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Barner-Rasmussen N, Molinaro A, Mol B, Ponsioen C, Bergquist A, Kautiainen H, Färkkilä MA. Surveillance of primary sclerosing cholangitis - a comparison of scheduled or on-demand ERCP with annual MRI surveillance: a multicenter study. Endoscopy 2025; 57:431-440. [PMID: 39875118 DOI: 10.1055/a-2511-3422] [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] [Indexed: 01/30/2025]
Abstract
Primary sclerosing cholangitis (PSC) is associated with a high risk of hepatobiliary malignancy, especially cholangiocarcinoma (CCA). There are no good tumor markers to screen for CCA, and current recommendations for PSC monitoring are mainly based on expert opinions. The optimal strategy to assess disease progression and screen for CCA - the main cause of death of PSC patients - remains unclear. We aimed to compare three different surveillance strategies and their effect on patient outcomes.Data from three distinct PSC cohorts with different surveillance strategies - scheduled endoscopic retrograde cholangiopancreatography (ERCP), annual magnetic resonance imaging/cholangiopancreatography (MRI/MRCP) surveillance, and on-demand ERCP according to ESGE/EASL guidelines - was collected. Patients with PSC diagnosed in 1990 or later were included and the last day of follow-up was 31 December 2023. The composite end point consisted of hepatobiliary malignancy, liver transplantation, or liver-related death.1629 PSC patients were included, with a median follow-up of 8-11 years. The cumulative incidence of the composite end point was lowest in the group undergoing scheduled ERCP (14.1%, 95%CI 12.0%-16.4%) and highest in the on-demand ERCP cohort (35.0%, 95%CI 28.4%-42.0%). Although the cumulative incidence of CCA was lower in the scheduled ERCP group than in the other groups, it did not differ statistically significantly from the MRI/MRCP surveillance group. No differences were seen in liver-related deaths between the surveillance strategies.In this study comparing scheduled ERCP, annual MRI/MRCP surveillance, and on-demand ERCP, the strategy based on scheduled ERCP using individual risk stratification is associated with better overall prognosis and outcome.
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Affiliation(s)
- Nina Barner-Rasmussen
- Department of Gastroenterology, HUS Abdominal Center, Helsinki University Central Hospital, Helsinki, Finland
| | - Antonio Molinaro
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Bregje Mol
- Department of Gastroenterology and Hepatology, Amsterdam UMC Locatie AMC, Amsterdam, Netherlands
| | - Cyriel Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam UMC Locatie AMC, Amsterdam, Netherlands
| | - Annika Bergquist
- Department of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden
| | - Hannu Kautiainen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Primary Health Care, Folkhalsan Research Centre, Helsinki, Finland
| | - Martti A Färkkilä
- Department of Gastroenterology, HUS Abdominal Center, Helsinki University Central Hospital, Helsinki, Finland
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Mol B, Werner E, Culver EL, van der Meer AJ, Bogaards JA, Ponsioen CY. Epidemiological and economical burden of cholestatic liver disease. Hepatology 2025:01515467-990000000-01224. [PMID: 40168457 DOI: 10.1097/hep.0000000000001341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 03/24/2025] [Indexed: 04/03/2025]
Abstract
The main cholestatic liver diseases comprise primary sclerosing cholangitis, primary biliary cholangitis, and IgG4-related cholangitis. Despite being classified as rare diseases, these are becoming gradually more important in the field of hepatology since their incidence is slowly rising while the viral hepatitis burden is declining. Cholestatic liver diseases now rank among the 3 most frequent indications for liver transplantation in many Western countries. An accurate understanding of the epidemiology and burden of disease on both the individual and society of cholestatic diseases is of great importance. This review aims to provide a comprehensive overview of the current literature on the epidemiology, health-related quality of life, and economic burden of primary sclerosing cholangitis, primary biliary cholangitis, and IgG4-related cholangitis.
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Affiliation(s)
- Bregje Mol
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
- Endocrinology and Metabolism, Amsterdam Institute of Gastroenterology, Amsterdam, The Netherlands
| | - Ellen Werner
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Emma L Culver
- Oxford Liver Unit, John Radcliffe Hospital, Oxford, UK
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Johannes A Bogaards
- Department of Epidemiology and Data Science, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
- Endocrinology and Metabolism, Amsterdam Institute of Gastroenterology, Amsterdam, The Netherlands
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Manns MP, Bergquist A, Karlsen TH, Levy C, Muir AJ, Ponsioen C, Trauner M, Wong G, Younossi ZM. Primary sclerosing cholangitis. Nat Rev Dis Primers 2025; 11:17. [PMID: 40082445 DOI: 10.1038/s41572-025-00600-x] [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] [Accepted: 02/07/2025] [Indexed: 03/16/2025]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic biliary inflammation associated with periductular fibrosis of the intrahepatic and extrahepatic bile ducts leading to strictures, bacterial cholangitis, decompensated liver disease and need for liver transplantation. This rare focal liver disease affects all races and ages, with a predominance of young males. There is an up to 88% association with inflammatory bowel disease. Although the aetiology is unknown and the pathophysiology is poorly understood, PSC is regarded as an autoimmune liver disease based on a strong immunogenetic background. Further, the associated risk for various malignancies, particularly cholangiocellular carcinoma, is also poorly understood. No medical therapy has been approved so far nor has been shown to improve transplant-free survival. However, ursodeoxycholic acid is widely used since it improves the biochemical parameters of cholestasis and is safe at low doses. MRI of the biliary tract is the primary imaging technology for diagnosis. Endoscopic interventions of the bile ducts should be limited to clinically relevant strictures for balloon dilatation, biopsy and brush cytology. End-stage liver disease with decompensation is an indication for liver transplantation with recurrent PSC in up to 38% of patients. Several novel therapeutic strategies are in various stages of development, including apical sodium-dependent bile acid transporter and ileal bile acid transporter inhibitors, integrin inhibitors, peroxisome proliferator-activated receptor agonists, CCL24 blockers, recombinant FGF19, CCR2/CCR5 inhibitors, farnesoid X receptor bile acid receptor agonists, and nor-ursodeoxycholic acid. Manipulation of the gut microbiome includes faecal microbiota transplantation. This article summarizes present knowledge and defines unmet medical needs to improve quality of life and survival.
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Affiliation(s)
- Michael P Manns
- Hannover Medical School (MHH) and Centre for Individualised Infection Medicine (CiiM), Hannover, Germany.
| | - Annika Bergquist
- Division of Hepatology, Department of Upper Gastrointestinal Disease, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Tom H Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Clinic of Surgery and Specialized medicine, Oslo University Hospital, Oslo, Norway
- Research Institute of Internal Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, FL, USA
| | - Andrew J Muir
- Division of Gastroenterology, Duke University School of Medicine, Durham, NC, USA
| | - Cyriel Ponsioen
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Grace Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Union Hospital, Hong Kong SAR, China
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Colapietro F, Maisonneuve P, Lytvyak E, Beuers U, Verdonk RC, van der Meer AJ, van Hoek B, Kuiken SD, Brouwer JT, Muratori P, Aghemo A, Carella F, van den Berg AP, Zachou K, Dalekos GN, Di Zeo-Sánchez DE, Robles M, Andrade RJ, Montano-Loza AJ, van den Brand FF, Slooter CD, Macedo G, Liberal R, de Boer YS, Lleo A. Incidence and predictors of hepatocellular carcinoma in patients with autoimmune hepatitis. J Hepatol 2024; 80:53-61. [PMID: 37802188 DOI: 10.1016/j.jhep.2023.09.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 08/28/2023] [Accepted: 09/01/2023] [Indexed: 10/08/2023]
Abstract
BACKGROUND AND AIMS Autoimmune hepatitis (AIH) is a rare chronic liver disease of unknown aetiology; the risk of hepatocellular carcinoma (HCC) remains unclear and risk factors are not well-defined. We aimed to investigate the risk of HCC across a multicentre AIH cohort and to identify predictive factors. METHODS We performed a retrospective, observational, multicentric study of patients included in the International Autoimmune Hepatitis Group Retrospective Registry. The assessed clinical outcomes were HCC development, liver transplantation, and death. Fine and Gray regression analysis stratified by centre was applied to determine the effects of individual covariates; the cumulative incidence of HCC was estimated using the competing risk method with death as a competing risk. RESULTS A total of 1,428 patients diagnosed with AIH from 1980 to 2020 from 22 eligible centres across Europe and Canada were included, with a median follow-up of 11.1 years (interquartile range 5.2-15.9). Two hundred and ninety-three (20.5%) patients had cirrhosis at diagnosis. During follow-up, 24 patients developed HCC (1.7%), an incidence rate of 1.44 cases/1,000 patient-years; the cumulative incidence of HCC increased over time (0.6% at 5 years, 0.9% at 10 years, 2.7% at 20 years, and 6.6% at 30 years of follow-up). Patients who developed cirrhosis during follow-up had a significantly higher incidence of HCC. The cumulative incidence of HCC was 2.6%, 4.6%, 5.6% and 6.6% at 5, 10, 15, and 20 years after the development of cirrhosis, respectively. Obesity (hazard ratio [HR] 2.94, p = 0.04), cirrhosis (HR 3.17, p = 0.01), and AIH/PSC variant syndrome (HR 5.18, p = 0.007) at baseline were independent risk factors for HCC development. CONCLUSIONS HCC incidence in AIH is low even after cirrhosis development and is associated with risk factors including obesity, cirrhosis, and AIH/PSC variant syndrome. IMPACT AND IMPLICATIONS The risk of developing hepatocellular carcinoma (HCC) in individuals with autoimmune hepatitis (AIH) seems to be lower than for other aetiologies of chronic liver disease. Yet, solid data for this specific patient group remain elusive, given that most of the existing evidence comes from small, single-centre studies. In our study, we found that HCC incidence in patients with AIH is low even after the onset of cirrhosis. Additionally, factors such as advanced age, obesity, cirrhosis, alcohol consumption, and the presence of the AIH/PSC variant syndrome at the time of AIH diagnosis are linked to a higher risk of HCC. Based on these findings, there seems to be merit in adopting a specialized HCC monitoring programme for patients with AIH based on their individual risk factors.
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Affiliation(s)
- Francesca Colapietro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Ellina Lytvyak
- Department of Medicine, Division of Preventive Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC, Amsterdam, the Netherlands
| | - Robert C Verdonk
- Department of Gastroenterology and Hepatology, St Antonius Hospital, Nieuwegein, The Netherlands
| | | | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Sjoerd D Kuiken
- Department of Gastroenterology and Hepatology, OLVG, Amsterdam, the Netherlands
| | | | - Paolo Muratori
- Division of Internal Medicine, Morgagni-Pierantoni Hospital, Forlì 47100, Italy; Department of Science for the Quality of Life, University of Bologna, Bologna, Italy
| | - Alessio Aghemo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Francesco Carella
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Ad P van den Berg
- University Medical Center Groningen, University of Groningen, the Netherlands
| | - Kalliopi Zachou
- Department of Medicine and Research, Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110, Larissa, Greece
| | - George N Dalekos
- Department of Medicine and Research, Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110, Larissa, Greece
| | - Daniel E Di Zeo-Sánchez
- Liver Unit, Vírgen de Victoria University Hospital-IBIMA, University of Málaga, CIBERehd, Malaga, Spain
| | - Mercedes Robles
- Liver Unit, Vírgen de Victoria University Hospital-IBIMA, University of Málaga, CIBERehd, Malaga, Spain
| | - Raul J Andrade
- Liver Unit, Vírgen de Victoria University Hospital-IBIMA, University of Málaga, CIBERehd, Malaga, Spain
| | - Aldo J Montano-Loza
- Department of Medicine, Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| | - Floris F van den Brand
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Charlotte D Slooter
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Guilherme Macedo
- Department of Gastroenterology and Hepatology, Centro Hospitalar São João, Porto, Portugal
| | - Rodrigo Liberal
- Department of Gastroenterology and Hepatology, Centro Hospitalar São João, Porto, Portugal
| | - Ynto S de Boer
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
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Catanzaro E, Gringeri E, Burra P, Gambato M. Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma: From Pathogenesis to Diagnostic and Surveillance Strategies. Cancers (Basel) 2023; 15:4947. [PMID: 37894314 PMCID: PMC10604939 DOI: 10.3390/cancers15204947] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/09/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Cholangiocarcinoma (CCA) is the most common malignancy in patients with primary sclerosing cholangitis (PSC), accounting for 2-8% of cases and being the leading cause of death in these patients. The majority of PSC-associated CCAs (PSC-CCA) develop within the first few years after PSC diagnosis. Older age and male sex, as well as concomitant inflammatory bowel disease (IBD) or high-grade biliary stenosis, are some of the most relevant risk factors. A complex combination of molecular mechanisms involving inflammatory pathways, direct cytopathic damage, and epigenetic and genetic alterations are involved in cholangiocytes carcinogenesis. The insidious clinical presentation makes early detection difficult, and the integration of biochemical, radiological, and histological features does not always lead to a definitive diagnosis of PSC-CCA. Surveillance is mandatory, but current guideline strategies failed to improve early detection and consequently a higher patient survival rate. MicroRNAs (miRNAs), gene methylation, proteomic and metabolomic profile, and extracellular vesicle components are some of the novel biomarkers recently applied in PSC-CCA detection with promising results. The integration of these new molecular approaches in PSC diagnosis and monitoring could contribute to new diagnostic and surveillance strategies.
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Affiliation(s)
- Elisa Catanzaro
- Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
| | - Enrico Gringeri
- Hepatobiliary Surgery and Liver Transplantation Center, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
| | - Patrizia Burra
- Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
| | - Martina Gambato
- Gastroenterology, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
- Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, 35128 Padova, Italy
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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: 125] [Impact Index Per Article: 62.5] [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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Chandrababu G, Sah SK, Kumar AR, M S, Nath LR. Green Synthesized Nanoparticles as a Plausible Therapeutic Strategy Against Hepatocellular Carcinoma: An Update on its Preclinical and Clinical Relevance. Recent Pat Anticancer Drug Discov 2023; 18:268-291. [PMID: 35616675 DOI: 10.2174/1574892817666220523124437] [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: 10/13/2021] [Revised: 01/29/2022] [Accepted: 02/18/2022] [Indexed: 11/22/2022]
Abstract
Green nanotechnology can offer notable advantages over the conventional drug delivery methods in terms of improved drug stability, drug-carrying capacity, site-specificity, and feasibility to apply different routes of administration with less systemic toxicities. Metal nanoparticles bio fabricated with phytoconstituents and microbial extracts have gained significant interest for the treatment of various solid tumors including hepatocellular carcinoma. Hepatocellular carcinoma (HCC) is an aggressive cancer with a very poor prognosis. The current treatments of HCC fails to provide tumor specificity, causing many systemic toxicities and poor overall survival benefits especially for patients in advanced and terminal stages. A novel therapeutic approach with maximal therapeutic effect and minimum adverse effects are urgently required for HCC patients. Green synthesized metal nanoparticles offer significant anticancer effects along with minimal systemic toxicities because of their site-specific delivery into the tumor microenvironment (TME). Green synthesized metal nanoparticles can therefore be a highly beneficial strategy for the treatment of HCC if properly validated with preclinical and clinical studies. This review focuses on the preclinical evidence of the most widely studied green metal nanoparticles such as green synthesized silver nanoparticles, gold nanoparticles and selenium nanoparticles. We have also summarised the clinical studies and the patents approved for nanoparticles against HCC.
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Affiliation(s)
- Gopika Chandrababu
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
| | - Sunil Kumar Sah
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
| | - Ayana R Kumar
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
| | - Sabitha M
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
| | - Lekshmi R Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi-682041, Kerala, India
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8
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Liu YB, Chen MK. Epidemiology of liver cirrhosis and associated complications: Current knowledge and future directions. World J Gastroenterol 2022; 28:5910-5930. [PMID: 36405106 PMCID: PMC9669831 DOI: 10.3748/wjg.v28.i41.5910] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 09/30/2022] [Accepted: 10/19/2022] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis causes a heavy global burden. In this review, we summarized up-to-date epidemiological features of cirrhosis and its complications. Recent epidemiological studies reported an increase in the prevalence of cirrhosis in 2017 compared to in 1990 in both men and women, with 5.2 million cases of cirrhosis and chronic liver disease occurring in 2017. Cirrhosis caused 1.48 million deaths in 2019, an increase of 8.1% compared to 2017. Disability-adjusted life-years due to cirrhosis ranked 16th among all diseases and 7th in people aged 50-74 years in 2019. The global burden of hepatitis B virus and hepatitis C virus-associated cirrhosis is decreasing, while the burden of cirrhosis due to alcohol and nonalcoholic fatty liver disease (NAFLD) is increasing rapidly. We described the current epidemiology of the major complications of cirrhosis, including ascites, variceal bleeding, hepatic encephalopathy, renal disorders, and infections. We also summarized the epidemiology of hepatocellular carcinoma in patients with cirrhosis. In the future, NAFLD-related cirrhosis will likely become more common due to the prevalence of metabolic diseases such as obesity and diabetes, and the prevalence of alcohol-induced cirrhosis is increasing. This altered epidemiology should be clinically noted, and relevant interventions should be undertaken.
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Affiliation(s)
- Yuan-Bin Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei Province, China
| | - Ming-Kai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei Province, China
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9
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Chazouilleres O, Beuers U, Bergquist A, Karlsen TH, Levy C, Samyn M, Schramm C, Trauner M. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761-806. [PMID: 35738507 DOI: 10.1016/j.jhep.2022.05.011] [Citation(s) in RCA: 152] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
Abstract
Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.
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10
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Rallis KS, Makrakis D, Ziogas IA, Tsoulfas G. Immunotherapy for advanced hepatocellular carcinoma: From clinical trials to real-world data and future advances. World J Clin Oncol 2022; 13:448-472. [PMID: 35949435 PMCID: PMC9244967 DOI: 10.5306/wjco.v13.i6.448] [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: 01/31/2022] [Revised: 04/27/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. HCC is an inflammation-associated immunogenic cancer that frequently arises in chronically inflamed livers. Advanced HCC is managed with systemic therapies; the tyrosine kinase inhibitor (TKI) sorafenib has been used in 1st-line setting since 2007. Immunotherapies have emerged as promising treatments across solid tumors including HCC for which immune checkpoint inhibitors (ICIs) are licensed in 1st- and 2nd-line treatment setting. The treatment field of advanced HCC is continuously evolving. Several clinical trials are investigating novel ICI candidates as well as new ICI regimens in combination with other therapeutic modalities including systemic agents, such as other ICIs, TKIs, and anti-angiogenics. Novel immunotherapies including adoptive cell transfer, vaccine-based approaches, and virotherapy are also being brought to the fore. Yet, despite advances, several challenges persist. Lack of real-world data on the use of immunotherapy for advanced HCC in patients outside of clinical trials constitutes a main limitation hindering the breadth of application and generalizability of data to this larger and more diverse patient cohort. Consequently, issues encountered in real-world practice include patient ineligibly for immunotherapy because of contraindications, comorbidities, or poor performance status; lack of response, efficacy, and safety data; and cost-effectiveness. Further real-world data from high-quality large prospective cohort studies of immunotherapy in patients with advanced HCC is mandated to aid evidence-based clinical decision-making. This review provides a critical and comprehensive overview of clinical trials and real-world data of immunotherapy for HCC, with a focus on ICIs, as well as novel immunotherapy strategies underway.
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Affiliation(s)
- Kathrine S Rallis
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, United Kingdom
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
| | - Dimitrios Makrakis
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
- Division of Oncology, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Ioannis A Ziogas
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Aristotle University School of Medicine, Thessaloniki 54622, Greece
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Beheshti-Maal A, Tamimi A, Iravani S, Memarnejadian A, Sorouri M, Aghdaei HA, Zali MR, Hossein Khannazer N, Vosough M. PSC associated inflammatory bowel disease: a distinct entity. Expert Rev Gastroenterol Hepatol 2022; 16:129-139. [PMID: 35078376 DOI: 10.1080/17474124.2022.2031979] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is a rare, chronic, and progressive cholestatic disease involving intra- and/or extrahepatic bile ducts. PSC in many patients results in end-stage liver diseases. Nearly 60% of the PSC patients suffer from concomitant inflammatory bowel diseases (IBDs). Classically, IBDs are divided into two principle types: Crohn's disease (CD) and ulcerative colitis (UC). However, with growing knowledge, PSC-associated IBD (PSC-IBD) seems to be a rather distinct entity with specific genetics, clinical, and microbiota characteristics. AREAS COVERED In this article, we aim to review the unique characteristics of PSC-IBD from clinical, genetic, and microbiota point of view. EXPERT OPINION PSC-IBD's unique characteristics contribute to the notion that it could be a distinct entity. Acknowledgment of PSC-IBD as a novel entity necessitates designing new clinical guidelines for diagnosis and developing novel therapies.
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Affiliation(s)
- Alireza Beheshti-Maal
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Acecr, Tehran, Iran
| | - Atena Tamimi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Acecr, Tehran, Iran
| | - Shahrokh Iravani
- Gastroenterology and Hepatobiliary Research Center, Imam Reza Hospital, Tehran, Iran
| | | | - Majid Sorouri
- Digestive Diseases Research Center, Digestive Diseases Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nikoo Hossein Khannazer
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Acecr, Tehran, Iran
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Losurdo G, Brescia IV, Lillo C, Mezzapesa M, Barone M, Principi M, Ierardi E, Di Leo A, Rendina M. Liver involvement in inflammatory bowel disease: What should the clinician know? World J Hepatol 2021; 13:1534-1551. [PMID: 34904028 PMCID: PMC8637677 DOI: 10.4254/wjh.v13.i11.1534] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/06/2021] [Accepted: 10/11/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) may show a wide range of extraintestinal manifestations. In this context, liver involvement is a focal point for both an adequate management of the disease and its prognosis, due to possible serious comorbidity. The association between IBD and primary sclerosing cholangitis is the most known example. This association is relevant because it implies an increased risk of both colorectal cancer and cholangiocarcinoma. Additionally, drugs such as thiopurines or biologic agents can cause drug-induced liver damage; therefore, this event should be considered when planning IBD treatment. Additionally, particular consideration should be given to the evidence that IBD patients may have concomitant chronic viral hepatitis, such as hepatitis B and hepatitis C. Chronic immunosuppressive regimens may cause a hepatitis flare or reactivation of a healthy carrier state, therefore careful monitoring of these patients is necessary. Finally, the spread of obesity has involved even IBD patients, thus increasing the risk of non-alcoholic fatty liver disease, which has already proven to be more common in IBD patients than in the non-IBD population. This phenomenon is considered an emerging issue, as it will become the leading cause of liver cirrhosis.
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Affiliation(s)
- Giuseppe Losurdo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy.
| | - Irene Vita Brescia
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Chiara Lillo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Martino Mezzapesa
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Michele Barone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Mariabeatrice Principi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Enzo Ierardi
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Alfredo Di Leo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
| | - Maria Rendina
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, Bari 70124, Italy
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Nair AV, Macdonald DB, Kelly EM, Satheesh S, Venugopalan P, Soman DK. Utility of MRCP in surveillance of primary sclerosing cholangitis associated hepatobiliary malignancy: 15 year experience at a single institution in Ontario, Canada. Clin Imaging 2021; 81:47-53. [PMID: 34598005 DOI: 10.1016/j.clinimag.2021.08.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 08/18/2021] [Accepted: 08/23/2021] [Indexed: 11/03/2022]
Abstract
OBJECTIVE Magnetic resonance cholangiopancreatography (MRCP) is used for the surveillance of primary sclerosing cholangitis (PSC) and its associated complications. The time interval gap for subsequent follow-up MRCP is variable depending on clinical practice patterns, therefore this study was done to assess the MRCP follow-up strategy used in our institution for screening PSC-associated hepatobiliary malignancies. MATERIALS AND METHODS This retrospective observational cohort included MRCP studies in adult patients, with clinical and radiological diagnosis of PSC over the past 15-year period between January 1, 2003 to December 31, 2018. The study population was grouped based on the presence and absence of PSC-associated malignancy. The frequency of MRCP follow-up was compared between the groups to look for MRI ordering trends in surveillance for PSC-associated complications. RESULTS The overall median interval follow-up with MRCP was 14 months. The median follow-up interval in cases with PSC-associated malignancy was 6.0 months, compared to 13.1 months in the PSC group without malignancy (p 0.013). During the study period, the PSC-associated malignancy group had a median number of 7.5 scans, while the no malignancy group had a median number of 4 scans. Three patients (3/10, 30%) developed hepatobiliary malignancies within the first year of clinical diagnosis of PSC. The most common malignancy associated with PSC was cholangiocarcinoma (4.6%,7/10). Other PSC-associated malignancies included carcinoma gallbladder (1.3%,2/10), and hepatocellular carcinoma (0.6%,1/10). The median age of PSC associated malignancies was 56 (IQR 15) and higher compared to median age of PSC group without malignancies 46 (IQR 25.5), p 0.035. CONCLUSION The median interval for subsequent follow-up MRCP in our study cohort was 14 months. One-third of PSC-associated hepato-biliary malignancies developed within the first year of clinical diagnosis of PSC, and the risk of PSC-associated hepato-biliary malignancy is constant after the first year.
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Affiliation(s)
| | - D Blair Macdonald
- Dept of Medical Imaging, The Ottawa Hospital Research Institute, Ottawa, Canada
| | - Erin M Kelly
- Dept of Gastro-enterology, The Ottawa Hospital, University of Ottawa, Canada
| | - Soumya Satheesh
- Dept of Pathology, VPS Lakeshore Hospital, Kochi, Kerala, India
| | - Prasanna Venugopalan
- Dept of Obstetrics and Gynaecology, Travancore Medical College, Kollam, Kerala, India
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Hepatocellular carcinoma in primary sclerosing cholangitis and primary biliary cholangitis: a clinical and pathological study in an uncommon but emerging setting. Virchows Arch 2021; 479:1131-1143. [PMID: 34414507 DOI: 10.1007/s00428-021-03183-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 08/01/2021] [Accepted: 08/10/2021] [Indexed: 11/09/2022]
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are biliary tract pathologies with increased risk of HCC, although HCC is more commonly associated with viral hepatitis and steatohepatitis. HCC risk stratification in PBC/PSC populations may help select patients for surveillance. We hypothesized that metabolic syndrome associated diagnoses and co-morbid nonalcoholic fatty liver disease (NAFLD) may be risk factors for HCC in patients with PBC and PSC. We undertook a multi-institutional case control study of PSC (19 cases, 38 controls) and PBC (39 cases and controls) patients with advanced fibrosis, matched for known HCC risk factors of age and sex, who had native liver explant or resection specimens. In the PSC population, HCC risk was significantly associated with multiple metabolic syndrome associated diagnoses (OR 13, p = 0.02), hyperlipidemia (OR 29, p = 0.03), and obesity (OR 6.8, p = 0.01). In the PBC cohort, only type 2 diabetes was a risk factor for HCC (OR 4.7, p = 0.03). In the PSC cohort, thick fibrous septae were associated with HCC risk (OR 3.4, p = 0.04). No other pathologic features of the nonneoplastic liver were significantly associated with HCC, including features of NAFLD such as macrovesicular steatosis, pericellular fibrosis, and steatohepatitis. Metabolic syndrome associated diagnoses, specifically type 2 diabetes among PBC patients, is associated with HCC risk in patients with biliary type cirrhosis. However, we found no evidence that HCC risk is related to co-morbid NAFLD, indicating a likely distinct mechanism of metabolic syndrome-associated carcinogenesis in these populations.
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Fung BM, Tabibian JH. Primary sclerosing cholangitis-associated cholangiocarcinoma: special considerations and best practices. Expert Rev Gastroenterol Hepatol 2021; 15:487-496. [PMID: 33682586 DOI: 10.1080/17474124.2021.1900732] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/05/2021] [Indexed: 10/22/2022]
Abstract
Introduction: Primary sclerosing cholangitis (PSC) is a rare, heterogenous, chronic cholestatic liver disease that causes fibro-inflammatory destruction of the intra- and/or extrahepatic bile ducts. The disease course may be variable, though in many cases it ultimately leads to biliary cirrhosis and its associated complications. PSC is also associated with malignancies, in particular cholangiocarcinoma (CCA), a dreaded neoplasm of the biliary tract with a poor prognosis. Risk stratification and surveillance for this malignancy are important components of the care of patients with PSC.Areas covered: In this review, we discuss important considerations in the clinical epidemiology, risk factors, diagnosis, and surveillance of PSC-associated CCA.Expert opinion: Despite growing awareness of PSC, high-quality evidence regarding the management of PSC and its associated risk of CCA remains limited. Early diagnosis of PSC-associated CCA remains difficult, and treatment options are limited, especially when diagnosed at later stages. The recent introduction of recommendations for CCA surveillance will likely improve outcomes, though an optimal surveillance approach has yet to be validated prospectively. Further research is needed in the development of high-accuracy (and noninvasive) surveillance and diagnostic tools that may facilitate earlier diagnosis of CCA and potential disease cure.
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Affiliation(s)
- Brian M Fung
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA, USA
- David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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16
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McCain JD, Chascsa DM, Lindor KD. Assessing and managing symptom burden and quality of life in primary sclerosing cholangitis patients. Expert Opin Orphan Drugs 2021. [DOI: 10.1080/21678707.2021.1898370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Josiah D. McCain
- Department of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
| | - David M. Chascsa
- Department of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
- Department of Transplant Center, Mayo Clinic, Phoenix, Arizona, USA
| | - Keith D. Lindor
- Office of University Provost, Arizona State University, Arizona, USA
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17
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Rigopoulou EI, Dalekos GN. Current Trends and Characteristics of Hepatocellular Carcinoma in Patients with Autoimmune Liver Diseases. Cancers (Basel) 2021; 13:1023. [PMID: 33804480 PMCID: PMC7957658 DOI: 10.3390/cancers13051023] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/17/2021] [Accepted: 02/24/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the commonest among liver cancers, is one of the leading causes of mortality among malignancies worldwide. Several reports demonstrate autoimmune liver diseases (AILDs), including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) to confer increased risk of hepatobiliary malignancies, albeit at lower frequencies compared to other liver diseases. Several parameters have been recognized as risk factors for HCC development in AIH and PBC, including demographics such as older age and male sex, clinical features, the most decisive being cirrhosis and other co-existing factors, such as alcohol consumption. Moreover, biochemical activity and treatment response have been increasingly recognized as prognostic factors for HCC development in AIH and PBC. As available treatment modalities are effective only when HCC diagnosis is established early, surveillance has been proven essential for HCC prognosis. Considering that the risk for HCC is not uniform between and within disease groups, refinement of screening strategies according to prevailing demographic, clinical, and molecular risk factors is mandated in AILDs patients, as personalized HCC risk prediction will offer significant advantage in patients at high and/or medium risk. Furthermore, future investigations should draw attention to whether modification of immunosuppression could benefit AIH patients after HCC diagnosis.
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Affiliation(s)
| | - George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Greece;
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18
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Pinter M, Scheiner B, Peck-Radosavljevic M. Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups. Gut 2021; 70:204-214. [PMID: 32747413 PMCID: PMC7788203 DOI: 10.1136/gutjnl-2020-321702] [Citation(s) in RCA: 168] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/27/2020] [Accepted: 06/13/2020] [Indexed: 02/06/2023]
Abstract
Following the success of immune checkpoint blockers (ICBs) in different cancer types, a large number of studies are currently investigating ICBs in patients with hepatocellular carcinoma (HCC), alone or in combination with other treatments. Both nivolumab and pembrolizumab, as well as the combination of nivolumab plus ipilimumab have been granted accelerated approval by the United States Food and Drug Administration for sorafenib-pretreated patients. While nivolumab and pembrolizumab both failed to meet their primary endpoints in phase III trials, the combination of atezolizumab plus bevacizumab eventually improved overall and progression-free survival compared with sorafenib in a front-line phase III trial, and thus, will become the new standard of care in this setting. Despite this breakthrough, there are patient populations with certain underlying conditions that may not be ideal candidates for this new treatment either due to safety concerns or potential lack of efficacy. In this review, we discuss the safety of ICBs in patients with pre-existing autoimmune disease, IBD or a history of solid organ transplantation. Moreover, we summarise emerging preclinical and clinical data suggesting that ICBs may be less efficacious in patients with underlying non-alcoholic steatohepatitis or HCCs with activated Wnt/β-catenin signalling.
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Affiliation(s)
- Matthias Pinter
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria .,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria,Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Markus Peck-Radosavljevic
- Department of Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Worthersee, Klagenfurt, Kärnten, Austria
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19
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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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20
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Cebada Chaparro E, Lloret del Hoyo J, Méndez Fernández R. Chronic cholangitis: Differential diagnosis and role of MRI. RADIOLOGIA 2020. [DOI: 10.1016/j.rxeng.2020.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Cebada Chaparro E, Lloret Del Hoyo J, Méndez Fernández R. Chronic cholangitides: Differential diagnosis and role of MRI. RADIOLOGIA 2020; 62:452-463. [PMID: 33138982 DOI: 10.1016/j.rx.2020.08.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 07/06/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023]
Abstract
The idiopathic chronic cholangitides comprise a group of hepatobiliary diseases of probable autoimmune origin that are usually asymptomatic in the initial stages and can lead to cirrhosis of the liver. Elevated cholestatic enzymes on blood tests raise suspicion of these entities. Among the idiopathic cholangitides, the most common is primary sclerosing cholangitis, which is associated with inflammatory bowel disease and with an increased incidence of hepatobiliary and digestive tract tumors. It is important to establish the differential diagnosis with IgG4-associated cholangitis, primary biliary cholangitis, and secondary cholangitides, because the therapeutic management is different. Magnetic resonance cholangiopancreatography (MRCP) is the best test to evaluate the intrahepatic and extrahepatic biliary tract, and MRI also provides information about the liver and other abdominal organs. An appropriate MRCP protocol and knowledge of the different findings that are characteristic of each entity are essential to reach the correct diagnosis.
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Affiliation(s)
- E Cebada Chaparro
- Servicio de Radiodiagnóstico, Hospital Clínico San Carlos, Madrid, España.
| | - J Lloret Del Hoyo
- Servicio de Radiodiagnóstico, Hospital Clínico San Carlos, Madrid, España
| | - R Méndez Fernández
- Servicio de Radiodiagnóstico, Hospital Clínico San Carlos, Madrid, España
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22
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Khoshpouri P, Ghadimi M, Rezvani Habibabadi R, Motaghi M, Venkatesh BA, Shaghaghi M, Pandey A, Hazhirkarzar B, Ameli S, Ghasabeh MA, Pandey P, Kamel IR. Cross-sectional imaging in patients with primary sclerosing cholangitis: Single time-point liver or spleen volume is associated with survival. Eur J Radiol 2020; 132:109331. [PMID: 33091863 DOI: 10.1016/j.ejrad.2020.109331] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 09/20/2020] [Accepted: 09/26/2020] [Indexed: 02/08/2023]
Abstract
AIM To evaluate the association between single time-point quantitative liver and spleen volumes in patients with PSC and transplant-free survival, independent of Mayo risk score. MATERIALS AND METHODS This HIPAA-compliant retrospective study included 165 PSC patients in a hospital. Total (T), and lobar (right [R], left [L], and caudate [C]) liver volumes and spleen volume (S) were measured. Adverse outcome was identified as being on liver transplantation list, transplantation or death (outcome 1), and transplantation or death (outcome 2). Cox-regression was performed to assess the predictive value of volumetric parameters to predict transplant-free survival with and without Mayo risk score. Stratified analysis by Mayo risk score categories was performed to assess the discriminative value of volumes in the model. Prediction models were developed dependent of Mayo score, based on patients demographics, lab values and volumetric measures for both defined outcomes. Kaplan-Meier curves were depicted for different liver and spleen volumes. P value <0.05 was considered statistically significant. RESULTS In this cohort (age 43 ± 17 years; 59 % men) 51 % of patients had adverse outcome. Cox-regression analysis demonstrated statistically significant association between values of T, L, R, C, S, L/T, and C/T and outcome 1; and also statistically significant association between values C, S, and C/T and outcome 2. Prediction models included age, INR, total bilirubin, AST, variceal bleeding, S, and C for outcome 1 and age, INR, total bilirubin, AST, variceal bleeding, and S for outcome 2. CONCLUSIONS Based on our observational study, quantitative liver and spleen volumes may be associated with transplant-free survival in patients with PSC and may have the potential for predicting the outcome but this should be validated by randomized clinical trial studies.
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Affiliation(s)
- Pegah Khoshpouri
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD 21287, USA
| | - Maryam Ghadimi
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD 21287, USA
| | - Roya Rezvani Habibabadi
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD 21287, USA
| | - Mina Motaghi
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD 21287, USA
| | - Bharath Ambale Venkatesh
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD 21287, USA
| | - Mohammadreza Shaghaghi
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD 21287, USA
| | - Ankur Pandey
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD 21287, USA
| | - Bita Hazhirkarzar
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD 21287, USA
| | - Sanaz Ameli
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD 21287, USA
| | - Mounes Aliyari Ghasabeh
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD 21287, USA
| | - Pallavi Pandey
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD 21287, USA
| | - Ihab R Kamel
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD 21287, USA.
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23
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Trivedi PJ, Crothers H, Mytton J, Bosch S, Iqbal T, Ferguson J, Hirschfield GM. Effects of Primary Sclerosing Cholangitis on Risks of Cancer and Death in People With Inflammatory Bowel Disease, Based on Sex, Race, and Age. Gastroenterology 2020; 159:915-928. [PMID: 32445859 DOI: 10.1053/j.gastro.2020.05.049] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 05/05/2020] [Accepted: 05/11/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS There are insufficient population-level data on the effects of primary sclerosing cholangitis (PSC) in patients with inflammatory bowel disease (IBD). METHODS We identified incident cases of IBD, with PSC (PSC-IBD) and without, from April 2006 to April 2016 and collected data on outcomes through April 2019. We linked data from national health care registries maintained for all adults in England on hospital attendances, imaging and endoscopic evaluations, surgical procedures, cancer, and deaths. Our primary aim was to quantify the effects of developing PSC in patients with all subtypes of IBD and evaluate its effects on hepatopancreatobiliary disease, IBD-related outcomes, and all-cause mortality, according to sex, race, and age. RESULTS Over 10 years, we identified 284,560 incident cases of IBD nationwide; of these, 2588 patients developed PSC. In all, we captured 31,587 colectomies, 5608 colorectal cancers (CRCs) 6608 cholecystectomies, and 41,055 patient deaths. Development of PSC was associated with increased risk of death and CRC (hazard ratios [HRs], 3.20 and 2.43, respectively; P < .001) and a lower median age at CRC diagnosis (59 y vs 69 y without PSC; P < .001). Compared to patients with IBD alone, patients with PSC-IBD had a 4-fold higher risk of CRC if they received a diagnosis of IBD at an age younger than 40 years; there was no difference between groups for patients diagnosed with IBD at an age older than 60 years. Development of PSC also increased risks of cholangiocarcinoma (HR, 28.46), hepatocellular carcinoma (HR, 21.00), pancreatic cancer (HR, 5.26), and gallbladder cancer (HR, 9.19) (P < .001 for all). Risk of hepatopancreatobiliary cancer-related death was lower among patients with PSC-IBD who received annual imaging evaluations before their cancer diagnosis, compared to those who did not undergo imaging (HR, 0.43; P = .037). The greatest difference in mortality between the PSC-IBD alone group vs the IBD alone group was for patients younger than 40 years (incidence rate ratio >7), in contrast to those who received a diagnosis of IBD when older than 60 years (incidence rate ratio, <1.5). Among patients with PSC-IBD we observed 173 first liver transplants. Liver transplantation and PSC-related events accounted for approximately 75% of clinical events when patients received a diagnosis of PSC at an age younger than 40 years vs 31% of patients who received a diagnosis when older than 60 years (P < .001). African Caribbean heritage was associated with increased risks of liver transplantation or PSC-related death compared with white race (HR, 2.05; P < .001), whereas female sex was associated with reduced risk (HR, 0.74; P = .025). CONCLUSIONS In a 10-year, nationwide study, we confirmed that patients with PSC-IBD have increased risks of CRC, hepatopancreatobiliary cancers, and death compared to patients with IBD alone. In the PSC-IBD group, diagnosis of IBD at age younger than 40 years was associated with greater risks of CRC and all-cause mortality compared with diagnosis of IBD at older ages. Patients who receive a diagnosis of PSC at an age younger than 40 years, men, and patients of African Caribbean heritage have an increased incidence of PSC-related events.
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Affiliation(s)
- Palak J Trivedi
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, Birmingham, United Kingdom; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, United Kingdom.
| | - Hannah Crothers
- Department of Informatics, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, United Kingdom
| | - Jemma Mytton
- Department of Informatics, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, United Kingdom
| | - Sofie Bosch
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Tariq Iqbal
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, Birmingham, United Kingdom; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Department of Gastroenterology, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, United Kingdom
| | - James Ferguson
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, Birmingham, United Kingdom; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, United Kingdom
| | - Gideon M Hirschfield
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, Birmingham, United Kingdom; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Toronto Centre for Liver Disease, University Health Network and Department of Medicine, University of Toronto, Toronto, Canada.
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Abstract
PURPOSE OF REVIEW Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by progressive fibroinflammatory destruction of the intrahepatic and/or extrahepatic bile ducts. It is associated with a significantly increased risk of malignancy, particularly cholangiocarcinoma (CCA). In this review, we discuss what is currently known about the epidemiology of and risk factors for CCA in PSC as well as recent advances in its prevention, diagnosis, and surveillance. RECENT FINDINGS An area of major focus has been finding novel biomarkers (in serum, bile, and urine) for CCA. With the advancement of computing power, metabolomic and proteomic approaches, among other methods, may provide enhanced capability for differentiating between benign and malignant bile duct disease. Another area of focus has been the approach to CCA surveillance in PSC; a recent study has found that CCA surveillance in patients with PSC is associated with improved outcomes, including increased survival, thus advocating for its importance. SUMMARY Despite ongoing advancements in the study of PSC-associated CCA, early diagnosis of CCA remains difficult, treatment options are limited, and prognosis is often consequently poor. Continued research in the development of high-accuracy diagnostic tools, novel biomarkers, and surveillance techniques may help to increase the likelihood of diagnosing CCA at earlier stages, when therapeutic options have the highest likelihood of resulting in cure.
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Affiliation(s)
- Brian M Fung
- UCLA-Olive View Internal Medicine Residency Program
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, California, USA
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25
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van Erp LW, Cunningham M, Narasimman M, Ale Ali H, Jhaveri K, Drenth JPH, Janssen HLA, Levy C, Hirschfield GM, Hansen BE, Gulamhusein AF. Risk of gallbladder cancer in patients with primary sclerosing cholangitis and radiographically detected gallbladder polyps. Liver Int 2020; 40:382-392. [PMID: 31823479 DOI: 10.1111/liv.14326] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 11/15/2019] [Accepted: 12/08/2019] [Indexed: 01/09/2023]
Abstract
BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is associated with an increased risk of gallbladder cancer (GBC). Gallbladder polyps potentially harbour malignancy and thus international guidelines recommend prophylactic cholecystectomy for gallbladder polyps of any size in patients with PSC. To best inform patient care we sought to quantify the malignant risk of gallbladder polyps in patients with PSC. METHODS A retrospective cohort study of patients followed in secondary and tertiary care settings in two large PSC clinics in North America was performed. RESULTS In total, 453 patients were included with a median (IQR) follow-up time of 7.7 (4.1-12) years. A gallbladder polyp was radiographically detected in 16% (n = 71) with median size (range) of 4 (2-18) mm. In this group, post-cholecystectomy histology (n = 17) reported benign or no polyp in 77% (n = 13), dysplasia in 5.9% (n = 1) and malignancy in 18% (n = 3). The GBC rate was 8.8 (95% CI 1.8-25.7) per 1000 person-years in patients with a radiographically detected gallbladder polyp. GBC was associated with polyps >10 mm, interval growth or mass-like lesions on pre-operative imaging. In patients who did not have cholecystectomy (n = 50), the polyp was only transiently seen in 80% (n = 40), remained stable or decreased in size in 10% (n = 5) and increased in size in 6% (n = 3). The majority of gallbladder polyps did not show significant growth over time (0.041 mm/year [95% CI -0.017 to 0.249]). CONCLUSIONS Most gallbladder polyps in patients with PSC are benign. Short-term surveillance imaging may be considered prior to recommending immediate cholecystectomy in patients with PSC without high-risk imaging features.
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Affiliation(s)
- Liselot W van Erp
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, ON, Canada.,Department of Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Morven Cunningham
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, ON, Canada
| | | | - Hamideh Ale Ali
- Department of Radiology, Toronto General Hospital, Toronto, ON, Canada
| | - Kartik Jhaveri
- Department of Radiology, Toronto General Hospital, Toronto, ON, Canada
| | - Joost P H Drenth
- Department of Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, ON, Canada
| | - Cynthia Levy
- Division of Hepatology, University of Miami, Miami, FL, USA
| | | | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, ON, Canada.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada
| | - Aliya F Gulamhusein
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, ON, Canada
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26
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Bowlus CL, Lim JK, Lindor KD. AGA Clinical Practice Update on Surveillance for Hepatobiliary Cancers in Patients With Primary Sclerosing Cholangitis: Expert Review. Clin Gastroenterol Hepatol 2019; 17:2416-2422. [PMID: 31306801 DOI: 10.1016/j.cgh.2019.07.011] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 06/19/2019] [Accepted: 07/08/2019] [Indexed: 02/07/2023]
Abstract
DESCRIPTION The purpose of this clinical practice update is to define key principles in the surveillance of hepatobiliary cancers including cholangiocarcinoma, gallbladder adenocarcinoma, and hepatocellular carcinoma in patients with primary sclerosing cholangitis (PSC). METHODS The recommendations outlined in this expert review are based on available published evidence including observational studies and systematic reviews, and incorporates expert opinion where applicable. BEST PRACTICE ADVICE 1: Surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with PSC regardless of disease stage, especially in the first year after diagnosis and in patients with ulcerative colitis and those diagnosed at an older age. BEST PRACTICE ADVICE 2: Surveillance for cholangiocarcinoma and gallbladder cancer should include imaging by ultrasound, computed tomography, or magnetic resonance imaging, with or without serum carbohydrate antigen 19-9, every 6 to 12 months BEST PRACTICE ADVICE 3: Endoscopic retrograde cholangiopancreatography with brush cytology should not be used routinely for surveillance of cholangiocarcinomas in PSC. BEST PRACTICE ADVICE 4: Cholangiocarcinomas should be investigated by endoscopic retrograde cholangiopancreatography with brush cytology with or without fluorescence in situ hybridization analysis and/or cholangioscopy in PSC patients with worsening clinical symptoms, worsening cholestasis, or a dominant stricture. BEST PRACTICE ADVICE 5: Fine-needle aspiration of perihilar biliary strictures should be used with caution in PSC patients considered to be liver transplant candidates because of concerns for tumor seeding if the lesion is a cholangiocarcinoma. BEST PRACTICE ADVICE 6: Surveillance for cholangiocarcinoma should not be performed in PSC patients with small-duct PSCs or those younger than age 20. BEST PRACTICE ADVICE 7: The decision to perform a cholecystectomy in PSC patients with a gallbladder polyp should be based on the size and growth of the polyp, as well as the clinical status of the patient, with the knowledge of the increased risk of gallbladder cancer in polyps greater than 8 mm. BEST PRACTICE ADVICE 8: Surveillance for hepatocellular carcinoma in PSC patients with cirrhosis should include ultrasound, computed tomography, or magnetic resonance imaging, with or without α-fetoprotein every 6 months.
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Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Davis, California.
| | - Joseph K Lim
- Section of Digestive Diseases, Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona; Arizona State University, Phoenix, Arizona
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27
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Chascsa DM, Lindor KD. Cancer risk, screening and surveillance in primary sclerosing cholangitis. MINERVA GASTROENTERO 2019; 65:214-228. [PMID: 31220911 DOI: 10.23736/s1121-421x.19.02586-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Primary sclerosing cholangitis (PSC) is a rare chronic inflammatory condition mainly of the large bile ducts, affecting predominantly young men, and is associated with the presence of inflammatory bowel disease. There is no known cure for PSC, which progresses to cirrhosis or death over 10-20 years. Hepatobiliary malignancy, especially cholangiocarcinoma, is a feared complication associated with poor overall survival. Screening and surveillance appear to improve overall outcomes. To capture as many relevant studies, broad search criteria were employed within the PubMed database. Given the high prevalence of IBD and its own associations with the development of malignancy two separate search strategies were employed. Results were filtered by English language. The first search identified the risks, epidemiological factors and surveillance strategies for patients with PSC at risk for developing malignancy. MeSH terms included: cholangitis, sclerosing, digestive system neoplasms, liver neoplasms, biliary tract neoplasms, cholangiocarcinoma, gallbladder neoplasms, colonic neoplasms, rectal neoplasms, or pancreatic neoplasms, risk factors, risk, surveillance, epidemiology and screen. The second included inflammatory bowel diseases, Crohn's, or colitis, and assessed for additional malignancies such as lymphoma and skin neoplasms. A total of 288 results returned with 21 duplicates; 267 remaining abstracts were assessed for relevance for inclusion by the authors. Patients with PSC show significantly higher than average risk for the development of hepatobiliary and colonic malignancies including cholangiocarcinoma, gallbladder carcinoma and colorectal carcinoma. Yearly ultrasound surveillance followed with more definitive cross-sectional imaging is prudent to arrive in a timely diagnosis of carcinoma, reducing morbidity and mortality.
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Affiliation(s)
- David M Chascsa
- Departments of Gastroenterology and Hepatology and Transplant Center, Mayo Clinic, Phoenix, AZ, USA -
| | - Keith D Lindor
- Office of University Provost, Arizona State University, Phoenix, AZ, USA
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28
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Khoshpouri P, Hazhirkarzar B, Ameli S, Pandey A, Ghadimi M, Rezvani Habibabadi R, Aliyari Ghasabeh M, Pandey P, Shaghaghi M, Kamel I. Quantitative spleen and liver volume changes predict survival of patients with primary sclerosing cholangitis. Clin Radiol 2019; 74:734.e13-734.e20. [DOI: 10.1016/j.crad.2019.05.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 05/20/2019] [Indexed: 01/01/2023]
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Chapman MH, Thorburn D, Hirschfield GM, Webster GGJ, Rushbrook SM, Alexander G, Collier J, Dyson JK, Jones DE, Patanwala I, Thain C, Walmsley M, Pereira SP. British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut 2019; 68:1356-1378. [PMID: 31154395 PMCID: PMC6691863 DOI: 10.1136/gutjnl-2018-317993] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 02/21/2019] [Accepted: 03/24/2019] [Indexed: 12/11/2022]
Abstract
These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.
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Affiliation(s)
- Michael Huw Chapman
- GI Division, UCL Hospitals NHS Foundation Trust, London, UK
- Liver Unit, Royal Free London NHS Foundation Trust, London, UK
| | | | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, University Health Network and University of Toronto, Toronto, Canada
| | | | - Simon M Rushbrook
- Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK
| | | | | | - Jessica K Dyson
- Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - David Ej Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - Imran Patanwala
- Gastroenterology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
- University of Liverpool, Liverpool, UK
| | | | | | - Stephen P Pereira
- GI Division, UCL Hospitals NHS Foundation Trust, London, UK
- Institute for Liver & Digestive Health, University College London, London, UK
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30
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Lleo A, de Boer YS, Liberal R, Colombo M. The risk of liver cancer in autoimmune liver diseases. Ther Adv Med Oncol 2019; 11:1758835919861914. [PMID: 31320937 PMCID: PMC6628541 DOI: 10.1177/1758835919861914] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 06/13/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the dominant primary malignancy of the liver, has almost invariably a fatal outcome that can be averted only by early diagnosis and treatment. While the close association of HCC with chronic viral hepatitis and alcohol abuse has impacted favourably on screening and treatment of this deadly tumour, at the same time it has long obscured the etiologic role of autoimmune liver diseases. Recently, a systematic analysis of 25 published cohorts disclosed a 3.1 × 1000 patients/year incidence of HCC in autoimmune hepatitis patients that tripled in those with cirrhosis. HCC is also a sequela of primary biliary cholangitis, where the incidence is more relevant in males, those with advanced liver disease and nonresponders to ursodeoxycholic acid therapy. Cholangiocarcinoma (CCA), the second ranking primary cancer of the liver, is also on the rise with its intrahepatic pattern, in part reflecting an association with chronic liver diseases of diverse aetiology. In the USA and northern Europe, perihilar CCA is a frequent complication of primary sclerosing cholangitis, a cholestatic disorder thought to be immune mediated. International Guidelines clearly recommend HCC screening with abdominal ultrasonography every 6 months in autoimmune cirrhotic patients. While surveillance of patients with autoimmune liver disorders who are at risk of HCC affects both early diagnosis and radical therapy of this tumour, this is not the case for CCA, where early diagnosis is challenged by the lack of sensitive and accurate tests for screening.
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Affiliation(s)
- Ana Lleo
- Department of Biomedical Sciences, Humanitas
University, Division of Internal Medicine and Hepatology, Department of
Gastroenterology, Humanitas Clinical and Research Center IRCCS, Via A.
Manzoni 56, 20089 Rozzano (MI), Italy
| | - Ynto S. de Boer
- Department of Gastroenterology and Hepatology,
Amsterdam University Medical Centers - VU University Medical Center, The
Netherlands
| | | | - Massimo Colombo
- Humanitas Clinical and Research Center, IRCCS,
Rozzano, Italy
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31
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Malik A, Kardashian AA, Zakharia K, Bowlus CL, Tabibian JH. Preventative care in cholestatic liver disease: Pearls for the specialist and subspecialist. LIVER RESEARCH (BEIJING, CHINA) 2019; 3:118-127. [PMID: 32042471 PMCID: PMC7008979 DOI: 10.1016/j.livres.2019.04.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cholestatic liver diseases (CLDs) encompass a variety of disorders of abnormal bile formation and/or flow. CLDs often lead to progressive hepatic insult and injury and following the development of cirrhosis and associated complications. Many such complications are clinically silent until they manifest with severe sequelae, including but not limited to life-altering symptoms, metabolic disturbances, cirrhosis, and hepatobiliary diseases as well as other malignancies. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most common CLDs, and both relate to mutual as well as unique complications. This review provides an overview of PSC and PBC, with a focus on preventive measures aimed to reduce the incidence and severity of disease-related complications.
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Affiliation(s)
- Adnan Malik
- Department of Public Health and Business Administration, The University of Alabama at Birmingham, Birmingham, AL, USA
- Department of Internal Medicine, Beaumont Hospital, Dearborn, MI, USA
| | - Ani A. Kardashian
- University of California Los Angeles Gastroenterology Fellowship Training Program, Vatche and Tamar Manoukian Division of Digestive Diseases, Los Angeles, CA, USA
| | - Kais Zakharia
- Division of Gastroenterology and Hepatology, University of Iowa, Iowa, IA, USA
| | - Christopher L. Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA
| | - James H. Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-University of California Los Angeles Medical Center, Sylmar, CA, USA
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Abstract
PURPOSE OF REVIEW To discuss current knowledge and recent findings regarding the epidemiology of hepatocellular carcinoma (HCC) in the USA. RECENT FINDING The US incidence rate of HCC is increasing, although the pace may have somewhat slowed since 2010. In 2012, incidence rates of HCC in Hispanics surpassed those of Asians. The recent epidemiological changes in major risk factors for HCC include increasing hepatitis C virus post-sustained virologic response, suppressed hepatitis B virus on nucleoside analogues, and alcoholic and non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease has the greatest proportion of the burden of the main risk factors for HCC in the USA, followed by alcoholic liver disease, and hepatitis C virus and hepatitis B virus infections. This review focuses on current knowledge regarding the recent epidemiological trends in HCC, with an emphasis on future directions.
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Fung BM, Lindor KD, Tabibian JH. Cancer risk in primary sclerosing cholangitis: Epidemiology, prevention, and surveillance strategies. World J Gastroenterol 2019; 25:659-671. [PMID: 30783370 PMCID: PMC6378537 DOI: 10.3748/wjg.v25.i6.659] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 01/10/2019] [Accepted: 01/14/2019] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by progressive fibroinflammatory destruction of the intra- and/or extrahepatic biliary ducts. While its features and disease course can be variable, most patients with PSC have concurrent inflammatory bowel disease and will eventually develop liver cirrhosis and end-stage liver disease, with liver transplantation representing the only potentially curative option. Importantly, PSC is associated with a significantly increased risk of malignancy compared to the general population, mainly cholangiocarcinoma, gallbladder carcinoma, hepatocellular carcinoma, and colorectal cancer, with nearly 50% of deaths in patients with PSC being due to cancer. Therefore, robust surveillance strategies are needed, though uncertainty remains regarding how to best do so. In this review, we discuss the epidemiology, prevention, and surveillance of cancers in patients with PSC. Where evidence is limited, we present pragmatic approaches based on currently available data and expert opinion.
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Affiliation(s)
- Brian M Fung
- UCLA-Olive View Internal Medicine Residency Program, Olive View-UCLA Medical Center, Sylmar, CA 91342, United States
| | - Keith D Lindor
- Office of the University Provost, Arizona State University, Phoenix, AZ 85004, United States
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA 91342, United States
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Mertz A, Nguyen NA, Katsanos KH, Kwok RM. Primary sclerosing cholangitis and inflammatory bowel disease comorbidity: an update of the evidence. Ann Gastroenterol 2019; 32:124-133. [PMID: 30837784 PMCID: PMC6394256 DOI: 10.20524/aog.2019.0344] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 11/29/2018] [Indexed: 12/12/2022] Open
Abstract
Comorbid primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) represent a unique disease phenotype with a different risk profile than PSC or IBD alone. While the pathogenetic mechanisms behind both diseases remain unclear, recent studies have targeted several immune-mediated pathways in an attempt to find a potential therapeutic target. Patients with PSC-associated IBD typically exhibit pancolitis with a right-to-left intestinal inflammatory gradient associated with a greater incidence of backwash ileitis and rectal sparing. Although there is an increased incidence of pancolitis in this population, bowel symptoms tend to be less significant than in IBD alone. Likewise, the degree of inflammation and symptoms of PSC-associated IBD are characteristically less clinically significant. Despite the relatively quiescent clinical presentation of PSC-associated IBD, there is an increased risk for colorectal and hepatobiliary malignancy making vigilance for malignancy essential.
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Affiliation(s)
- Andrew Mertz
- Department of Internal Medicine (Andrew Mertz), Walter Reed National Military Medical Center Bethesda, MD, USA
| | - Nhu An Nguyen
- Gastroenterology (Nhu An Nguyen, Ryan M. Kwok), Walter Reed National Military Medical Center Bethesda, MD, USA
| | - Konstantinos H Katsanos
- Gastroenterology, Medical School and University Hospital of Ioannina, Greece (Konstantinos H. Katsanos)
| | - Ryan M Kwok
- Gastroenterology (Nhu An Nguyen, Ryan M. Kwok), Walter Reed National Military Medical Center Bethesda, MD, USA
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35
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McGee EE, Castro FA, Engels EA, Freedman ND, Pfeiffer RM, Nogueira L, Stolzenberg-Solomon R, McGlynn KA, Hemminki K, Koshiol J. Associations between autoimmune conditions and hepatobiliary cancer risk among elderly US adults. Int J Cancer 2018; 144:707-717. [PMID: 30155920 DOI: 10.1002/ijc.31835] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 07/07/2018] [Accepted: 07/25/2018] [Indexed: 12/17/2022]
Abstract
Growing evidence suggests that people with autoimmune conditions may be at increased risk of hepatobiliary tumors. In the present study, we evaluated associations between autoimmune conditions and hepatobiliary cancers among adults aged ≥66 in the United States. We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data (1992-2013) to conduct a population-based, case-control study. Cases (n = 32,443) had primary hepatobiliary cancer. Controls (n = 200,000) were randomly selected, cancer-free adults frequency-matched to cases by sex, age and year of selection. Using multivariable logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for associations with 39 autoimmune conditions identified via Medicare claims. We also conducted separate analyses for diagnoses obtained via inpatient versus outpatient claims. Sixteen conditions were associated with at least one hepatobiliary cancer. The strongest risk estimates were for primary biliary cholangitis with hepatocellular carcinoma (OR: 31.33 [95% CI: 23.63-41.56]) and primary sclerosing cholangitis with intrahepatic cholangiocarcinoma (7.53 [5.73-10.57]), extrahepatic cholangiocarcinoma (5.59 [4.03-7.75]), gallbladder cancer (2.06 [1.27-3.33]) and ampulla of Vater cancer (6.29 [4.29-9.22]). Associations with hepatobiliary-related conditions as a group were observed across nearly all cancer sites (ORs ranging from 4.53 [95% CI: 3.30-6.21] for extrahepatic cholangiocarcinoma to 7.18 [5.94-8.67] for hepatocellular carcinoma). Restricting to autoimmune conditions diagnosed via inpatient claims, 6 conditions remained associated with at least one hepatobiliary cancer, and several risk estimates increased. In the outpatient restricted analysis, 12 conditions remained associated. Multiple autoimmune conditions are associated with hepatobiliary cancer risk in the US Medicare population, supporting a shared immuno-inflammatory etiology to these cancers.
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Affiliation(s)
- Emma E McGee
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
| | - Felipe A Castro
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.,Real World Data Science (RWD-S) Oncology, Roche, Basel, Switzerland
| | - Eric A Engels
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
| | - Neal D Freedman
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
| | - Ruth M Pfeiffer
- Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
| | - Leticia Nogueira
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.,American Cancer Society, Atlanta, GA
| | - Rachael Stolzenberg-Solomon
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
| | - Katherine A McGlynn
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
| | - Kari Hemminki
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Center for Primary Health Care Research, Lund University, Malmö, Sweden
| | - Jill Koshiol
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
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36
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Khoshpouri P, Ameli S, Ghasabeh MA, Pandey A, Zarghampour M, Varzaneh FN, Jacob A, Pandey P, Luo Y, Kamel IR. Correlation between quantitative liver and spleen volumes and disease severity in primary sclerosing cholangitis as determined by Mayo risk score. Eur J Radiol 2018; 108:254-260. [PMID: 30396665 DOI: 10.1016/j.ejrad.2018.10.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 08/29/2018] [Accepted: 10/05/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To correlate total and lobar liver and spleen volume with disease severity in primary sclerosing cholangitis (PSC) as determined by Mayo risk score. METHODS This HIPAA-compliant single center retrospective study included 147 PSC patients with available imaging studies (MRCP/CT) and laboratory data between January 2003 and January 2018. Total and lobar (right, left and caudate) liver volume and spleen volume were measured. ANOVA test was performed to assess the differences in volumes between low, intermediate and high-risk groups (Mayo risk score <0, >0 and <2, >2, respectively). Correlations between volumes and Mayo risk score were calculated. ROC analysis was performed to assess the accuracy of the variable with the strongest correlation to PSC severity to predict Mayo risk score. P value <0.05 was considered statistically significant. RESULTS The mean age of this cohort was 45 ± 17 years; 58% were men. Absolute volumes of left lobe, caudate and spleen and volume ratios of left lobe and caudate to total liver volume of the high-risk group were significantly higher compared to those of low and intermediate risk groups (p < 0.05). Left lobe to total liver volume ratio had the highest correlation to Mayo risk score (Pearson correlation coefficient 0.61, p < 0.05) and on ROC analysis it had 84.4% accuracy in detecting high-risk PSC. CONCLUSIONS In this single institution large cohort study, the left lobe to total liver volume ratio was the best quantifiable volumetric biomarker to correlate with severity of PSC as identified by Mayo risk score.
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Affiliation(s)
- Pegah Khoshpouri
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD, 21287, USA
| | - Sanaz Ameli
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD, 21287, USA
| | - Mounes Aliyari Ghasabeh
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD, 21287, USA
| | - Ankur Pandey
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD, 21287, USA
| | - Manijeh Zarghampour
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD, 21287, USA
| | - Farnaz Najmi Varzaneh
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD, 21287, USA
| | - Angela Jacob
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD, 21287, USA
| | - Pallavi Pandey
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD, 21287, USA
| | - Yan Luo
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD, 21287, USA
| | - Ihab R Kamel
- Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St, Room 143, Baltimore, MD, 21287, USA.
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37
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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: 273] [Impact Index Per Article: 39.0] [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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38
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Christen U, Hintermann E. Autoantibodies in Autoimmune Hepatitis: Can Epitopes Tell Us about the Etiology of the Disease? Front Immunol 2018; 9:163. [PMID: 29503645 PMCID: PMC5820307 DOI: 10.3389/fimmu.2018.00163] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/18/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are serious autoimmune liver diseases that are characterized by a progressive destruction of the liver parenchyma and/or the hepatic bile ducts and the development of chronic fibrosis. Left untreated autoimmune liver diseases are often life-threatening, and patients require a liver transplantation to survive. Thus, an early and reliable diagnosis is paramount for the initiation of a proper therapy with immunosuppressive and/or anticholelithic drugs. Besides the analysis of liver biopsies and serum markers indicating liver damage, the screening for specific autoantibodies is an indispensable tool for the diagnosis of autoimmune liver diseases. Such liver autoantigen-specific antibodies might be involved in the disease pathogenesis, and their epitope specificity may give some insight into the etiology of the disease. Here, we will mainly focus on the generation and specificity of autoantibodies in AIH patients. In addition, we will review data from animal models that aim toward a better understanding of the origins and pathogenicity of such autoantibodies.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
| | - Edith Hintermann
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
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39
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Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis - a comprehensive review. J Hepatol 2017; 67:1298-1323. [PMID: 28802875 DOI: 10.1016/j.jhep.2017.07.022] [Citation(s) in RCA: 550] [Impact Index Per Article: 68.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Revised: 07/15/2017] [Accepted: 07/22/2017] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a rare disorder characterised by multi-focal bile duct strictures and progressive liver disease. Inflammatory bowel disease is usually present and there is a high risk of cholangiocarcinoma and colorectal cancer. Most patients ultimately require liver transplantation, after which disease recurrence may occur. With limited therapeutic options and a lack of proven surveillance strategies, patients currently have significant unmet needs. In the present seminar, we provide a comprehensive review of the status of the field. We emphasise developments related to patient stratification and disease behaviour, and provide an overview of management options from a practical, patient-centered perspective. We survey advances made in the understanding of PSC pathogenesis and summarise the ongoing efforts to develop an effective therapy based on these insights.
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Affiliation(s)
- Tom H Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Douglas Thorburn
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, UK; Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
| | - Mette Vesterhus
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway
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40
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Gossard AA, Gores GJ. Primary Sclerosing Cholangitis: What the Gastroenterologist and Hepatologist Needs to Know. Clin Liver Dis 2017; 21:725-737. [PMID: 28987259 DOI: 10.1016/j.cld.2017.06.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, idiopathic biliary tract disease characterized by segmental strictures. The disease is progressive with no proven treatments and may eventually lead to cirrhosis and end-stage liver disease. Abrupt changes in liver biochemistries, pain, and/or cholangitis may suggest a dominant stricture amenable to endoscopic therapy or the development of cholangiocarcinoma. Patients with PSC are at increased risk of cholangiocarcinoma. There is a strong association with inflammatory bowel disease, and an associated increased risk of colorectal cancer. Colonoscopy every 1 to 2 years is appropriate.
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Affiliation(s)
- Andrea A Gossard
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55901, USA.
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55901, USA
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41
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Chung BK, Karlsen TH, Folseraas T. Cholangiocytes in the pathogenesis of primary sclerosing cholangitis and development of cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1390-1400. [PMID: 28844951 DOI: 10.1016/j.bbadis.2017.08.020] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 08/16/2017] [Accepted: 08/21/2017] [Indexed: 12/15/2022]
Abstract
Primary sclerosing cholangitis (PSC) is an idiopathic cholangiopathy strongly associated with inflammatory bowel disease (IBD) and characterized by cholestasis, chronic immune infiltration and progressive fibrosis of the intrahepatic and extrahepatic bile ducts. PSC confers a high risk of cholangiocarcinoma (CCA) with PSC-CCA representing the leading cause of PSC-associated mortality. PSC-CCA is derived from cholangiocytes and associated progenitor cells - a heterogeneous group of dynamic epithelial cells lining the biliary tree that modulate the composition and volume of bile production by the liver. Infection, inflammation and cholestasis can trigger cholangiocyte activation leading to an increased expression of adhesion and antigen-presenting molecules as well as the release of various inflammatory and fibrogenic mediators. As a result, activated cholangiocytes engage in a myriad of cellular processes, including hepatocellular proliferation, apoptosis, angiogenesis and fibrosis. Cholangiocytes can also regulate the recruitment of immune cells, mesenchymal cells, and endothelial cells that participate in tissue repair and destruction in settings of persistent inflammation. In PSC, the role of cholangiocytes and the mechanisms governing their transformation to PSC-CCA are unclear however localization of disease suggests that cholangiocytes are a key target and potential regulator of hepatobiliary immunity, fibrogenesis and tumorigenesis. Herein, we summarize mechanisms of cholangiocyte activation in PSC and highlight new insights into disease pathways that may contribute to the development of PSC-CCA. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Affiliation(s)
- Brian K Chung
- Centre for Liver Research and NIHR Birmingham Inflammation Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
| | - Tom Hemming Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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42
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Horsley-Silva JL, Rodriguez EA, Franco DL, Lindor KD. An update on cancer risk and surveillance in primary sclerosing cholangitis. Liver Int 2017; 37:1103-1109. [PMID: 28028930 DOI: 10.1111/liv.13354] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 12/20/2016] [Indexed: 02/13/2023]
Abstract
Malignancy represents substantial morbidity and mortality in patients with primary sclerosing cholangitis (PSC). This subset of patients has been proven to be at increased risk for developing cholangiocarcinoma, gallbladder carcinoma and colorectal cancer in those with overlapping inflammatory bowel disease. Herein, we review the prevalence of these malignancies and recommend screening tools and current knowledge to reduce the disease burden in this population. Cholangiocarcinoma is the most dominant malignancy affecting PSC patients, with a lifetime risk ranging from 5% to 20%. We advocate for serial US or MRI/MRCP and CA 19-9 to screen for cholangiocarcinoma. Gallbladder cancer has a lifetime risk around 2% in this population and we agree with annual imaging for lesions as recommended by national guidelines. Patients with PSC and concomitant IBD are at increased risk of colorectal carcinoma from time of diagnosis and therefore should likely undergo annual surveillance. The low rates of hepatocellular cancer and pancreatic cancer indicate surveillance for these malignancies is less advantageous.
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Affiliation(s)
| | | | - Diana L Franco
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA.,College of Health Solutions, Arizona State University, Phoenix, AZ, USA
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43
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Tansel A, Katz LH, El-Serag HB, Thrift AP, Parepally M, Shakhatreh MH, Kanwal F. Incidence and Determinants of Hepatocellular Carcinoma in Autoimmune Hepatitis: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2017; 15:1207-1217.e4. [PMID: 28215616 PMCID: PMC5522646 DOI: 10.1016/j.cgh.2017.02.006] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 01/31/2017] [Accepted: 02/06/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH) is unclear. We conducted a systematic review and meta-analysis of the incidence of HCC and associated risk factors among patients with AIH. METHODS We searched PubMed, Embase, and reference lists from relevant articles through June 2016 to identify cohort studies that examined the incidence of HCC in patients with AIH. We used random effects models to estimate pooled incidence rates overall and in subgroup of patients with cirrhosis. The between-study heterogeneity was assessed using I2 statistic. RESULTS A total of 25 studies (20 papers and 5 abstracts), including 6528 patients, met the eligibility criteria. The median cohort size was 170 patients with AIH (range, 25-1721 patients), followed for a median of 8.0 years (range, 3.3-16.0 years). The pooled incidence rate for HCC in patients with AIH was 3.06 per 1000 patient-years (95% confidence interval, 2.22-4.23; I2 = 51.5%; P = .002). The pooled incidence of HCC in patients with cirrhosis at AIH diagnosis was 10.07 per 1000 patient-years (95% confidence interval, 6.89-14.70; I2 = 48.8%; P = .015). In addition, 92 of 93 patients who had HCC had evidence of cirrhosis before or at the time of their HCC diagnosis. The risk of HCC seems to be lower in patients with AIH and cirrhosis than that reported for patients with cirrhosis from hepatitis B, hepatitis C, or primary biliary cholangitis. CONCLUSIONS Based on the increased risked of HCC shown in this meta-analysis, there may be a role for HCC surveillance in patients with AIH and cirrhosis.
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Affiliation(s)
- Aylin Tansel
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas.
| | - Lior H Katz
- The Department of Gastroenterology, Sheba Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Hashomer, Israel
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Aaron P Thrift
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Mayur Parepally
- Division of Gastroenterology and Nutrition, Department of Medicine, Loyola University Medical Center, Chicago, Illinois
| | - Mohammad H Shakhatreh
- Section of Gastroenterology and Hepatology, Virginia Tech Carilion School of Medicine and Research Institute, Roanoke, Virginia
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
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44
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Weismüller TJ, Trivedi PJ, Bergquist A, Imam M, Lenzen H, Ponsioen CY, Holm K, Gotthardt D, Färkkilä MA, Marschall HU, Thorburn D, Weersma RK, Fevery J, Mueller T, Chazouillères O, Schulze K, Lazaridis KN, Almer S, Pereira SP, Levy C, Mason A, Naess S, Bowlus CL, Floreani A, Halilbasic E, Yimam KK, Milkiewicz P, Beuers U, Huynh DK, Pares A, Manser CN, Dalekos GN, Eksteen B, Invernizzi P, Berg CP, Kirchner GI, Sarrazin C, Zimmer V, Fabris L, Braun F, Marzioni M, Juran BD, Said K, Rupp C, Jokelainen K, Benito de Valle M, Saffioti F, Cheung A, Trauner M, Schramm C, Chapman RW, Karlsen TH, Schrumpf E, Strassburg CP, Manns MP, Lindor KD, Hirschfield GM, Hansen BE, Boberg KM. Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis. Gastroenterology 2017; 152:1975-1984.e8. [PMID: 28274849 PMCID: PMC5546611 DOI: 10.1053/j.gastro.2017.02.038] [Citation(s) in RCA: 356] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 01/09/2017] [Accepted: 02/28/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 41-50 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P < .001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn's disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002). CONCLUSIONS In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients with PSC and select patients for clinical trials.
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Affiliation(s)
- Tobias J Weismüller
- Department of Internal Medicine I, University of Bonn, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Palak J Trivedi
- National Institute for Health Research (NIHR) Birmingham, Liver Biomedical Research Centre (BRC), University of Birmingham, United Kingdom; Liver Unit, University Hospitals Birmingham Queen Elizabeth, United Kingdom
| | - Annika Bergquist
- Center for Digestive Diseases, Division of Hepatology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
| | - Mohamad Imam
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Department of Internal Medicine, University of North Dakota, Grand Forks, North Dakota
| | - Henrike Lenzen
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Kristian Holm
- Norwegian PSC Research Center and Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Daniel Gotthardt
- Department of Gastroenterology, Infectious Diseases and Intoxications, University Hospital Heidelberg, Heidelberg, Germany
| | - Martti A Färkkilä
- Helsinki University, Clinic of Gastroenterology, Helsinki University Hospital, Helsinki, Finland
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Douglas Thorburn
- The Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center, Groningen, The Netherlands
| | - Johan Fevery
- Department of Hepatology, University Hospital Gasthuisberg, Leuven, Belgium
| | - Tobias Mueller
- Department of Internal Medicine, Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Olivier Chazouillères
- Service d'Hépatologie, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Pierre et Marie Curie, Paris, France
| | - Kornelius Schulze
- 1st Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | | | - Sven Almer
- Division of Gastroenterology and Hepatology, Linköping University, Linköping; Sweden
| | - Stephen P Pereira
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Cynthia Levy
- Division of Hepatology, University of Miami, Miami, Florida
| | - Andrew Mason
- Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, AB, Canada
| | - Sigrid Naess
- Norwegian PSC Research Center and Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis, Davis, California
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Kidist K Yimam
- Department of Hepatology and Liver Transplantation, California Pacific Medical Center, San Francisco, California
| | - Piotr Milkiewicz
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, Szczecin, Poland; Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Dep K Huynh
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA, Australia
| | - Albert Pares
- Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Spain
| | - Christine N Manser
- Division for Gastroenterology and Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece
| | - Bertus Eksteen
- University of Calgary, Snyder Institute for Chronic Diseases, Alberta, AB, Canada
| | - Pietro Invernizzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Christoph P Berg
- Department of Gastroenterology, Hepatology, and Infectiology, Medical Clinic, University of Tübingen, Germany
| | - Gabi I Kirchner
- Department of Internal Medicine 1, University Hospital of Regensburg, Regensburg, Germany
| | - Christoph Sarrazin
- Department of Internal Medicine 1, Johann Wolfgang Goethe-University Hospital, Frankfurt, Germany
| | - Vincent Zimmer
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
| | - Felix Braun
- Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, Campus Kiel, UKSH, Kiel, Germany
| | - Marco Marzioni
- Clinic of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy
| | - Brian D Juran
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Karouk Said
- Center for Digestive Diseases, Division of Hepatology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
| | - Christian Rupp
- Department of Gastroenterology, Infectious Diseases and Intoxications, University Hospital Heidelberg, Heidelberg, Germany
| | - Kalle Jokelainen
- Helsinki University, Clinic of Gastroenterology, Helsinki University Hospital, Helsinki, Finland
| | - Maria Benito de Valle
- Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Francesca Saffioti
- The Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | - Angela Cheung
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Christoph Schramm
- 1st Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Roger W Chapman
- Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom; Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, United Kingdom
| | - Tom H Karlsen
- Norwegian PSC Research Center and Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Erik Schrumpf
- Norwegian PSC Research Center and Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | | | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona; Arizona State University, College of Health Solutions, Phoenix, Arizona
| | - Gideon M Hirschfield
- National Institute for Health Research (NIHR) Birmingham, Liver Biomedical Research Centre (BRC), University of Birmingham, United Kingdom
| | - Bettina E Hansen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada; Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Canada
| | - Kirsten M Boberg
- Norwegian PSC Research Center and Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
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Risk of cholangiocarcinoma in patients with primary sclerosing cholangitis: diagnosis and surveillance. Curr Opin Gastroenterol 2017; 33:78-84. [PMID: 28146445 DOI: 10.1097/mog.0000000000000335] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Primary sclerosing cholangitis (PSC) is associated with an increased risk of hepatobiliary and extrahepatic malignancy. Particularly the risk of cholangiocarcinoma (CCA) is greatly increased. To provide potentially curative treatments for affected patients an early diagnosis of CCA is crucial. We here review the current advances with respect to CCA diagnosis and surveillance and discuss a rational approach on how to perform surveillance of CCA in PSC patients. RECENT FINDINGS Given the shortcomings of the current modalities for the surveillance and diagnosis of CCA in PSC, recent studies have focused on novel biomarkers for CCA. These include serum biomarkers (e.g., circulating angiopoeitin-2, cytokeratin-19 fragments, and antiglycoprotein 2 IgA autoantibodies, microRNA) as well as proteomics obtained from urine and/or bile. Novel approaches that may enhance the diagnostic value of brush cytology in future include the optimization of fluorescence in situ hybridization probes and the assessment of genetic aberrations. In addition, studies on advanced techniques (e.g., single-operator cholangioscopy and probe-based confocal laser endomicroscopy) have shown promising results with respect to CCA detection. SUMMARY Despite recent advances in the diagnosis of CCA in PSC, the detection of early-stage CCA remains difficult. A better understanding of CCA pathogenesis and large prospective studies on novel biomarkers and techniques are required to timely diagnose CCA in the future.
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No Evidence That Azathioprine Increases Risk of Cholangiocarcinoma in Patients With Primary Sclerosing Cholangitis. Clin Gastroenterol Hepatol 2016; 14:1806-1812. [PMID: 27521513 DOI: 10.1016/j.cgh.2016.07.032] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 07/11/2016] [Accepted: 07/26/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with primary sclerosing cholangitis (PSC) are at increased risk for developing cholangiocarcinoma (CCA). Patients with PSC also can have inflammatory bowel diseases (IBDs) or features of autoimmune hepatitis (AIH), and therefore are treated with azathioprine. Azathioprine has been associated with an increased risk for malignancy, therefore we investigated whether azathioprine use affects the risk of CCA in persons with PSC. METHODS We performed a retrospective study of well-defined patients with PSC using data collected from 3 large-volume, tertiary care centers in Germany and Norway. We analyzed data from 638 patients (70% men; 5900 patient-years of follow-up evaluation); 91 patients had received azathioprine therapy (considered to be effective at 90 days after first intake). Risk analysis was performed using the Cox proportional hazard model when risks competing with study end points were present. RESULTS Of patients who received azathioprine treatment, 3.3% developed CCA, compared with 6.8% of patients without azathioprine treatment. However, azathioprine did not significantly affect the risk for CCA (hazard ratio, 0.96; 95% confidence interval, 0.29-3.13; P = .94). The only factor associated with an increased risk of CCA was age 35 years or older at PSC diagnosis (hazard ratio, 3.87; 95% confidence interval, 1.96-7.67; P < .01). Patient sex, concomitant IBD, or AIH did not affect the risk of CCA. Overall, the cumulative 10-year incidence of CCA was 4.6% and the cumulative 15-year incidence was 7.7%. CONCLUSIONS A retrospective analysis of patients with PSC treated at tertiary centers in Europe found no evidence that azathioprine significantly affects the risk of CCA. Azathioprine therefore should not be withheld from patients with PSC and concomitant IBD and/or AIH.
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Horsley-Silva JL, Carey EJ, Lindor KD. Advances in primary sclerosing cholangitis. Lancet Gastroenterol Hepatol 2016; 1:68-77. [DOI: 10.1016/s2468-1253(16)30010-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 05/24/2016] [Accepted: 05/26/2016] [Indexed: 12/13/2022]
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Risk and Surveillance of Cancers in Primary Biliary Tract Disease. Gastroenterol Res Pract 2016; 2016:3432640. [PMID: 27413366 PMCID: PMC4930812 DOI: 10.1155/2016/3432640] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 04/14/2016] [Accepted: 05/18/2016] [Indexed: 12/20/2022] Open
Abstract
Primary biliary diseases have been associated in several studies with various malignancies. Understanding the risk and optimizing surveillance strategy of these malignancies in this specific subset of patients are an important facet of clinical care. For instance, primary sclerosing cholangitis is associated with an increased risk for cholangiocarcinoma (which is very challenging to diagnose) and when IBD is present for colorectal cancer. On the other hand, primary biliary cirrhosis patients with cirrhosis or not responding to 12 months of ursodeoxycholic acid therapy are at increased risk of hepatocellular carcinoma. In this review we will discuss in detail the risks and optimal surveillance strategies for patients with primary biliary diseases.
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Abstract
Biliary strictures and masses are commonly a result of cholangiocarcinoma. However, there are several congenital, infectious, inflammatory, autoimmune, iatrogenic, and neoplastic etiologies that should also be considered in the differential diagnosis. Knowledge of the key imaging and clinical findings will aid in facilitating the diagnosis and treatment.
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Abstract
Liver transplantation (LT) is an established lifesaving therapy for patients with cholestatic liver diseases, including primary cholestatic diseases, namely primary sclerosing cholangitis and primary biliary cirrhosis, as well as secondary forms of cholestatic liver disease, including those with cholestatic complications of LT needing a retransplant. Patients with cholestatic liver diseases can be transplanted for complications of end-stage liver disease or for disease-specific symptoms before the onset of end-stage liver disease. These patients should be regularly assessed. Patient survival after LT for cholestatic liver diseases is generally better than for other indications.
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Affiliation(s)
- Vandana Khungar
- Division of Gastroenterology, University of Pennsylvania, 3400 Spruce Street, 2 Dulles, Philadelphia, PA 19104, USA
| | - David Seth Goldberg
- Division of Gastroenterology, University of Pennsylvania, Blockley Hall, 423 Guardian Drive, Room 730, Philadelphia, PA 19104, USA.
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