Silverberg
- Inflammatory Bowel Disease (IBD) Group Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital Toronto, Ontario, Canada
| | - Brijesh Srivastava
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Martina Sterneck
- Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas Teufel
- 1st Department of Medicine, University of Mainz, Mainz, Germany
| | - Ludovic Vallier
- Department of Surgery, Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge, UK,Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Cambridge, UK
| | - Joanne Verheij
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
| | - Arnau Vich Vila
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Boudewijn de Vries
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Kalliopi Zachou
- Department of Internal Medicine, University of Thessaly, Larissa, Greece
| | | | - Roger W Chapman
- Department of Hepatology, John Radcliffe University Hospitals NHS Trust, Cambridge, UK
| | - Michael P Manns
- Department of Gastroenterology Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,Integrated Research and Treatment Center-Transplantation (IFB-tx) Hannover Medical School, Hannover, Germany
| | - Massimo Pinzani
- Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK
| | - Simon M Rushbrook
- Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK
| | | | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Carl A Anderson
- Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Cambridge, UK
| | - Tom H Karlsen
- Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway,Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
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46
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Tse CS, Deepak P, De La Fuente J, Bledsoe AC, Larson JJ, Murray JA, Papadakis KA. Phenotype and Clinical Course of Inflammatory Bowel Disease With Co-existent Celiac Disease. J Crohns Colitis 2018; 12:973-980. [PMID: 29741603 DOI: 10.1093/ecco-jcc/jjy061] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 05/06/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Inflammatory bowel diseases, principally Crohn's disease and ulcerative colitis, and celiac disease are among the most common immune-mediated gastrointestinal diseases. We aim to elucidate the clinical course and outcomes of patients with concomitant inflammatory bowel disease and celiac disease, a unique population that remains scarcely studied to date. METHODS A retrospective matched case-control study of adults with co-existent inflammatory bowel disease [IBD] and celiac disease was performed at a tertiary referral institution in North America. Logistic regression and Kaplan-Meier curves compared disease characteristics and clinical outcomes of the two groups. RESULTS A total of 342 inflammatory bowel disease patients were included in this study, of whom 114 had co-existent celiac disease and 228 did not. Patients with co-existent inflammatory bowel disease and celiac disease had higher rates of primary sclerosing cholangitis [19.3% vs 5.7%; odds ratio, 4.4; 95% confidence interval, 2.1-9.4; p <0.001], extensive ulcerative colitis [78.1% vs 59.0%; odds ratio, 2.8; 95% confidence interval, 1.5-5.5; p =0.002], and family history of celiac disease [10.5% vs 3.5%; odds ratio 3.2; 95% confidence interval, 1.3-8.2; p =0.01], compared with patients without concomitant celiac disease. CONCLUSIONS Patients with inflammatory bowel disease with concomitant celiac disease have unique phenotypic features compared with non-celiac inflammatory bowel disease, with higher risks for colitis-related hospitalisations, extensive colitis, and primary sclerosing cholangitis. Increased recognition of co-existent IBD and celiac disease can prompt clinicians to investigate for concomitant disease sooner, particularly in patients with seemingly refractory disease.
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Affiliation(s)
- Chung Sang Tse
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Parakkal Deepak
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.,Division of Gastroenterology, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | | | - Adam C Bledsoe
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Joseph J Larson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Joseph A Murray
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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47
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Dyson JK, Beuers U, Jones DEJ, Lohse AW, Hudson M. Primary sclerosing cholangitis. Lancet 2018; 391:2547-2559. [PMID: 29452711 DOI: 10.1016/s0140-6736(18)30300-3] [Citation(s) in RCA: 282] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 11/24/2017] [Accepted: 01/03/2018] [Indexed: 12/13/2022]
Abstract
Primary sclerosing cholangitis is a rare, chronic cholestatic liver disease characterised by intrahepatic or extrahepatic stricturing, or both, with bile duct fibrosis. Inflammation and fibrosis of bile ducts and the liver are followed by impaired bile formation or flow and progressive liver dysfunction. Patients might be asymptomatic at presentation or might have pruritus, fatigue, right upper quadrant pain, recurrent cholangitis, or sequelae of portal hypertension. The key diagnostic elements are cholestatic liver biochemistry and bile duct stricturing on cholangiography. Genetic and environmental factors are important in the cause of the disease, with the intestinal microbiome increasingly thought to play a pathogenetic role. Approximately 70% of patients have concurrent inflammatory bowel disease and patients require colonoscopic screening and surveillance. Primary sclerosing cholangitis is associated with increased malignancy risk and surveillance strategies for early cholangiocarcinoma detection are limited. No single drug has been proven to improve transplant-free survival. Liver transplantation is effective for advanced disease but at least 25% of patients develop recurrent disease in the graft.
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Affiliation(s)
- Jessica K Dyson
- Department of Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - David E J Jones
- Department of Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mark Hudson
- Department of Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle, UK
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48
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Tabibian JH, Bowlus CL. WITHDRAWN: Primary sclerosing cholangitis: A review and update. LIVER RESEARCH 2018. [DOI: 10.1016/j.livres.2017.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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49
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Zakharia K, Tabibian A, Lindor KD, Tabibian JH. Complications, symptoms, quality of life and pregnancy in cholestatic liver disease. Liver Int 2018; 38:399-411. [PMID: 28921801 DOI: 10.1111/liv.13591] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 09/12/2017] [Indexed: 12/11/2022]
Abstract
Cholestatic liver diseases (CLDs) encompass a variety of disorders of bile formation and/or flow which generally result in progressive hepatobiliary injury and ultimately end-stage liver disease. Many patients with CLD are diagnosed between the ages of 20-50 years, a particularly productive period of life professionally, biologically and in other respects; it is not surprising, thus, that CLD is often associated with impaired health-related quality of life (HRQOL) and uncertainty regarding implications for and outcomes of pregnancy. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most prominent CLDs, both having considerable morbidity and mortality and representing major indications for liver transplantation. These disorders, as a consequence of their complications (eg ascites, hepatic osteodystrophy), associated conditions (eg inflammatory bowel disease) and symptoms (eg pruritus and fatigue), can significantly impair an array of domains of HRQOL. Here we review these impactful clinical aspects of PSC and PBC as well as the topics of fertility and pregnancy.
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Affiliation(s)
- Kais Zakharia
- Internal Medicine Residency Program, Beaumont Health - Dearborn, Dearborn, MI, USA
| | - Anilga Tabibian
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA
| | - Keith D Lindor
- Arizona State University, Phoenix, AZ, USA
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA, USA
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50
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Nordenvall C, Olén O, Nilsson PJ, von Seth E, Ekbom A, Bottai M, Myrelid P, Bergquist A. Colectomy prior to diagnosis of primary sclerosing cholangitis is associated with improved prognosis in a nationwide cohort study of 2594 PSC-IBD patients. Aliment Pharmacol Ther 2018; 47:238-245. [PMID: 29064110 DOI: 10.1111/apt.14393] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 06/12/2017] [Accepted: 10/02/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Despite the close relationship between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD), the association between colectomy and the prognosis of PSC remains controversial. AIM To explore whether colectomy prior to PSC-diagnosis is associated with transplant-free survival. METHODS A nationwide cohort study in Sweden including all patients aged 18 to 69 years in whom both PSC and IBD was diagnosed between 1987 and 2014 was undertaken. Each patient was followed from date of both PSC and IBD diagnoses until liver transplantation or death, or 31 December 2014. Patients with colon in situ, and colectomy prior to PSC-diagnosis were compared. Survival analyses were performed using the Kaplan-Meier method and multivariable Cox regression models. RESULTS Of the 2594 PSC-IBD patients, 205 patients were treated with colectomy before PSC-diagnosis. During follow-up, liver transplantations were performed in 327 patients and 509 died. The risk of liver transplantation or death was lower in patients treated with colectomy prior to PSC-diagnosis (HR 0.71, 95% CI 0.53-0.95) than in patients with colon in situ. Male gender, longer time between IBD and PSC-diagnosis and older age were all associated with an increased risk of liver transplantation or death. Colectomy after PSC-diagnosis was however not associated with an increased risk of liver transplantation or death during long-term follow-up. CONCLUSIONS In PSC-IBD patients, colectomy prior to PSC-diagnosis is associated with a decreased risk of liver transplantation or death.
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Affiliation(s)
- C Nordenvall
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Division of Coloproctology, Center for Digestive Disease, Karolinska University Hospital, Stockholm, Sweden
| | - O Olén
- Department of Medicine Solna, Karolinska Institutet, Clinical Epidemiology Unit, Stockholm, Sweden.,Department of Pediatric Gastroenterology and Nutrition, Sachs' Children's Hospital, Stockholm, Sweden
| | - P J Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Division of Coloproctology, Center for Digestive Disease, Karolinska University Hospital, Stockholm, Sweden
| | - E von Seth
- Department of Medicine Huddinge, Division of Hepatology, Karolinska Institutet Center for Digestive Disease, Karolinska University Hospital, Stockholm, Sweden
| | - A Ekbom
- Department of Medicine Solna, Karolinska Institutet, Clinical Epidemiology Unit, Stockholm, Sweden
| | - M Bottai
- Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - P Myrelid
- Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.,Department of Surgery, County Council of Östergötland, Linköping, Sweden
| | - A Bergquist
- Department of Medicine Huddinge, Division of Hepatology, Karolinska Institutet Center for Digestive Disease, Karolinska University Hospital, Stockholm, Sweden
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