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Zhang C, Wang J. Adverse events associated with obeticholic acid: a real-world, pharmacovigilance study. Expert Opin Drug Saf 2025:1-9. [PMID: 40162628 DOI: 10.1080/14740338.2025.2487144] [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: 09/16/2024] [Accepted: 03/17/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease predominantly affecting middle-aged women. While ursodeoxycholic acid (UDCA) is the first-line treatment, 30-40% of patients do not respond adequately, necessitating alternative therapies like Obeticholic Acid (OCA), an FXR agonist. The long-term safety of OCA remains insufficiently studied. RESEARCH DESIGN AND METHODS This study utilized the US FDA Adverse Event Reporting System (FAERS) to evaluate OCA safety through large-scale data mining, using disproportionality analyses (ROR, PRR, BCPNN, and MGPS) to identify adverse event signals. RESULTS From Q2 2016 to Q1 2024, 5,864 reports linked to OCA usage were identified among 13,245,871 AE reports. Significant signals across 27 System Organ Classes were found, with pruritus (12.54%), fatigue (4.16%), and nausea (1.64%) being the most prevalent adverse events. Severe hepatic events like liver failure were rare (0.6%). Median time to onset of AEs was 178 days. The most common outcomes reported were important medical events (18.6%), hospitalization (17.8%), and death (6.5%). CONCLUSION This study provides key insights into the safety profile of OCA, highlighting the importance of monitoring for pruritus and hepatic complications, particularly within the first six months of treatment.
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Affiliation(s)
- Chunxia Zhang
- Department of Gastroenterology, Inner Mongolia Forestry General Hospital, Yakeshi, Inner Mongolia, China
| | - Jianguo Wang
- Department of Hepatobiliary Surgery, Inner Mongolia Forestry General Hospital, Yakeshi, Inner Mongolia, China
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2
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An J, Chon YE, Kim G, Kim MN, Kim HY, Lee HA, Yu JH, Choi M, Jun DW, Kim SU, Han JW, Jin YJ. Diagnostic accuracy of vibration-controlled transient elastography for staging liver fibrosis in autoimmune liver diseases: A systematic review and meta-analysis. Clin Mol Hepatol 2024; 30:S134-S146. [PMID: 39165158 PMCID: PMC11493360 DOI: 10.3350/cmh.2024.0586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 08/17/2024] [Accepted: 08/20/2024] [Indexed: 08/22/2024] Open
Abstract
BACKGROUND/AIMS The assessment of liver fibrosis is crucial for managing autoimmune liver diseases such as primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC). However, data on the efficacy of noninvasive tests for these diseases are limited. This meta-analysis evaluated the diagnostic accuracy of vibration-controlled transient elastography (VCTE) for staging fibrosis in patients with autoimmune liver disease. METHODS Searches were conducted in PubMed, Embase, CINAHL, Web of Science, and Cochrane Library databases to assess the diagnostic accuracy of VCTE against histology as the reference standard in adult patients with autoimmune liver disease. The summary area under the curve (sAUC) and diagnostic odds ratio were calculated for significant fibrosis (SF), advanced fibrosis (AF), and cirrhosis, according to liver biopsy. RESULTS Fourteen articles were included, comprising 559 PBC patients from six studies, 388 AIH patients from five studies, and 151 PSC patients from three studies. VCTE demonstrated good performance for fibrosis staging in PBC, AIH, and PSC. In PBC, sAUCs of VCTE were 0.87, 0.89, and 0.99 for staging SF, AF, and cirrhosis, respectively. In AIH, the sAUCs were 0.88, 0.88, and 0.92, respectively, while in PSC, they were 0.88, 0.95, and 0.92, respectively. The cutoff values for AF were 7.5-17.9 kPa in PBC, 8.18-12.1 kPa in AIH, and 9.6 kPa in PSC. CONCLUSION VCTE shows high diagnostic accuracy for staging liver fibrosis in patients with autoimmune liver diseases. This non-invasive method serves as a valuable tool for the evaluation and monitoring of fibrosis in these lifelong diseases.
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Affiliation(s)
- Jihyun An
- Department of Gastroenterology and Hepatology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Young Eun Chon
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Gunho Kim
- Hanyang University College of Medicine, Seoul, Korea
| | - Mi Na Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Hee Yeon Kim
- Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Han Ah Lee
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Jung Hwan Yu
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Miyoung Choi
- Division of Health Technology Assessment Research, National EvidenceBased Healthcare Collaborating Agency (NECA), Seoul, Korea
| | - Dae Won Jun
- Department of Gastroenterology, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Ji Won Han
- Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
| | - Young-Joo Jin
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
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Akepati PR, Gochanour EM. Investigational farnesoid X receptor agonists for the treatment of primary biliary cholangitis. Expert Opin Investig Drugs 2024; 33:627-638. [PMID: 38676426 DOI: 10.1080/13543784.2024.2348743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 04/24/2024] [Indexed: 04/28/2024]
Abstract
INTRODUCTION Up to 40% of Primary biliary cholangitis (PBC) patients have a suboptimal response to Ursodeoxycholic acid (UDCA). Close to half of such patients show a remarkable improvement when additionally treated with Obeticholic acid (OCA) but have a dose-dependent increase of pruritus. This relative success of OCA, a first-in-class Farnesoid receptor (FXR) agonist, has positioned FXR as an attractive target for drug development. Novel candidates have since emerged, providing hope for this subgroup of patients who lack effective and safe treatments. AREAS COVERED We discussed the role of bile acids in PBC pathogenesis and how the FXR agonists provide therapeutic value by affecting bile acid synthesis and transport. Novel FXR agonists undergoing pre-clinical and clinical trials for PBC were enlisted via literature search by including the terms 'FXR agonists,' 'FXR PBC,' 'PBC clinical trials' on PubMed, MEDLINE via Ovid, and Clinicaltrials.gov. EXPERT OPINION Novel FXR agonists currently under investigation for PBC improve the disease surrogate markers in early trials. However, as with OCA, pruritus remains a concern with the newer drugs despite targeted chemical modifications to increase FXR specificity. Directing future resources toward studying the molecular mechanisms behind pruritus may lead to better drug design and efficacious yet safer drugs.
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Affiliation(s)
- Prithvi Reddy Akepati
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA
| | - Eric M Gochanour
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA
- The Gastroenterology Center, Valley View Hospital, Glenwood Springs, CO, USA
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MacDonald N, Loh R, Fenkel JM, Sass DA, Halegoua-DeMarzio D. Pharmacotherapy for primary biliary cholangitis: an assessment of medication candidacy and rates of treatment. BMC Gastroenterol 2024; 24:18. [PMID: 38178006 PMCID: PMC10768361 DOI: 10.1186/s12876-023-03108-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 12/27/2023] [Indexed: 01/06/2024] Open
Abstract
BACKGROUND Ursodeoxycholic acid is the preferred first-line therapy for primary biliary cholangitis. Alternative therapies, such as obeticholic acid, are recommended for patients who cannot tolerate ursodeoxycholic acid or who have an inadequate response to ursodeoxycholic acid monotherapy. Prior investigations have suggested that as many as 30% of patients with primary biliary cholangitis may have never received treatment with ursodeoxycholic acid. No prior investigations have examined usage rates of obeticholic acid in the treatment of primary biliary cholangitis. METHODS All patients with an ICD-10 diagnosis of primary biliary cholangitis who had any records within the health system were included. A review of medical records was performed to confirm the diagnosis of primary biliary cholangitis and determine which medications had been prescribed for treatment, as well as candidacy for second-line therapies. RESULTS A total of 495 patients met inclusion criteria. Notably, 95% of patients were taking ursodeoxycholic acid for treatment of their primary biliary cholangitis, with 67% of patients having disease that was well-controlled on ursodeoxycholic acid monotherapy. In total, 8% of patients were taking obeticholic acid (either as combination or monotherapy). Only 3% would benefit from the addition of a second line therapy but had not yet been offered medication. Only 3% of patients were not on any medication for management of their primary biliary cholangitis. CONCLUSIONS Ursodeoxycholic acid is a readily available and generally well-tolerated medication that should be offered to all patients with primary biliary cholangitis as first-line therapy. While prior investigations have suggested that up to 30% of patients with primary biliary cholangitis may never have received treatment for the disorder, the present study suggests that patients are generally being managed according to guidelines. Moreover, a significant proportion of patients with primary biliary cholangitis will qualify for second line therapies and prescribers should be aware of the indications to use these medications.
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Affiliation(s)
- Nicholas MacDonald
- Department of Medicine, Thomas Jefferson University Hospital, 33 S 9 TH St, Suite 220, 19107, Philadelphia, PA, USA.
| | - Rebecca Loh
- Department of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, 132 South 10th Street, Suite 480, 19107, Philadelphia, PA, USA
| | - Jonathan M Fenkel
- Department of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, 132 South 10th Street, Suite 480, 19107, Philadelphia, PA, USA
| | - David A Sass
- Department of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, 132 South 10th Street, Suite 480, 19107, Philadelphia, PA, USA
| | - Dina Halegoua-DeMarzio
- Department of Medicine, Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, 132 South 10th Street, Suite 480, 19107, Philadelphia, PA, USA
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Gazda J, Drazilova S, Gazda M, Janicko M, Koky T, Macej M, Carbone M, Jarcuska P. Treatment response to ursodeoxycholic acid in primary biliary cholangitis: A systematic review and meta-analysis. Dig Liver Dis 2023; 55:1318-1327. [PMID: 36593158 DOI: 10.1016/j.dld.2022.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/09/2022] [Accepted: 12/19/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND Several ursodeoxycholic acid (UDCA) treatment response definitions have been introduced in primary biliary cholangitis (PBC). However, the lack of a gold standard results in heterogeneity in second-line treatment research and clinical practice. AIMS This study aimed to explore which UDCA treatment response endpoint serves as the most accurate predictive model of long-term outcome. METHODS A systematic review and meta-analysis of UDCA treatment response endpoints (and corresponding validations) were performed. RESULTS Sixteen individual UDCA treatment response endpoints and 96 external validations were found. Barcelona, Paris-1, Paris-2, Rotterdam, Toronto and GLOBE and UK-PBC Risk Scores are currently most robustly validated in external populations. The results show that the continuous models (GLOBE and UK-PBC Risk Scores) serve as the most accurate predictive models. Besides standard UDCA treatment response endpoints, the alkaline phosphatase and total bilirubin normalization has been suggested as a new therapeutic target. CONCLUSIONS The GLOBE and UK-PBC Risk Scores are the most suitable for the real-world allocation of second-line therapies (obeticholic acid and fibrates). However, in the wake of the recent findings, alkaline phosphatase and total bilirubin normalization should be the primary outcome in trial research in PBC.
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Affiliation(s)
- Jakub Gazda
- 2nd Department of Internal Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 040 12, Kosice, Slovakia
| | - Sylvia Drazilova
- 2nd Department of Internal Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 040 12, Kosice, Slovakia.
| | - Matej Gazda
- Intelligent Information Systems Laboratory, Technical University of Kosice, Bozeny Nemcovej 32, 04201 Kosice, Slovakia
| | - Martin Janicko
- 2nd Department of Internal Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 040 12, Kosice, Slovakia
| | - Tomas Koky
- 2nd Department of Internal Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 040 12, Kosice, Slovakia
| | - Marian Macej
- 2nd Department of Internal Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 040 12, Kosice, Slovakia
| | - Marco Carbone
- Division of Gastroenterology and Centre for Autoimmune Liver Disease, University of Milano-Bicocca, Piazza dell'Ateneo Nuovo, 1, 20126 Milano, Italy
| | - Peter Jarcuska
- 2nd Department of Internal Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 040 12, Kosice, Slovakia
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Sohal A, Kowdley KV. Primary Biliary Cholangitis: Promising Emerging Innovative Therapies and Their Impact on GLOBE Scores. Hepat Med 2023; 15:63-77. [PMID: 37312929 PMCID: PMC10259525 DOI: 10.2147/hmer.s361077] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/30/2023] [Indexed: 06/15/2023] Open
Abstract
Primary biliary cholangitis (PBC), previously referred to as primary biliary cirrhosis, is an autoimmune disorder leading to the destruction of intra-hepatic bile ducts. If untreated, progressive bile duct damage and cholestasis can lead to ductopenia and result in cirrhosis. Ursodiol, the first drug approved for PBC, has changed the natural history of this disease and improved patient outcomes. Subsequently, several new prediction models incorporating a response to ursodiol were developed. These include the GLOBE score, which was shown to predict long-term outcomes in patients with PBC. In 2016, obeticholic acid (OCA) became the second drug to be approved by the FDA, predominantly based on improvement in alkaline phosphatase (ALP) levels. This trial has subsequently influenced the design of clinical trials. Several drugs are currently being evaluated as therapeutic options for PBC, with improvement in ALP being a main endpoint. In this review, we will discuss the impact of new therapies on GLOBE scores in patients with PBC.
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Affiliation(s)
- Aalam Sohal
- Department of Hepatology, Liver Institute Northwest, Seattle, WA, USA
| | - Kris V Kowdley
- Department of Hepatology, Liver Institute Northwest, Seattle, WA, USA
- Department of Gastroenterology and Hepatology, Elson Floyd College of Medicine, Spokane, WA, USA
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Manzo-Francisco LA, Aquino-Matus J, Vidaña-Pérez D, Uribe M, Chavez-Tapia N. Systematic review and meta-analysis: Transient elastography compared to liver biopsy for staging of liver fibrosis in primary biliary cholangitis. Ann Hepatol 2023; 28:101107. [PMID: 37088420 DOI: 10.1016/j.aohep.2023.101107] [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: 02/10/2023] [Revised: 04/11/2023] [Accepted: 04/14/2023] [Indexed: 04/25/2023]
Abstract
INTRODUCTION AND OBJECTIVES Primary biliary cholangitis (PBC) is an autoimmune liver disease, with 60% of patients being asymptomatic at diagnosis and 30% progressing rapidly into liver fibrosis. Liver biopsy is standard for staging fibrosis, but performance of non-invasive methods such as transient elastography (TE) have not been evaluated. We conducted a meta-analysis of articles up to May 2022 to evaluate the performance of TE compared with liver biopsy in adult patients with PBC. MATERIALS AND METHODS Two reviewers performed the search and assessed which articles were included. The quality of each study was evaluated according to QUADAS-2 and NOS. Meta-analysis of sensitivity and specificity was conducted with a bivariate random-effects model. The protocol was registered in PROSPERO, ID CRD42020199915. RESULTS Four studies involving 377 patients were included. Only stages F3 and F4 were computed in the meta-analysis. TE had a pooled sensitivity of 68% and specificity of 92% for stage F3 and a pooled sensitivity of 90% and specificity of 94% for stage F4. The AUROC curves were 0.91 (95% Confidence Interval (CI) 0.88-0.93) and 0.97 (95% CI 0.96-0.98) for stages F3 and F4, respectively. The mean cut-off points of TE for stage F3 were 9.28 kPa (95% CI 4.98-13.57) and for stage F4 were 15.2 kPa (95% CI 7.02-23.37). CONCLUSIONS TE performance compared with liver biopsy in adult patients with PBC was excellent for staging liver fibrosis and was able to rule out cirrhosis in clinical practice.
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Affiliation(s)
| | - Jorge Aquino-Matus
- Obesity and Digestive Diseases Unit, Medica Sur Hospital, Mexico City, Mexico
| | - Dèsirée Vidaña-Pérez
- Center for Research Evaluation and Surveys, National Institute of Public Health, Mexico City, Mexico
| | - Misael Uribe
- Obesity and Digestive Diseases Unit, Medica Sur Hospital, Mexico City, Mexico
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Tu Z, Wang Y, Wang Y, Huang J, Han Y, Ji Q, Cao X, Wen X, Wang Y, Jin Q. TR score: A noninvasive model to predict histological stages in patients with primary biliary cholangitis. Front Immunol 2023; 14:1152294. [PMID: 37006277 PMCID: PMC10060872 DOI: 10.3389/fimmu.2023.1152294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
IntroductionThe aim of this study was to develop a noninvasive prediction model for histological stages in PBC that is simple, easy to implement, and highly accurate.MethodsA total of 114 patients with PBC were included in this study. Demographic, laboratory data and histological assessments were collected. The independent predictors of histological stages were selected to establish a noninvasive serological model. The scores of 22 noninvasive models were calculated and compared with the established model.ResultsThis study included 99 females (86.8%) and 15 males (13.2%). The number of patients in Scheuer’s stage 1, 2, 3 and 4 was 33 (29.0%), 34 (29.8%), 16 (14.0%), and 31 (27.2%), respectively. TBA and RDW are independent predictors of PBC histological stages. The above indexes were used to establish a noninvasive model-TR score. When predicting early histological change (S1) or liver fibrosis and cirrhosis (S3-S4), the AUROC of TR score were 0.887 (95% CI, 0.809-0.965) and 0.893 (95% CI, 0.816-0.969), higher than all of the other 22 models included in this study. When predicting cirrhosis (S4), its AUROC is still as high as 0.921 (95% CI, 0.837-1.000).ConclusionTR score is an easy, cheap and stable noninvasive model, without complex calculation formulas and tools, and shows good accuracy in diagnosing the histological stages of PBC.
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Affiliation(s)
- Zhixin Tu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yao Wang
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
| | - Yan Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Jianjie Huang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yujin Han
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Qijia Ji
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xiaoxuan Cao
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xiaoyu Wen
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yang Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Qinglong Jin
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
- *Correspondence: Qinglong Jin,
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Application of the Latest Advances in Evidence-Based Medicine in Primary Biliary Cholangitis. Am J Gastroenterol 2023; 118:232-242. [PMID: 36729104 PMCID: PMC9889200 DOI: 10.14309/ajg.0000000000002070] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 09/23/2022] [Indexed: 02/03/2023]
Abstract
Primary biliary cholangitis (PBC) is a chronic, cholestatic, autoimmune liver disease that can progress to end-stage liver disease and its complications. A previous expert review panel collaborated on a consensus document for gastroenterologists and other healthcare professionals regarding the care of patients with PBC. Subsequently, there have been several recent important developments in the diagnosis, treatment, and monitoring of patients with PBC. These include updates to prognostic models on risk stratification, new noninvasive tools for staging of disease, updates to the appropriate use of and long-term treatment results with obeticholic acid as a second-line treatment, the emerging therapeutic role of fibrates, and the advancement of investigational agents for managing PBC. In this updated expert consensus document, we provide updates on staging, the use of noninvasive prognostic tools, and a treatment algorithm to provide evidence-based and practical tools for clinicians who manage PBC, with the ultimate goal to improve the long-term outcomes for patients with this chronic liver disease.
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Liu BD, Qureshi K. Secondary Treatment of Primary Biliary Cholangitis: Early Prediction of Inadequate Response to Ursodeoxycholic Acid in Patients with PBC. Dig Dis Sci 2023; 68:346-348. [PMID: 36098875 DOI: 10.1007/s10620-022-07661-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/31/2022] [Indexed: 12/09/2022]
Affiliation(s)
- Benjamin D Liu
- Department of Medicine, Case Western Reserve University/MetroHealth Campus, Cleveland, USA
| | - Kamran Qureshi
- Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, USA.
- SLUCare Academic Pavilion, 1008 S. Spring Avenue, Rm 2205, St. Louis, MO, 63110, USA.
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Liu CH, Bowlus CL. Treatment of Primary Biliary Cholangitis: First-Line and Second-Line Therapies. Clin Liver Dis 2022; 26:705-726. [PMID: 36270725 DOI: 10.1016/j.cld.2022.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune disease of the interlobular bile ducts leading to secondary damage of hepatocytes and may progress to cirrhosis and liver failure. The first-line treatment is ursodeoxycholic acid; up to 40% of patients do not have an adequate response and remain at risk of disease progression. Obeticholic acid has been conditionally approved for the treatment of PBC as add-on therapy and bezafibrate has shown similar efficacy in this group of patients. Several new therapies are in development and may further add to the treatment options available to patients with PBC.
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Affiliation(s)
- Chung-Heng Liu
- Drexel University College of Medicine, 2900 W Queen Ln, Philadelphia, PA 19129 USA
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, 4150 V Street, PSSB 3500, Sacramento, CA 95817, USA.
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12
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Scaravaglio M, Carbone M. Prognostic Scoring Systems in Primary Biliary Cholangitis: An Update. Clin Liver Dis 2022; 26:629-642. [PMID: 36270720 DOI: 10.1016/j.cld.2022.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is a complex, chronic disease with a heterogeneous presentation, disease progression, and response to therapy. Several prognostic models based on disease stage and/or treatment response enhance risk stratification and therapeutic management. Recent work on disease modeling proposed early prediction of outcomes at PBC onset, yet this has not been implemented in clinical practice. Although early stratification of patients based on their individual risk of developing end-stage liver disease may prove cost-effective and actually become matter of medical deontology to timely offer the best therapeutic option, given the forthcoming availability of novel, disease-modifying drugs. This review outlines established and novel prognostic systems in PBC and provides some perspectives on the potential role of omics-derived biomarkers in developing reliable risk prediction models and promoting the implementation of personalized medicine in PBC.
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Affiliation(s)
- Miki Scaravaglio
- Division of Gastroenterology and Hepatology, Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy.
| | - Marco Carbone
- Division of Gastroenterology and Hepatology, Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza (MB), Italy.
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Mijic M, Saric I, Delija B, Lalovac M, Sobocan N, Radetic E, Martincevic D, Filipec Kanizaj T. Pretransplant Evaluation and Liver Transplantation Outcome in PBC Patients. Can J Gastroenterol Hepatol 2022; 2022:7831165. [PMID: 35910038 PMCID: PMC9337972 DOI: 10.1155/2022/7831165] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 06/01/2022] [Accepted: 06/07/2022] [Indexed: 11/17/2022] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic liver disease characterized by progressive cholangiocyte and bile duct destruction leading to fibrosis and finally to liver cirrhosis. The presence of disease-specific serological antimitochondrial antibody (AMA) together with elevated alkaline phosphatase (ALP) as a biomarker of cholestasis is sufficient for diagnosis. Ursodeoxycholic acid (UDCA) is the first treatment option for PBC. Up to 40% of patients have an incomplete response to therapy, and over time disease progresses to liver cirrhosis. Several risk scores are proposed for better evaluation of patients before and during treatment to stratify patients at increased risk of disease progression. GLOBE score and UK PBC risk score are used for the evaluation of UDCA treatment and Mayo risk score for transplant-free survival. Liver transplantation (LT) is the only treatment option for end-stage liver disease. More than 10 years after LT, 40% of patients experience recurrence of the disease. A liver biopsy is required to establish rPBC (recurrent primary biliary cholangitis). The only treatment option for rPBC is UDCA, and data show biochemical and clinical improvement, plus potential beneficial effects for use after transplantation for the prevention of rPBC development. Additional studies are required to assess the full impact of rPBC on graft and recipient survival and for treatment options for rPBC.
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Affiliation(s)
- Maja Mijic
- Department of Gastroenterology, University Hospital Merkur, Zajceva 19, Zagreb, Croatia
| | - Ivona Saric
- Department of Gastroenterology, University Hospital Merkur, Zajceva 19, Zagreb, Croatia
| | - Bozena Delija
- Department of Gastroenterology, University Hospital Merkur, Zajceva 19, Zagreb, Croatia
| | - Milos Lalovac
- Department of Gastroenterology, University Hospital Merkur, Zajceva 19, Zagreb, Croatia
| | - Nikola Sobocan
- Department of Gastroenterology, University Hospital Merkur, Zajceva 19, Zagreb, Croatia
- University of Zagreb, School of Medicine, Salata 3, Zagreb, Croatia
| | - Eva Radetic
- University of Zagreb, School of Medicine, Salata 3, Zagreb, Croatia
| | - Dora Martincevic
- University of Zagreb, School of Medicine, Salata 3, Zagreb, Croatia
| | - Tajana Filipec Kanizaj
- Department of Gastroenterology, University Hospital Merkur, Zajceva 19, Zagreb, Croatia
- University of Zagreb, School of Medicine, Salata 3, Zagreb, Croatia
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14
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Ceribelli A, Isailovic N, Gorlino C, Assandri R, Vecellio M, De Santis M, Satoh M, Selmi C. Antigen Reactivity and Clinical Significance of Autoantibodies Directed Against the Pyruvate Dehydrogenase Antigen Complex in Patients With Connective Tissue Disease. Front Immunol 2022; 13:822996. [PMID: 35296099 PMCID: PMC8918651 DOI: 10.3389/fimmu.2022.822996] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 02/04/2022] [Indexed: 11/17/2022] Open
Abstract
Introduction Antimitochondrial antibodies (AMAs) are the hallmark of primary biliary cholangitis (PBC) but can be identified also in patients with connective tissue disease, namely, systemic sclerosis (SSc). Protein immunoprecipitation (IP) and IP-Western blot (WB) can be used to confirm AMA positivity directed at the pyruvate dehydrogenase complex (PDC) subunits E1α, E1β, E2/E3, and E3BP in patients showing a cytoplasmic reticular pattern at indirect immunofluorescence when performed in a screening setting before the onset of overt cholestasis in rheumatic patients. Patients and Methods We studied sera from 285 patients affected by connective tissue disease [SSc, n = 144; dermato/polymyositis (DM/PM), n = 56; and undifferentiated connective tissue disease (UCTD), n = 85] by indirect immunofluorescence (IIF), protein-IP, and IP-WB to identify specific PDC subunits recognized by AMA. Results Twenty percent (57/285) of sera from patients with connective tissue disease had a cytoplasmic reticular pattern at IIF, and in 77% (44/57, including 20 SSc, 12 PM/DM, and 12 UCTD) of these, we detected different titers of autoantibodies against the PDC subunits, specifically against PDC-E2. Among these sera, 4 (9%) tested positive for anti-E1α, 15 (34%) for anti-E1β, and 16 (36%) for anti-E3BP. Four of the 20 AMA-positive SSc cases (20%) had been already diagnosed with PBC, and all were positive for autoantibodies against the subunits PDC-E2, E3, and E3BP. Conclusions Using IIF and IP, we confirm that autoantibodies against the PDC components are detected in rheumatic patients with PBC or without liver dysfunction. In view of the strong predictive value of AMA for PBC, a strict follow-up of these latter patients is warranted for an early diagnosis of the disease.
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Affiliation(s)
- Angela Ceribelli
- Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Natasa Isailovic
- Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Carolina Gorlino
- Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
| | | | - Matteo Vecellio
- Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Maria De Santis
- Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Minoru Satoh
- Department of Clinical Nursing, School of Health Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Carlo Selmi
- Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- *Correspondence: Carlo Selmi,
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15
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You H, Ma X, Efe C, Wang G, Jeong SH, Abe K, Duan W, Chen S, Kong Y, Zhang D, Wei L, Wang FS, Lin HC, Yang JM, Tanwandee T, Gani RA, Payawal DA, Sharma BC, Hou J, Yokosuka O, Dokmeci AK, Crawford D, Kao JH, Piratvisuth T, Suh DJ, Lesmana LA, Sollano J, Lau G, Sarin SK, Omata M, Tanaka A, Jia J. APASL clinical practice guidance: the diagnosis and management of patients with primary biliary cholangitis. Hepatol Int 2022; 16:1-23. [PMID: 35119627 PMCID: PMC8843914 DOI: 10.1007/s12072-021-10276-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 11/08/2021] [Indexed: 12/14/2022]
Affiliation(s)
- Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Xiong Ma
- Department of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, Mainland, China
| | - Cumali Efe
- Department of Gastroenterology, Gazi Yaşargil Education and Research Hospital, Diyarbakir, Turkey
| | - Guiqiang Wang
- Department of Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, Beijing, Mainland, China
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, South Korea
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Sha Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland, China
| | - Dong Zhang
- Experimental and Translational Research Center, Beijing Clinical Research Institute, Beijing, Mainland, China
| | - Lai Wei
- Hepatobiliary Pancreatic Center, Tsinghua Changgung Hospital, Tsinghua University, Beijing, Mainland, China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of PLA General Hospial, Beijing, Mainland, China
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jin Mo Yang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, St. Vincent’s Hospital, The Catholic University of Korea, Suwon, South Korea
| | - Tawesak Tanwandee
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Rino A. Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Diana A. Payawal
- Department of Medicine, Fatima University Medical Center, Manila, Philippines
| | | | - Jinlin Hou
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Mainland, China
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - A. Kadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Darrell Crawford
- School of Medicine, University of Queensland, Brisbane, Australia
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand
| | - Dong Jin Suh
- Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, South Korea
| | | | - Jose Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - George Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong SAR, China
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Tokyo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
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16
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Montano-Loza AJ, Corpechot C. Definition and Management of Patients With Primary Biliary Cholangitis and an Incomplete Response to Therapy. Clin Gastroenterol Hepatol 2021; 19:2241-2251.e1. [PMID: 32629125 DOI: 10.1016/j.cgh.2020.06.062] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 06/23/2020] [Accepted: 06/25/2020] [Indexed: 02/07/2023]
Abstract
Primary biliary cholangitis (PBC) is an immune-mediated chronic liver disease characterized by biliary epithelial injury, cholestasis, and progressive fibrosis that can lead to cirrhosis and requirement for liver transplantation. All patients with PBC should receive initial treatment with ursodeoxycholic acid (UDCA), and odds for response are based on characteristics at baseline. It is important to have clear definitions of patients at risk for a poor response to therapy, of biochemical markers of an incomplete response, and standardized management. Patients typically are assessed after 12 months of treatment with UDCA for biochemical markers of response. However, evaluation at 6 months has been proposed for patients with more severe disease or symptoms (such as pruritus or fatigue). Markers of response to therapy include reduced serum levels of alkaline phosphatase and bilirubin (Paris-2, Toronto, GLOBE, and so forth); patients with high levels of total and conjugated bilirubin or levels of alkaline phosphatase more than 1.5-fold the upper limit of normal should be considered for second-line therapy. Patients with adequate biochemical responses can continue UDCA monotherapy. Incomplete responders should be considered for second-line therapies with obeticholic acid (licensed) or fibrates (unlicensed) in addition to continued treatment with UDCA. Patients with PBC should be followed up for life.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
| | - Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris, European Reference Network Rare-Liver, Saint-Antoine Research Center, Sorbonne University, Paris, France.
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17
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Parés A. Practical management of primary biliary cholangitis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 114:410-417. [PMID: 34663072 DOI: 10.17235/reed.2021.8219/2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease of autoimmune pathogenesis that mainly affects middle-aged women. Patients show elevated alkaline phosphatase and bilirubin levels as the disease progresses. The main symptoms of the disease are pruritus and fatigue, which interfere with the quality of life of patients. Progressive damage leading to end stage liver disease could require liver transplantation. Despite the efficacy of ursodeoxycholic acid (UDCA), the current standard of care for PBC, up to 40% of patients have an inadequate response to the treatment, requiring a second-line therapy. Obeticholic acid is the only second-line treatment approved for PBC in combination with UDCA in adults with an inadequate response to UDCA, or as monotherapy in patients intolerant to UDCA. Although different clinical guidelines for the diagnosis and management of PBC have been published, PBC is still challenging for many physicians. In this article we briefly review the main characteristics of the disease and include a practical user-friendly algorithm for the diagnosis and management of PBC developed by Spanish PBC experts and based on the European Association for the Study of the Liver recommendations.
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18
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Berzigotti A, Tsochatzis E, Boursier J, Castera L, Cazzagon N, Friedrich-Rust M, Petta S, Thiele M. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update. J Hepatol 2021; 75:659-689. [PMID: 34166721 DOI: 10.1016/j.jhep.2021.05.025] [Citation(s) in RCA: 1020] [Impact Index Per Article: 255.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 05/28/2021] [Indexed: 02/07/2023]
Abstract
Non-invasive tests are increasingly being used to improve the diagnosis and prognostication of chronic liver diseases across aetiologies. Herein, we provide the latest update to the EASL Clinical Practice Guidelines on the use of non-invasive tests for the evaluation of liver disease severity and prognosis, focusing on the topics for which relevant evidence has been published in the last 5 years.
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19
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Mawardi M, Alalwan A, Fallatah H, Abaalkhail F, Hasosah M, Shagrani M, Alghamdi MY, Alghamdi AS. Cholestatic liver disease: Practice guidelines from the Saudi Association for the Study of Liver diseases and Transplantation. Saudi J Gastroenterol 2021; 27:S1-S26. [PMCID: PMC8411950 DOI: 10.4103/sjg.sjg_112_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/26/2021] [Accepted: 05/16/2021] [Indexed: 11/04/2022] Open
Abstract
Cholestatic liver diseases (CLDs) are a group of diseases characterized by jaundice and cholestasis as the main presentation with different complications, which have considerable impact on the liver and can lead to end-stage liver disease, cirrhosis, and liver-related complications. In the last few years, tremendous progress has been made in understanding the pathophysiology, diagnosis, and treatment of patients with these conditions. However, several aspects related to the management of CLDs remain deficient and unclear. Due to the lack of recommendations that can help in the management, treatment of those conditions, the Saudi Association for the Study of Liver diseases and Transplantation (SASLT) has created a task force group to develop guidelines related to CLDs management in order to provide a standard of care for patients in need. These guidelines provide general guidance for health care professionals to optimize medical care for patients with CLDs for both adult and pediatric populations, in association with clinical judgments to be considered on a case-by-case basis. These guidelines describe common CLDs in Saudi Arabia, with recommendations on the best approach for diagnosis and management of different diseases based on the Grading of Recommendation Assessment (GRADE), combined with a level of evidence available in the literature.
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Affiliation(s)
- Mohammad Mawardi
- Department of Medicine, Gastroenterology Section, King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia
| | - Abduljaleel Alalwan
- Department of Hepatobiliary Sciences and Liver Transplantation, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Hind Fallatah
- Department of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Faisal Abaalkhail
- Department of Medicine, Gastroenterology Section, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Mohammed Hasosah
- Department of Pediatrics, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Mohammad Shagrani
- Department of Liver and Small Bowel Transplantation, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Mohammed Y Alghamdi
- Department of Medicine, Gastroenterology Unit, King Fahd Military Complex, Dhahran, Saudi Arabia
| | - Abdullah S Alghamdi
- Department of Medicine, Gastroenterology Unit, King Fahad General Hospital, Jeddah, Saudi Arabia
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20
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Namisaki T, Fujinaga Y, Moriya K, Yoshiji H. The association of histological progression with biochemical response to ursodeoxycholic acid in primary biliary cholangitis. Hepatol Res 2021; 51:31-38. [PMID: 33210415 DOI: 10.1111/hepr.13593] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 11/01/2020] [Accepted: 11/03/2020] [Indexed: 02/08/2023]
Abstract
Primary biliary cholangitis (PBC) is currently diagnosed at an early stage; therefore, the number of patients with PBC without symptoms at the time of diagnosis is increasing. However, up to 30% of patients with PBC exhibit the suboptimal response to ursodeoxycholic acid (UDCA) and are at high risk of end-stage liver disease. Obeticholic acid is an approved second-line therapy for patients with PBC that are refractory to UDCA. Novel surrogate endpoints are required to identify individuals eligible for second-line therapies. An inadequate biochemical response to UDCA is a useful predictor of poor outcomes in patients with PBC. In addition to UDCA effects on biochemical parameters, histological outcomes could be considered as candidate surrogate endpoints. Alterations in liver histology are used as surrogate endpoints in clinical studies. However, current staging systems are insufficient to determine PBC disease severity and progression because of the pathological heterogeneity of the disease. Histological features at baseline and biochemical response to UDCA treatment can affect the disease course of PBC. Therefore, novel surrogate endpoints must be represented by parameters characterized by histological outcomes and treatment responses in PBC. In this review, we discuss the existing histological parameters and newly created factors to identify patients with PBC who are at a high risk of developing end-stage liver disease and, consequently, the potential need for additional treatments.
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Affiliation(s)
- Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Yukihisa Fujinaga
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
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21
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Clinical significance of IgG antimitochondrial M2 antibody levels in primary biliary cholangitis: A single center study from China. PLoS One 2020; 15:e0242164. [PMID: 33180817 PMCID: PMC7661052 DOI: 10.1371/journal.pone.0242164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 10/27/2020] [Indexed: 11/25/2022] Open
Abstract
Background and objective The relationship between antimitochondrial antibody (AMA) levels and the severity or prognosis of primary biliary cholangitis (PBC) is unclear. This study explored the clinical significance of serum IgG antimitochondrial M2 antibody (IgG-M2) levels. Methods From 2008 to 2017, a retrospective analysis was conducted with PBC patients who had available quantitative values of serum IgG-M2 levels obtained with ELISA based on triple expression hybrid clones. The patients were divided into two groups based on high and low concentrations of IgG-M2. Baseline parameters, the incidence of adverse events, and prognosis were compared. Results Among the 530 PBC patients, the levels of albumin, cholinesterase, hemoglobin, fibrinogen and triglycerides and the red blood cell count were significantly lower in the high-concentration group than in the low-concentration group (n = 263, 49.6%). The red cell distribution width (RDW) and levels of serum immunoglobulin (Ig) G, IgM and IgA were significantly higher in the high-concentration group than in the low-concentration group. Spearman’s correlation analysis suggested that the correlation between the above baseline indicators and IgG-M2 levels was statistically significant but weak (r < 0.2, P < 0.05). In total, 203 patients were followed up, of whom 87 (42.9%) were in the high-concentration group. During the median follow-up period of 52 months (range: 28–75), 121 (59.6%) experienced hepatic decompensation, and 37 (18.2%) died or underwent liver transplantation. There was no significant difference in the incidence of complications or survival (log-rank test: P = 0.079) between the two groups. One year after ursodeoxycholic acid (UDCA) treatment, the two groups had similar responses. In addition, the levels of IgG-M2 did not fluctuate significantly during treatment. Conclusion IgG-M2 levels were not related to the disease severity, prognosis or efficacy of UDCA. The levels of IgG-M2 did not change significantly during treatment.
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22
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Roberts SB, Ismail M, Kanagalingam G, Mason AL, Swain MG, Vincent C, Yoshida EM, Tsien C, Flemming JA, Janssen HLA, Hirschfield GM, Hansen BE, Gulamhusein AF. Real-World Effectiveness of Obeticholic Acid in Patients with Primary Biliary Cholangitis. Hepatol Commun 2020; 4:1332-1345. [PMID: 32923836 PMCID: PMC7471421 DOI: 10.1002/hep4.1518] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 02/07/2020] [Accepted: 03/26/2020] [Indexed: 12/30/2022] Open
Abstract
Patients with primary biliary cholangitis (PBC) with incomplete response to ursodeoxycholic acid are at risk of disease progression and need additional therapy. Obeticholic acid (OCA) was approved in Canada in May 2017, but its effectiveness in a real‐world setting has not been described. We sought to describe our experience with OCA in a Canadian cohort. OCA‐naive patients treated at two Canadian centers were included. Clinical and biochemical data were collected at OCA initiation and during follow‐up. Primary outcomes were changes in serum alkaline phosphatase (ALP), gamma‐glutamyl transferase (GGT), and total bilirubin (TB) over the duration of therapy. Secondary outcomes were changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), immunoglobulin M (IgM), platelets, and albumin; and achievement of the primary endpoint of the original phase 3 study that led to OCA approval (A Placebo‐Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis [POISE]), dose reductions, discontinuations, and tolerability. Repeated‐measures models were used to assess changes in biochemistry over time. Sixty‐four patients were included; 4 carried a diagnosis of overlap with autoimmune hepatitis. Mean age was 54.6 years, median ALP was 250 U/L, TB was 13 µmol/L, platelet count was 225 × 109/L, and 24% had liver stiffness measurements ≥16.9 kPa. There was a significant reduction in mean ALP of 55 U/L (P < 0.001), GGT of 138 U/L (P < 0.001), ALT of 11.9 U/L (P < 0.001), AST of 5.7 U/L (P < 0.05), and IgM of 0.70 g/L (P < 0.001) over 12 months; TB remained stable (P = 0.98). Forty‐four patients met POISE‐inclusion criteria, 39% (n = 17) of whom had 12‐month biochemical measurements. In this subset, 18% (n = 3/17) met the 12‐month POISE primary endpoint, but considering follow‐up to 19 months, 43% achieved this target (n = 9/21). Pruritus was the most commonly reported complaint. Conclusion: Use of OCA was associated with improvement in biochemical surrogates of outcome in PBC in a real‐world setting.
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Affiliation(s)
- Surain B Roberts
- Toronto Centre for Liver Disease Toronto General Hospital University Health Network Toronto ON Canada.,Institute of Health Policy, Management and Evaluation University of Toronto Toronto ON Canada
| | - Marwa Ismail
- Toronto Centre for Liver Disease Toronto General Hospital University Health Network Toronto ON Canada
| | - Gowthami Kanagalingam
- Toronto Centre for Liver Disease Toronto General Hospital University Health Network Toronto ON Canada
| | - Andrew L Mason
- Department of Medicine University of Alberta Edmonton AB Canada
| | - Mark G Swain
- Department of Medicine University of Calgary Calgary AB Canada
| | | | - Eric M Yoshida
- Department of Medicine University of British Columbia Vancouver BC Canada
| | - Cynthia Tsien
- Department of Medicine University of Ottawa Ottawa ON Canada
| | | | - Harry L A Janssen
- Toronto Centre for Liver Disease Toronto General Hospital University Health Network Toronto ON Canada
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease Toronto General Hospital University Health Network Toronto ON Canada
| | - Bettina E Hansen
- Toronto Centre for Liver Disease Toronto General Hospital University Health Network 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 University Health Network Toronto ON Canada.,Institute of Health Policy, Management and Evaluation University of Toronto Toronto ON Canada
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23
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Palmer M, Regev A, Lindor K, Avigan MI, Dimick‐Santos L, Treem W, Marcinak JF, Lewis JH, Anania FA, Seekins D, Shneider BL, Chalasani N. Consensus guidelines: best practices for detection, assessment and management of suspected acute drug-induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease. Aliment Pharmacol Ther 2020; 51:90-109. [PMID: 31762074 PMCID: PMC6972572 DOI: 10.1111/apt.15579] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/03/2019] [Accepted: 10/19/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Improved knowledge of the molecular pathophysiology and immunopathogenesis of cholestatic liver diseases in recent years has led to an increased interest in developing novel therapies. Patients with cholestatic liver disease often require different approaches to assessment and management of suspected drug-induced liver injury (DILI) compared to those with healthy livers and those with parenchymal liver diseases. At present, there are no regulatory guidelines or society position papers, that systematically address best practices pertaining to detection of DILI in these patients. AIMS To outline best practices for detection, assessment and management of suspected acute DILI during clinical trials in adults with the cholestatic liver diseases - Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). METHODS This is one of the several papers developed by the IQ DILI Initiative, which is comprised of members from 16 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. The contents are the result of an extensive literature review, as well as in-depth discussions among industry, regulatory and academic DILI experts, to achieve consensus recommendations on DILI-related issues occurring during clinical trials for cholestatic liver diseases. RESULTS Recommended best practices are outlined pertaining to hepatic eligibility criteria, monitoring of liver tests, approach to a suspected DILI signal, and hepatic discontinuation rules. CONCLUSIONS This paper provides a framework for the approach to detection, assessment and management of suspected acute DILI occurring during clinical trials in adults with cholestatic liver disease.
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Alomari M, Covut F, Al Momani L, Chadalavada P, Hitawala A, Young MF, Romero-Marrero C. Evaluation of the United Kingdom-primary biliary cholangitis and global primary biliary cholangitis group prognostic models for primary biliary cholangitis patients treated with ursodeoxycholic acid in the U.S. population. JGH OPEN 2019; 4:132-139. [PMID: 32280755 PMCID: PMC7144790 DOI: 10.1002/jgh3.12223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 06/06/2019] [Indexed: 01/25/2023]
Abstract
Background and Aim The United Kingdom‐primary biliary cholangitis (UK‐PBC) and global primary biliary cholangitis group (GLOBE) prognostic models have been recently developed to predict long‐term outcomes in primary biliary cholangitis (PBC). However, these predictive scores have not yet been well evaluated in the U.S. population. Methods We retrospectively reviewed newly diagnosed PBC patients at the Cleveland Clinic between November 1998 and February 2017. Adverse events were defined as liver transplantation, liver‐related mortality, and all‐cause mortality. Transplant‐free survival (TFS) was estimated using the Kaplan–Meier method. Predictive performances of all prognostic models were evaluated using the C‐statistic. Results We identified 352 patients who used ursodeoxycholic acid therapy. Of them, 311 (88.4%) only had PBC, while 41 (11.6%) were diagnosed with PBC‐autoimmune hepatitis overlap. A total of 22 (6%), 47 (13%), and 55 (16%) patients had adverse events within 5, 10, and 15 years after diagnosis, respectively. In patients with PBC only, the C‐statistic in predicting 15‐year adverse events was 0.75 per GLOBE compared to 0.74 per UK‐PBC (P = 0.94), 0.73 per Rotterdam (P = 0.44), 0.66 per Barcelona (P = 0.004), 0.65 per Paris 1 (P = 0.005), 0.62 per Paris 2 (P < 0.0001), 0.60 per Toronto (P < 0.0001), and 0.60 per Mayo (P < 0.0001) scores. Median follow‐up was 9.2 years. Ten‐year TFS for patients who had optimal versus suboptimal treatment response was 92 versus 74% per Paris 1 (P < 0.0001), 95 versus 79% per Paris 2 (P = 0.0002), 93 versus 65% per Barcelona (P < 0.0001), and 96 versus 68% per Rotterdam (P < 0.0001) risk scores, respectively. Conclusion In our cohort of PBC patients, the UK‐PBC and GLOBE scores were both accurate and reasonably valid prognostic models in the U.S. population.
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Affiliation(s)
- Mohammad Alomari
- Department of Internal Medicine Cleveland Clinic Foundation Cleveland Ohio USA
| | - Fahrettin Covut
- Department of Internal Medicine Cleveland Clinic Foundation Cleveland Ohio USA
| | - Laith Al Momani
- Department of Internal Medicine East Tennessee State University Johnson City Tennessee USA
| | | | - Asif Hitawala
- Department of Internal Medicine Cleveland Clinic Foundation Cleveland Ohio USA
| | - Mark F Young
- Department of Gastroenterology and Hepatology East Tennessee State University Johnson City Tennessee USA
| | - Carlos Romero-Marrero
- Department of Gastroenterology Hepatology and Nutrition, Cleveland Clinic Foundation Cleveland Ohio USA
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25
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Kennedy L, Francis H, Invernizzi P, Venter J, Wu N, Carbone M, Gershwin ME, Bernuzzi F, Franchitto A, Alvaro D, Marzioni M, Onori P, Gaudio E, Sybenga A, Fabris L, Meng F, Glaser S, Alpini G. Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis. FASEB J 2019; 33:10269-10279. [PMID: 31251081 DOI: 10.1096/fj.201802606r] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Primary biliary cholangitis (PBC) primarily targets cholangiocytes and is characterized by liver fibrosis and biliary proliferation. Activation of the secretin (Sct)/secretin receptor (SR) axis, expressed only by cholangiocytes, increases biliary proliferation, liver fibrosis, and bicarbonate secretion. We evaluated the effectiveness of SR antagonist treatment for early-stage PBC. Male and female dominant-negative TGF-β receptor II (dnTGF-βRII) (model of PBC) and wild-type mice at 12 wk of age were treated with saline or the SR antagonist, Sec 5-27, for 1 wk. dnTGF-βRII mice expressed features of early-stage PBC along with enhanced Sct/SR axis activation and Sct secretion. dnTGF-βRII mice had increased biliary proliferation or senescence, inflammation, and liver fibrosis. In dnTGF-βRII mice, there was increased microRNA-125b/TGF-β1/TGF-β receptor 1/VEGF-A signaling. Human early-stage PBC patients had an increase in hepatobiliary Sct and SR expression and serum Sct levels. Increased biliary Sct/SR signaling promotes biliary and hepatic damage during early-stage PBC.-Kennedy, L., Francis, H., Invernizzi, P., Venter, J., Wu, N., Carbone, M., Gershwin, M. E., Bernuzzi, F., Franchitto, A., Alvaro, D., Marzioni, M., Onori, P., Gaudio, E., Sybenga, A., Fabris, L., Meng, F., Glaser, S., Alpini, G. Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis.
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Affiliation(s)
- Lindsey Kennedy
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA.,Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, Texas, USA
| | - Heather Francis
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA.,Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, Texas, USA.,Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott and White Health, Temple, Texas, USA
| | | | - Julie Venter
- Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, Texas, USA
| | - Nan Wu
- Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, Texas, USA
| | - Marco Carbone
- Humanitas Clinical and Research Center, Rozzano (MI), Italy
| | - M Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California-Davis, Davis, California, USA
| | | | | | - Domenico Alvaro
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Universita Politecnica delle Marche, Ancona, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Amelia Sybenga
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Luca Fabris
- Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy.,Digestive Disease Section, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Fanyin Meng
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA.,Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott and White Health, Temple, Texas, USA
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, Texas, USA.,Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott and White Health, Temple, Texas, USA
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Temple, Texas, USA.,Department of Medical Physiology, Texas A&M University, College of Medicine, Temple, Texas, USA.,Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott and White Health, Temple, Texas, USA
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26
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Abstract
Primary biliary cholangitis (PBC) is a chronic, cholestatic, autoimmune disease with a variable progressive course. PBC can cause debilitating symptoms including fatigue and pruritus and, if left untreated, is associated with a high risk of cirrhosis and related complications, liver failure, and death. Recent changes to the PBC landscape include a name change, updated guidelines for diagnosis and treatment as well as new treatment options that have recently become available. Practicing clinicians face many unanswered questions when managing PBC. To assist these healthcare providers in managing patients with PBC, the American College of Gastroenterology (ACG) Institute for Clinical Research & Education, in collaboration with the Chronic Liver Disease Foundation (CLDF), organized a panel of experts to evaluate and summarize the most current and relevant peer-reviewed literature regarding PBC. This, combined with the extensive experience and clinical expertise of this expert panel, led to the formation of this clinical guidance on the diagnosis and management of PBC.
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27
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Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology 2019; 69:394-419. [PMID: 30070375 DOI: 10.1002/hep.30145] [Citation(s) in RCA: 407] [Impact Index Per Article: 67.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 05/30/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Keith D Lindor
- Arizona State University, Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ
| | | | | | | | - Marlyn Mayo
- University of Texas Southwestern Medical Center, Dallas, TX
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28
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. The clinical usage and definition of autoantibodies in immune-mediated liver disease: A comprehensive overview. J Autoimmun 2018; 95:144-158. [DOI: 10.1016/j.jaut.2018.10.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 10/09/2018] [Accepted: 10/11/2018] [Indexed: 02/06/2023]
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29
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Bansal A, Heagerty PJ. A Tutorial on Evaluating the Time-Varying Discrimination Accuracy of Survival Models Used in Dynamic Decision Making. Med Decis Making 2018; 38:904-916. [PMID: 30319014 DOI: 10.1177/0272989x18801312] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Many medical decisions involve the use of dynamic information collected on individual patients toward predicting likely transitions in their future health status. If accurate predictions are developed, then a prognostic model can identify patients at greatest risk for future adverse events and may be used clinically to define populations appropriate for targeted intervention. In practice, a prognostic model is often used to guide decisions at multiple time points over the course of disease, and classification performance (i.e., sensitivity and specificity) for distinguishing high-risk v. low-risk individuals may vary over time as an individual's disease status and prognostic information change. In this tutorial, we detail contemporary statistical methods that can characterize the time-varying accuracy of prognostic survival models when used for dynamic decision making. Although statistical methods for evaluating prognostic models with simple binary outcomes are well established, methods appropriate for survival outcomes are less well known and require time-dependent extensions of sensitivity and specificity to fully characterize longitudinal biomarkers or models. The methods we review are particularly important in that they allow for appropriate handling of censored outcomes commonly encountered with event time data. We highlight the importance of determining whether clinical interest is in predicting cumulative (or prevalent) cases over a fixed future time interval v. predicting incident cases over a range of follow-up times and whether patient information is static or updated over time. We discuss implementation of time-dependent receiver operating characteristic approaches using relevant R statistical software packages. The statistical summaries are illustrated using a liver prognostic model to guide transplantation in primary biliary cirrhosis.
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Affiliation(s)
- Aasthaa Bansal
- The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, School of Pharmacy, University of Washington, Seattle, WA (AB).,Department of Biostatistics, University of Washington, Seattle, WA (PJH)
| | - Patrick J Heagerty
- The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, School of Pharmacy, University of Washington, Seattle, WA (AB).,Department of Biostatistics, University of Washington, Seattle, WA (PJH)
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30
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Bossen L, Gerussi A, Lygoura V, Mells GF, Carbone M, Invernizzi P. Support of precision medicine through risk-stratification in autoimmune liver diseases – histology, scoring systems, and non-invasive markers. Autoimmun Rev 2018; 17:854-865. [PMID: 30005861 DOI: 10.1016/j.autrev.2018.02.013] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 02/26/2018] [Indexed: 02/07/2023]
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31
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Abstract
Patients with primary biliary cholangitis (PBC) are at risk for various harmful consequences of chronic cholestasis. These include fat-soluble vitamin deficiency, even in the setting of macronutrient sufficiency, as well as metabolic bone disease, including osteoporosis with fractures. Hyperlipidemia is often present and less commonly associated with risk of cardiovascular event; however, the long-term effect of new emerging therapies for PBC remains to be determined. Patients with PBC also have infrequent but notable risk of portal hypertension despite early-stage disease. This review discusses the background, evaluation, and practical management of these complications of chronic cholestasis.
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Affiliation(s)
- David N Assis
- Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street, 1080 LMP, New Haven, CT 06510, USA.
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32
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Tan D, Goodman ZD. Liver Biopsy in Primary Biliary Cholangitis: Indications and Interpretation. Clin Liver Dis 2018; 22:579-588. [PMID: 30259854 DOI: 10.1016/j.cld.2018.03.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis is a disease characterized by immune-mediated bile duct destruction, followed by inflammation, scarring, and the development of chronic cholestasis and a slow progression to cirrhosis over the course of years. Liver biopsy has traditionally been used in conjunction with clinical evaluation and serologic autoantibody testing to establish the diagnosis, but it is no longer required in typical cases with positive antimitochondrial antibodies. Biopsy remains essential, however, in antimitochondrial antibody-negative patients or suspected overlap syndrome with autoimmune hepatitis, and if an adequate biopsy is performed precise staging is possible for assessment of prognosis.
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Affiliation(s)
- Daisong Tan
- Division of Liver Pathology Research, Center for Liver Diseases, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042, USA
| | - Zachary D Goodman
- Division of Liver Pathology Research, Center for Liver Diseases, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042, USA.
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33
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Abstract
Primary biliary cholangitis (PBC) is considered a model autoimmune disease, characterized by circulating anti-mitochondrial antibodies and a selective autoimmune destruction of intrahepatic cholangiocytes. PBC is heterogeneous in its presentation, symptomatology, disease progression, and response to therapy. The pathogenesis is still largely unknown and epidemiologic studies have facilitated the identification of risk factors and the understanding of disease prevalence, geographic variations, heterogeneity, and differences in sex ratio. Recent studies from large international cohorts have better identified prognostic factors suggesting a change in patient management based on risk-stratification tools to identify subgroups at greatest potential benefit from second-line therapies.
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Affiliation(s)
- Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Milan 20090, Italy; Liver Unit, Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano 20089, Milan, Italy.
| | - Francesca Colapietro
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, Milan 20090, Italy
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34
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Shah I, Madgum N. Correlation of APRI Index with Metavir Index in Children with Neonatal Cholestasis Without Biliary Atresia. Ann Hepatol 2018; 17:592-595. [PMID: 29893700 DOI: 10.5604/01.3001.0012.0924] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Neonatal cholestasis constitutes for 19 to 33% of all chronic liver disease in India. Cholestasis leads to fibrosis of liver and ultimately cirrhosis. There are various methods of diagnosis of fibrosis of liver like fibroscan, APRI index, FIB-4, fibro index, forns index, heap score, magnetic elastography. Here we are comparing APRI index with METAVIR index in patients with neonatal cholestasis without biliary atresia and determining whether APRI index can be used as a tool to determine fibrosis in these patients. MATERIAL AND METHODS Patients with neonatal cholestasis without biliary atresia were included in the study. This retrospective analysis was done between 2009 and 2015. All patients underwent a liver biopsy and METAVIR index was calculated. APRI at the time of liver biopsy was determined. RESULTS Forty-eight patients were included in this study with mean age of 3.5 ± 2.8 months with a male: female ratio of 35:13. Metavir Index F0 was seen in was 32 (66.67%) patients, F1 in 6(12.5%), F2 in 4(8.33%), F3 in 0 and F4 in 6(12.5%) patients respectively. Mean APRI for F0-F3 was 1.38 and for F4 was 3.74 respectively. With an APRI of 1.38, the sensitivity and specificity to detect fibrosis/cirrhosis was 100% and 21.43% respectively. CONCLUSION APRI is not an effective tool to measure fibrosis or cirrhosis in patients with non-BA neonatal cholestasis in Indian children.
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Affiliation(s)
- Ira Shah
- Department of Pediatric Gastroenterology and Hepatology, B J Wadia Hospital for Children, Mumbai, India
| | - Nikita Madgum
- Department of Pediatric Gastroenterology and Hepatology, B J Wadia Hospital for Children, Mumbai, India
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35
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Goet JC, Harms MH, Carbone M, Hansen BE. Risk stratification and prognostic modelling in primary biliary cholangitis. Best Pract Res Clin Gastroenterol 2018; 34-35:95-106. [PMID: 30343715 DOI: 10.1016/j.bpg.2018.06.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 06/08/2018] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is a slowly progressive chronic cholestatic liver disease that, in a subgroup of patients, may result in liver failure or death. The definition of specific risk profiles, i.e. risk stratification, is of critical importance for the identification of these subgroups and thereby the targeting of care. Over the last few years large multicentre cohort studies have improved our knowledge regarding factors associated with progressive disease. Stratification based on biochemical response to ursodoxycholic acid provides a readily available measure to identify groups that might benefit from additional therapies to further improve prognosis. In addition, serum total bilirubin and alkaline phosphatase are now considered the most robustly validated biomarkers of long-term outcome in PBC and are used as endpoints in clinical trials. The GLOBE score and UK-PBC risk score enable us to quantify the risk of future events for the individual patient, allowing more individualized risk prediction. In this review, we discuss both established prognostic factors and newly developed tools to estimate prognosis in PBC, highlighting their strengths, limitations and applicability in clinical practice.
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Affiliation(s)
- Jorn C Goet
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
| | - Maren H Harms
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
| | - Marco Carbone
- Division of Gastroenterology and Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.
| | - Bettina E Hansen
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands; Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.
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36
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Burman BE, Jhaveri MA, Kowdley KV. An Update on the Treatment and Follow-up of Patients with Primary Biliary Cholangitis. Clin Liver Dis 2017; 21:709-723. [PMID: 28987258 DOI: 10.1016/j.cld.2017.06.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by chronic granulomatous lymphocytic cholangitis of the small bile ducts. PBC was a leading indication for liver transplant in the United States; with early diagnosis and treatment, the majority of patients with PBC have a normal life expectancy. Pathogenesis involves inflammatory damage of bile duct epithelium secondary to innate and adaptive immune responses, and toxicity from accumulated bile acids. Cholestasis and disease progression can lead to cirrhosis. Extrahepatic complications include dyslipidemia, metabolic bone disease, and fat-soluble vitamin deficiency. Ursodeoxycholic acid is a well-established therapy. Novel targeted therapeutics are being developed.
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Affiliation(s)
- Blaire E Burman
- Division of Gastroenterology and Hepatology, Virginia Mason Medical Center, 1100 Ninth Avenue, Seattle, WA 98101, USA
| | - Manan A Jhaveri
- Department of Organ Transplant & Liver Center, Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, 1124 Columbia Street, WA 98101, USA
| | - Kris V Kowdley
- Department of Organ Transplant & Liver Center, Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, 1124 Columbia Street, WA 98101, USA.
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37
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A brief review on prognostic models of primary biliary cholangitis. Hepatol Int 2017; 11:412-418. [DOI: 10.1007/s12072-017-9819-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 08/29/2017] [Indexed: 12/12/2022]
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38
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Hirschfield GM, Beuers U, Corpechot C, Invernizzi P, Jones D, Marzioni M, Schramm C. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017; 67:145-172. [PMID: 28427765 DOI: 10.1016/j.jhep.2017.03.022] [Citation(s) in RCA: 889] [Impact Index Per Article: 111.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 03/23/2017] [Indexed: 02/07/2023]
Abstract
Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune cholestatic liver disease, which when untreated will culminate in end-stage biliary cirrhosis. Diagnosis is usually based on the presence of serum liver tests indicative of a cholestatic hepatitis in association with circulating antimitochondrial antibodies. Patient presentation and course can be diverse and risk stratification is important to ensure all patients receive a personalised approach to their care. The goals of treatment and management are the prevention of end-stage liver disease, and the amelioration of associated symptoms. Pharmacologic approaches in practice, to reduce the impact of the progressive nature of disease, currently include licensed therapies (ursodeoxycholic acid and obeticholic acid) and off-label therapies (fibric acid derivatives, budesonide). These clinical practice guidelines summarise the evidence for the importance of a structured, life-long and individualised, approach to the care of patients with PBC, providing a framework to help clinicians diagnose and effectively manage patients.
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39
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Floreani A, Tanaka A, Bowlus C, Gershwin ME. Geoepidemiology and changing mortality in primary biliary cholangitis. J Gastroenterol 2017; 52:655-662. [PMID: 28365879 DOI: 10.1007/s00535-017-1333-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 03/16/2017] [Indexed: 02/04/2023]
Abstract
Primary biliary cholangitis (PBC), formerly called primary biliary cirrhosis, is a chronic cholestatic disease characterized by an autoimmune-mediated destruction of small and medium-sized intrahepatic bile ducts. Originally PBC was considered to be rare and almost invariably fatal, mainly because the diagnosis was made in patients presenting with advanced symptomatic disease (jaundice and decompensated cirrhosis). However, the development of a reproducible indirect immunofluorescence assay for antimitochondrial antibody made it possible to diagnose the disease at an earlier stage, and introduction of ursodeoxycholic acid therapy as the first-line therapy for PBC drastically changed PBC-related mortality. At present, patients with an early histological stage have survival rates similar to those of an age- and sex-matched control population. Although 30% of patients treated with ursodeoxycholic acid may exhibit incomplete responses, obeticholic acid and drugs currently in development are expected to be effective for these patients and improve outcomes. Meanwhile, more etiology and immunopathology studies using new technologies and novel animal models are needed to dissect variances of clinical course, treatment response, and outcome in each patient with PBC. Precision medicine that is individualized for each patient on the basis of the cause identified is eagerly awaited.
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Affiliation(s)
- Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, via Giustiniani, 2, Padova, Italy
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Christopher Bowlus
- Division of Gastroenterology and Hepatology, School of Medicine, University of California, Davis, Davis, CA, USA
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, Davis, CA, USA.
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40
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Diagnostic autoantibodies for autoimmune liver diseases. Clin Transl Immunology 2017; 6:e139. [PMID: 28690845 PMCID: PMC5493583 DOI: 10.1038/cti.2017.14] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 03/22/2017] [Accepted: 03/22/2017] [Indexed: 12/17/2022] Open
Abstract
Autoimmune liver diseases are conditions of low prevalence that comprise the triad of autoimmune hepatitis, primary biliary cholangitis (cirrhosis) and primary sclerosing cholangitis and their poorly characterised overlapping syndromes. Diagnostic autoantibodies are associated with autoimmune hepatitis and primary biliary cholangitis but not with primary sclerosing cholangitis. Autoantibodies are useful disease markers that facilitate early diagnosis of autoimmune hepatitis and primary biliary cholangitis and allow for therapeutic intervention to prevent progression to liver cirrhosis and associated complications. Adult onset type 1 autoimmune hepatitis is associated with F-actin reactive smooth muscle autoantibody, antinuclear autoantibody in 60% of patients, and autoantibody to SLA/LP in 15–20%. Juvenile onset type 2 autoimmune hepatitis is associated with LKM-1 and LC-1 autoantibodies. Primary biliary cholangitis is associated with a mitochondria-associated autoantibody designated M2 in >90% of patients and with disease-specific antinuclear autoantibodies in 50% that bind to antigens in the nuclear core complex and in multiple nuclear dots. Autoantibodies to the nuclear core complex target gp210, nucleoporin p62 and nuclear lamin B receptor. Autoantibodies to multiple nuclear dots target Sp100 and PML antigens. Liver autoantibodies in asymptomatic patients with normal liver function may precede the subsequent development of overt autoimmune liver disease. For routine diagnostic immunology laboratories, initial screening for liver autoantibodies by immunofluorescence remains the method of choice with confirmation for reactivity with their target antigen by enzyme-linked immunosorbent assay (ELISA) or line blot when required.
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41
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Chascsa D, Carey EJ, Lindor KD. Old and new treatments for primary biliary cholangitis. Liver Int 2017; 37:490-499. [PMID: 28371104 DOI: 10.1111/liv.13294] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 10/27/2016] [Indexed: 02/13/2023]
Abstract
Primary biliary cholangitis (formerly primary biliary cirrhosis) is a rare progressive cholestatic liver disease, whose hallmark features include a persistently elevated alkaline phosphatase level, presence of anti-mitochondrial antibodies and characteristic histology. Since 1998, ursodeoxycholic acid (UDCA), a bile acid, has been the only available therapeutic agent. Primary biliary cholangitis is associated with the development of end-stage liver disease, increased morbidity and mortality. UDCA has been shown to improve serum biochemistries, histology and delay the need for liver transplantation. The clinical issue is that approximately 25%-40% of patients do not respond to this standard therapy. In recent years, many trials have investigated alternative and adjunctive treatments, leading to the recent approval of obeticholic acid, an analogue of chenodeoxycholic acid, which has shown significant and sustained reductions in alkaline phosphatase levels in combination with UDCA. Obeticholic acid has rapidly been embraced as a new agent to improve the biochemical profile in refractory patients, in addition to being approved for use as monotherapy in patients who cannot tolerate UDCA. There are several other studies and targets which are being investigated. This review is intended to highlight the benefits of UDCA, educate the reader on the newly available obeticholic acid, and to summarize the many ongoing trials and therapeutic targets being investigated in attempts to control and cure primary biliary cholangitis.
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Affiliation(s)
- David Chascsa
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Elizabeth J Carey
- 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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Abstract
Despite the central role of the liver in drug metabolism, surprisingly there is lack of certainty in anticipating the extent of modification of the clearance of a given drug in a given patient. The intent of this review is to provide a conceptual framework in considering the impact of liver disease on drug disposition and reciprocally the impact of drug disposition on liver disease. It is proposed that improved understanding of the situation is gained by considering the issue as a special example of a drug-gene-environment interaction. This requires an integration of knowledge of the drug's properties, knowledge of the gene products involved in its metabolism, and knowledge of the pathophysiology of its disposition. This will enhance the level of predictability of drug disposition and toxicity for a drug of interest in an individual patient. It is our contention that advances in pharmacology, pharmacogenomics, and hepatology, together with concerted interests in the academic, regulatory, and pharmaceutical industry communities provide an ideal immediate environment to move from a qualitative reactive approach to quantitative proactive approach in individualizing patient therapy in liver disease.
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Affiliation(s)
- Nathalie K Zgheib
- a Department of Pharmacology and Toxicology , American University of Beirut Faculty of Medicine , Beirut , Lebanon
| | - Robert A Branch
- b Department of Medicine, School of Medicine , University of Pittsburgh , Pittsburgh , PA , USA
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Liberal R, Grant CR. Cirrhosis and autoimmune liver disease: Current understanding. World J Hepatol 2016; 8:1157-1168. [PMID: 27729952 PMCID: PMC5055585 DOI: 10.4254/wjh.v8.i28.1157] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 05/14/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) constitute the classic autoimmune liver diseases (AILDs). While AIH target the hepatocytes, in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells. Persistent liver injury, associated with chronic AILD, leads to un-resolving inflammation, cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts. Liver cirrhosis, and the resultant loss of normal liver function, inevitably ensues. Patients with cirrhosis have higher risks or morbidity and mortality, and that in the decompensated phase, complications of portal hypertension and/or liver dysfunction lead to rapid deterioration. Accurate diagnosis and monitoring of cirrhosis is, therefore of upmost importance. Liver biopsy is currently the gold standard technique, but highly promising non-invasive methodology is under development. Liver transplantation (LT) is an effective therapeutic option for the management of end-stage liver disease secondary to AIH, PBC and PSC. LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy; in addition, LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.
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Abstract
Methods of liver fibrosis assessment have changed considerably in the last 20 years, and noninvasive markers now have been recognized as major first-line tools in the management of patients with chronic viral hepatitis infection. But what about the efficiency and utility of these surrogate indices for the more uncommon chronic cholestatic liver diseases, namely primary biliary cirrhosis and primary sclerosing cholangitis? This article provides clinicians with a global overview of what is currently known in the field. Both diagnostic and prognostic aspects of noninvasive markers of fibrosis in cholestatic liver diseases are presented and discussed.
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Affiliation(s)
- Christophe Corpechot
- Hepatology Department, Reference Center for Chronic Inflammatory Biliary Diseases (MIVB), French Network for Childhood and Adult Rare Liver Diseases (FILFOIE), Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris (APHP), 184 rue du Faubourg Saint-Antoine, 75571, Paris Cedex 12, France; Inserm UMR_S938, Faculty of Medicine Pierre et Marie Curie, Saint-Antoine Site, Paris 6 University, 27 rue de Chaligny, Paris 75012, France.
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Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor KD, Janssen HLA, Floreani A, Ponsioen CY, Mayo MJ, Invernizzi P, Battezzati PM, Parés A, Burroughs AK, Mason AL, Kowdley KV, Kumagi T, Harms MH, Trivedi PJ, Poupon R, Cheung A, Lleo A, Caballeria L, Hansen BE, van Buuren HR. Development and Validation of a Scoring System to Predict Outcomes of Patients With Primary Biliary Cirrhosis Receiving Ursodeoxycholic Acid Therapy. Gastroenterology 2015; 149:1804-1812.e4. [PMID: 26261009 DOI: 10.1053/j.gastro.2015.07.061] [Citation(s) in RCA: 313] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 07/27/2015] [Accepted: 07/30/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Approaches to risk stratification for patients with primary biliary cirrhosis (PBC) are limited, single-center based, and often dichotomous. We aimed to develop and validate a better model for determining prognoses of patients with PBC. METHODS We performed an international, multicenter meta-analysis of 4119 patients with PBC treated with ursodeoxycholic acid at liver centers in 8 European and North American countries. Patients were randomly assigned to derivation (n = 2488 [60%]) and validation cohorts (n = 1631 [40%]). A risk score (GLOBE score) to predict transplantation-free survival was developed and validated with univariate and multivariable Cox regression analyses using clinical and biochemical variables obtained after 1 year of ursodeoxycholic acid therapy. Risk score outcomes were compared with the survival of age-, sex-, and calendar time-matched members of the general population. The prognostic ability of the GLOBE score was evaluated alongside those of the Barcelona, Paris-1, Rotterdam, Toronto, and Paris-2 criteria. RESULTS Age (hazard ratio = 1.05; 95% confidence interval [CI]: 1.04-1.06; P < .0001); levels of bilirubin (hazard ratio = 2.56; 95% CI: 2.22-2.95; P < .0001), albumin (hazard ratio = 0.10; 95% CI: 0.05-0.24; P < .0001), and alkaline phosphatase (hazard ratio = 1.40; 95% CI: 1.18-1.67; P = .0002); and platelet count (hazard ratio/10 units decrease = 0.97; 95% CI: 0.96-0.99; P < .0001) were all independently associated with death or liver transplantation (C-statistic derivation, 0.81; 95% CI: 0.79-0.83, and validation cohort, 0.82; 95% CI: 0.79-0.84). Patients with risk scores >0.30 had significantly shorter times of transplant-free survival than matched healthy individuals (P < .0001). The GLOBE score identified patients who would survive for 5 years and 10 years (responders) with positive predictive values of 98% and 88%, respectively. Up to 22% and 21% of events and nonevents, respectively, 10 years after initiation of treatment were correctly reclassified in comparison with earlier proposed criteria. In subgroups of patients aged <45, 45-52, 52-58, 58-66, and ≥66 years, age-specific GLOBE-score thresholds beyond which survival significantly deviated from matched healthy individuals were -0.52, 0.01, 0.60, 1.01 and 1.69, respectively. Transplant-free survival could still be accurately calculated by the GLOBE score with laboratory values collected at 2-5 years after treatment. CONCLUSIONS We developed and validated scoring system (the GLOBE score) to predict transplant-free survival of ursodeoxycholic acid-treated patients with PBC. This score might be used to select strategies for treatment and care.
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Affiliation(s)
- Willem J Lammers
- Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - Gideon M Hirschfield
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Christophe Corpechot
- Centre de Référence des Maladies Inflammatoires des Voies Biliaires, Hôpital Saint-Antoine, APHP, Paris, France
| | - Frederik Nevens
- Department of Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Keith D Lindor
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Arizona State University, College of Health Solutions, Phoenix, Arizona
| | - Harry L A Janssen
- Liver Clinic, Toronto Western and General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Marlyn J Mayo
- Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas
| | - Pietro Invernizzi
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Pier M Battezzati
- Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Albert Parés
- Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Andrew K Burroughs
- The Sheila Sherlock Liver Centre, The Royal Free Hospital, London, United Kingdom
| | - Andrew L Mason
- Divison of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada
| | - Kris V Kowdley
- Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington
| | - Teru Kumagi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Maren H Harms
- Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - Palak J Trivedi
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Raoul Poupon
- Centre de Référence des Maladies Inflammatoires des Voies Biliaires, Hôpital Saint-Antoine, APHP, Paris, France
| | - Angela Cheung
- Liver Clinic, Toronto Western and General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Ana Lleo
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Llorenç Caballeria
- Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Bettina E Hansen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - Henk R van Buuren
- Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
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Vierling JM. Autoimmune Hepatitis and Overlap Syndromes: Diagnosis and Management. Clin Gastroenterol Hepatol 2015; 13:2088-108. [PMID: 26284592 DOI: 10.1016/j.cgh.2015.08.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/11/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
Affiliation(s)
- John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St Luke's Medical Center, Houston, Texas.
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Chan AWH, Chan RCK, Wong GLH, Wong VWS, Choi PCL, Chan HLY, To KF. New simple prognostic score for primary biliary cirrhosis: Albumin-bilirubin score. J Gastroenterol Hepatol 2015; 30:1391-6. [PMID: 25753927 DOI: 10.1111/jgh.12938] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/01/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Serum albumin and bilirubin are the most significant independent prognostic factors to predict hepatic events in patients with primary biliary cirrhosis (PBC). We aimed to investigate the prognostic significance of a new prognostic score, the albumin-bilirubin (ALBI) score, among PBC patients. METHODS In a retrospective longitudinal cohort of 61 Chinese PBC patients with follow-up period up to 18.3 years, the prognostic performance of the ALBI in prediction of hepatic events was compared with other well-established prognostic scores: Child-Pugh score, model of end-stage liver disease, Mayo risk score, Yale, European, and Newcastle models. RESULTS Fifteen patients (24.6%) developed hepatic events during follow-up. The c-index (0.894) and χ(2) by likelihood ratio test (36.34) of the ALBI score were highest in comparison to other models. The ALBI score was the only independent prognostic factor by multivariate analysis and its adjusted hazard ratio of developing hepatic event was 27.8 (P < 0.001). There were three prognostically different groups stratified by the ALBI score: ALBI grade 1 (≤ -2.60), grade 2 (> -2.60 to -1.39), and grade 3 (> -1.39) groups. The 2-, 5-, and 10-year event-free survivals for grade 1, grade 2, and grade 3 groups were 100.0% versus 100.0% versus 57.1%, 100.0% versus 88.5% versus 14.3%, and 100.0% versus 81.7% versus 0.0%, respectively (P < 0.001). CONCLUSION The ALBI score is readily derived from a blood test without using those factors evaluated subjectively or obtained by invasive procedures. It is an independent prognostic factor for PBC patients and provides better/similar prognostic performance compared with other prognostic scores.
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Affiliation(s)
- Anthony W H Chan
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
| | - Ronald C K Chan
- Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Grace L H Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Vincent W S Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Paul C L Choi
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
| | - Henry L Y Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China
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Predictive scores in primary biliary cirrhosis: a retrospective single center analysis of 204 patients. J Clin Gastroenterol 2015; 49:438-47. [PMID: 25014239 DOI: 10.1097/mcg.0000000000000176] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
GOALS The aim of this study was to assess the long-term outcome of primary biliary cirrhosis (PBC) patients and to test the clinical value of various outcome models, such as the Mayo Risk Score (MRS), in a large single-center cohort in Germany. BACKGROUND PBC is a chronic autoimmune liver disease with a female gender predominance and a peak incidence in the fifth decade of life. PBC is characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts in liver histology and the presence of antimitochondrial antibodies in the serum of nearly 95% of patients. In 5% to 20% of patients an overlap syndrome with autoimmune hepatitis (AIH) is diagnosed. Ursodeoxycholic acid is widely accepted as the standard medical treatment. STUDY A total of 204 patients with PBC or PBC/AIH were retrospectively analyzed with regard to their clinical, biochemical, serological, and histologic features. PBC was diagnosed on the basis of the American Association for the Study of Liver Diseases criteria. Specific PBC scores, such as the MRS, the European and the Yale model, as well as nonspecific scores such as the Child-Pugh, the Model for End-stage Liver Disease, and Aspartate Aminotransferase to Platelet Ratio Index score were analyzed for their utility to predict the clinical outcome of patients. RESULTS One hundred eighty-four patients with PBC alone and 20 with primary biliary cirrhosis/autoimmune hepatitis overlap were followed up for an average of 7.0 (range, 0.5 to 33.2) years. Importantly, baseline values of serum bilirubin, alkaline phosphatase, immunoglobulin M (IgM) and IgG, as well as antimitochondrial antibodies titers did not allow in properly predicting patient's outcome. The MRS proved clinical applicability. Patients with an R-value <6 did not develop liver-related complications. The Aspartate Aminotransferase to Platelet Ratio Index score had a significant correlation with the histologic degree of liver fibrosis, with limited value of scores between 1.0 and 1.5. Patients with a Model for End-stage Liver Disease score ≥8 (n=17) had a significantly higher risk to undergo liver transplantation or liver-related death. Outcome was less favorable than predicted by the European model. All scores showed low positive predictive values, limiting their applicability in clinical practice. CONCLUSIONS Herein, we demonstrate that clinical risk scores in PBC should be interpreted with care. The MRS proved to be helpful to predict a favorable outcome. Novel approaches to predict outcome are needed to identify patients who may benefit from alternative, intensified treatment regimens.
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50
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Tanaka T, Yamashiki N, Sugawara Y, Tamura S, Nakamura M, Kaneko J, Aoki T, Sakamoto Y, Hasegawa K, Kokudo N. Chronologic changes of explanted liver volume and the use of ursodeoxycholic acid in patients with end-stage primary biliary cirrhosis. Hepatol Res 2014; 44:993-999. [PMID: 24298893 DOI: 10.1111/hepr.12283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 11/12/2013] [Accepted: 11/26/2013] [Indexed: 12/13/2022]
Abstract
AIM The clinical presentation of Primary biliary cirrhosis (PBC) at the time of liver transplantation (LT) may have changed, due to the long-term use of ursodeoxycholic acid (UDCA). The aim of this retrospective study was to investigate whether the clinical characteristics of LT recipients with PBC have changed over the years. METHODS Of all 421 adults undergoing LT from 1997 to 2012 at our center, we included 85 recipients with PBC into the present study. The 85 recipients were divided into three groups according to the year LT was performed: group 1 (1997-2001, n = 29), group 2 (2002-2005, n = 29) and group 3 (2006-2012, n = 27). RESULTS There were no significant differences in sex, recipient age, Model for End-Stage Liver Disease score, updated Mayo risk score for PBC, or liver-related complications except for esophageal varices among the three groups. Patients in group 1 were complicated with esophageal varices less frequently than those in the other two groups. In older cases, the ratio of explanted liver volume to standard liver volume (ELV/SLV) was significantly higher, and the duration of pre-LT UDCA treatment was significantly shorter. The duration of UDCA treatment was significantly correlated with ELV/SLV. CONCLUSION Recent LT patients were characterized by more frequent portal hypertension and more severe liver atrophy, with longer UDCA therapy prior to LT, which might have prevented the somewhat rapid progression of liver failure characterized by hepatomegaly with insignificant fibrosis or portal hypertension.
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Affiliation(s)
- Tomohiro Tanaka
- Organ Transplantation Service, The University of Tokyo Hospital, Tokyo, Japan
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