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Mol B, Werner E, Culver EL, van der Meer AJ, Bogaards JA, Ponsioen CY. Epidemiological and economical burden of cholestatic liver disease. Hepatology 2025:01515467-990000000-01224. [PMID: 40168457 DOI: 10.1097/hep.0000000000001341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 03/24/2025] [Indexed: 04/03/2025]
Abstract
The main cholestatic liver diseases comprise primary sclerosing cholangitis, primary biliary cholangitis, and IgG4-related cholangitis. Despite being classified as rare diseases, these are becoming gradually more important in the field of hepatology since their incidence is slowly rising while the viral hepatitis burden is declining. Cholestatic liver diseases now rank among the 3 most frequent indications for liver transplantation in many Western countries. An accurate understanding of the epidemiology and burden of disease on both the individual and society of cholestatic diseases is of great importance. This review aims to provide a comprehensive overview of the current literature on the epidemiology, health-related quality of life, and economic burden of primary sclerosing cholangitis, primary biliary cholangitis, and IgG4-related cholangitis.
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Affiliation(s)
- Bregje Mol
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
- Endocrinology and Metabolism, Amsterdam Institute of Gastroenterology, Amsterdam, The Netherlands
| | - Ellen Werner
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Emma L Culver
- Oxford Liver Unit, John Radcliffe Hospital, Oxford, UK
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Johannes A Bogaards
- Department of Epidemiology and Data Science, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
- Endocrinology and Metabolism, Amsterdam Institute of Gastroenterology, Amsterdam, The Netherlands
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Bowlus C, Levy C, Kowdley KV, Kachru N, Jeyakumar S, Rodriguez-Guadarrama Y, Smith N, Briggs A, Sculpher M, Ollendorf D. Development of the natural history component of an early economic model for primary sclerosing cholangitis. Orphanet J Rare Dis 2025; 20:133. [PMID: 40102907 PMCID: PMC11921552 DOI: 10.1186/s13023-025-03658-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 03/06/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a rare, chronic cholestatic disease that can progress to cirrhosis and liver failure. The natural history of PSC is variable as liver enzymes and liver symptoms fluctuate over time. Several drugs for PSC are under investigation, but there are currently no economic models to evaluate the cost-effectiveness and value of new treatments. The objective of this study was to develop an early economic model for PSC and validate the natural history component. METHODS A lifetime horizon Markov cohort model was developed to track the progression of adults with PSC with or without inflammatory bowel disease. Based on relevant literature and clinical expert advice, fibrosis staging was used to model disease progression. Evidence on disease progression, mortality, PSC-related complications, and secondary cancers was identified by literature searches and validated by interviews with clinical and cost-effectiveness modelling experts. Model outcomes were overall survival and transplant-free survival years, and the proportions of patients receiving liver transplants, 2nd liver transplants after recurrent PSC (rPSC), and developing rPSC after liver transplantation during their lifetime. Cumulative incidence of secondary cancers and quality-adjusted life-years (QALYs) were also tracked. RESULTS Model outcomes are in line with estimates reported in literature recommended by clinical experts. Overall survival (95% uncertainty interval [UI]) was estimated to be 25.0 (23.2-26.3) years and transplant-free survival was estimated to be 22.0 (20.2-23.6) years. The estimated proportion (95% UI) of patients receiving first liver transplants was 14.5% (11.6-17.1%), while the proportion of patients developing rPSC and receiving 2nd liver transplants after rPSC was 24.2% (20.4-28.0%) and 21.6% (12.9-29.7%), respectively. The cumulative incidence (95% UI) of cholangiocarcinoma, colorectal cancer, and gallbladder cancer were estimated at 5.2% (2.1-10.0%), 3.6% (1.4-5.4%), and 3.3% (1.2-7.6%), respectively. Discounted lifetime QALYs per patient (95% UI) were estimated at 16.4 (15.6-17.1). CONCLUSIONS We have developed a model framework to simulate the progression of PSC with estimates of overall and transplant-free survival. This model, which calibrates well with existing estimates of disease progression, may be useful to evaluate the clinical and economic benefits of future treatments.
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Affiliation(s)
| | - Cynthia Levy
- University of Miami Miller School of Medicine, Miami, FL, USA
| | | | | | | | | | | | | | | | - Daniel Ollendorf
- Center for the Evaluation of Value and Risk in Health, Tufts Medical Center, Boston, MA, USA
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Zhang L, Yu J, Gao X, Yan Y, Wang X, Shi H, Fang M, Liu Y, Kim YB, Zhu H, Wu X, Huang C, Fan S. Targeting farnesoid X receptor as aging intervention therapy. Acta Pharm Sin B 2025; 15:1359-1382. [PMID: 40370561 PMCID: PMC12069902 DOI: 10.1016/j.apsb.2025.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/21/2024] [Accepted: 11/14/2024] [Indexed: 05/16/2025] Open
Abstract
Environmental toxicants have been linked to aging and age-related diseases. The emerging evidence has shown that the enhancement of detoxification gene expression is a common transcriptome marker of long-lived mice, Drosophila melanogaster, and Caenorhabditis elegans. Meanwhile, the resistance to toxicants was increased in long-lived animals. Here, we show that farnesoid X receptor (FXR) agonist obeticholic acid (OCA), a marketed drug for the treatment of cholestasis, may extend the lifespan and healthspan both in C. elegans and chemical-induced early senescent mice. Furthermore, OCA increased the resistance of worms to toxicants and activated the expression of detoxification genes in both mice and C. elegans. The longevity effects of OCA were attenuated in Fxr -/- mice and Fxr homologous nhr-8 and daf-12 mutant C. elegans. In addition, metabolome analysis revealed that OCA increased the endogenous agonist levels of the pregnane X receptor (PXR), a major nuclear receptor for detoxification regulation, in the liver of mice. Together, our findings suggest that OCA has the potential to lengthen lifespan and healthspan by activating nuclear receptor-mediated detoxification functions, thus, targeting FXR may offer to promote longevity.
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Affiliation(s)
- Lijun Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jing Yu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaoyan Gao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yingxuan Yan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xinyi Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hang Shi
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Minglv Fang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ying Liu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Young-Bum Kim
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
| | - Huanhu Zhu
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Xiaojun Wu
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Cheng Huang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Shengjie Fan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Zhang W, Wang Z, Sun R, Zeng Y, Chen Y, Hu Q, Chen L, Ma X, Guo Y, Zhao Y. Exploration of the Combined Mechanism of Direct and Indirect Effects of Paeoniflorin in the Treatment of Cholestasis. Inflammation 2025:10.1007/s10753-025-02245-0. [PMID: 39869299 DOI: 10.1007/s10753-025-02245-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 12/16/2024] [Accepted: 01/12/2025] [Indexed: 01/28/2025]
Abstract
Cholestasis is a multifactorial hepatobiliary disorder, characterized by obstruction of bile flow and accumulation of bile, which in turn causes damage to liver cells and other tissues. In severe cases, it can result in the development of life-threatening conditions, including cirrhosis and liver cancer. Paeoniflorin (PF) has been demonstrated to possess favourable therapeutic potential for the treatment of cholestasis. The objective of this research was to examine the molecular mechanism of PF in the treatment of ANIT-induced cholestasis and to propose novel avenues for further research on the pharmacological effects of PF. In vivo and in vitro models of cholestasis were developed. The histopathological changes in the bile ducts and liver were evaluated through the use of hematoxylin and eosin (HE) staining. The extent of apoptosis was evaluated through the use of immunofluorescence (IF), immunoblotting (WB), and electron microscopy. The JNK signalling pathway was identified as the direct mechanism of action of PF through the utilisation of HuProt™ 20 K chips and other technologies. The present study demonstrated that PF markedly alleviated liver injury in an ANIT-induced cholestasis model. Specifically, PF was observed to attenuate cholestasis-induced liver injury by reducing the abnormal elevation of liver function indices and suppressing the expression of inflammatory mediators. Furthermore, PF exhibited anti-apoptotic properties in both in vivo and in vitro experiments, thereby mitigating cholestasis-induced hepatocyte apoptosis. These protective effects are attributable to the fact that PF exerts its action through direct interaction with the JNK pathway. It has been demonstrated that PF is capable of binding directly to MAPK8 (JNK1) and MAPK9 (JNK2), thereby inhibiting JNK activation and reducing apoptosis. With regard to the protection of bile ducts, PF may indirectly inhibit hepatocyte apoptosis by maintaining the structural integrity and tight junctions of bile duct cells. PF improved cholestasis by inhibiting hepatocyte apoptosis directly by targeting the JNK signaling pathway and indirectly inhibited hepatocyte apoptosis by improving the tight junctions of bile duct cells to regulate the bile duct microenvironment.
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Affiliation(s)
- Wenwen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zexin Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Rong Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yi Zeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qichao Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lisheng Chen
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Yaoguang Guo
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Yanling Zhao
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China.
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Chang ML, Le PH, Chen WT, Chen TD, Su CW, Chen CJ, Lin CY, Wu CH, Kuo CJ, Sung KF, Chien RN. Distinct characteristics of various autoimmune liver diseases: A 22-year hospital-based study in Taiwan. J Gastroenterol Hepatol 2024; 39:2835-2844. [PMID: 39307997 DOI: 10.1111/jgh.16736] [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: 05/15/2024] [Revised: 08/13/2024] [Accepted: 08/27/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND AND AIM The characteristics of autoimmune liver diseases (AILDs), including primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and PBC-AIH overlap syndrome (OS), have rarely been investigated and compared in Asia. METHODS At the Taiwan tertiary referral center, 330 PBC patients (87% treated with ursodeoxycholic acid [UDCA]), 143 AIH patients (94.4% treated with immunosuppressive therapy [IST]) and 21 PBC-AIH OS patients (85.7% treated with UDCA and IST) were enrolled. RESULTS Compared with AIH patients, PBC patients were older at baseline and had greater female-to-male sex ratios, alkaline phosphatase (ALP) and γ-glutamyl transferase (γ-GT) levels, and liver cirrhosis (LC), dyslipidemia, and hepatic and cardiometabolic complication rates. PBC patients had the lowest transaminase levels, whereas AIH patients had the highest transaminase levels. PBC patients had greater 22-year all-cause mortality and liver transplantation (ACMaLT) (43.5 vs 25.4%, P = 0.004), LC (75 vs 58.5%, P < 0.01), dyslipidemia (54.4 vs 45.9%, P = 0.001), and cerebrovascular accident (11.3 vs 0.8%, P = 0.019) cumulative incidences (CIs) than did AIH patients; PBC-AIH OS patients had greater systemic lupus erythematosus (28.9 vs 8.9%, P = 0.009) CI than did PBC patients. Baseline ALP (hazard ratio: 1.001), albumin (0.514), platelet count (0.997), and LC (3.438) were associated with ACMaLT; age (1.110), albumin (0.350), cirrhosis (46.219), and hepatitis C virus antibody positivity (5.068) were associated with hepatocellular carcinoma (HCC); and female sex (2.183) and body mass index (1.054) were associated with autoimmune diseases. CONCLUSIONS Compared with AIH patients, PBC patients had greater cardiometabolic CI, and ACMaLT CI, which was associated with cholestasis, liver functional reserve and LC. Older AILD patients with LC and females with obesity demand special caution for the development of HCC and extrahepatic autoimmune diseases, respectively.
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Affiliation(s)
- Ming-Ling Chang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Puo-Hsien Le
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Ting Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tai-Di Chen
- Department of Anatomic Pathology, Chang Gung Memorial Hospital Linkou Main Branch, Taoyuan, Taiwan
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Chung-Wei Su
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Jen Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Yu Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chi-Huan Wu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Jung Kuo
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kei-Feng Sung
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Shang S, Li W, Zhou F, Zhao Y, Yu M, Tong L, Xin H, Yu A. Cyclosporine-A induced cytotoxicity within HepG2 cells by inhibiting PXR mediated CYP3A4/CYP3A5/MRP2 pathway. Drug Chem Toxicol 2024; 47:739-747. [PMID: 38166548 DOI: 10.1080/01480545.2023.2276084] [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: 05/06/2023] [Revised: 09/16/2023] [Accepted: 10/13/2023] [Indexed: 01/04/2024]
Abstract
Cyclosporine-A (CsA) is currently used to treat immune rejection after organ transplantation as a commonly used immunosuppressant. Liver injury is one of the most common adverse effects of CsA, whose precise mechanism has not been fully elucidated. Pregnane X receptor (PXR) plays a critical role in mediating drug-induced liver injury as a key regulator of drug and xenobiotic clearance. As a nuclear receptor, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and drug transporters, including cytochrome P4503A (CPY3A) and multidrug resistance-associated protein 2 (MRP2). Our study established CsA-induced cytotoxic hepatocytes in an in vitro model, demonstrating that CsA dose-dependently increased the aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) level secreted in the HepG2 cell supernatant, as well as viability and oxidative stress of HepG2 cells. CsA also dose-dependently decreased the PXR, CYP3A4, CPY3A5, and MRP2 levels of HepG2 cells. Mechanistically, altering the expression of PXR, CYP3A4, CYP3A5, and MRP2 affected the impact of CsA on AST and LDH levels. Moreover, altering the expression of PXR also changed the level of CYP3A4, CPY3A5, and MRP2 of HepG2 cells treated by CsA. Our presented findings provide experimental evidence that CsA-induced liver injury is PXR tightly related. We suggest that PXR represents an attractive target for therapy of liver injury due to its central role in the regulation of the metabolizing enzymes CYP3A and MRP2-mediated bile acid transport and detoxification.
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Affiliation(s)
- Shenglan Shang
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Weiliang Li
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Fan Zhou
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Yan Zhao
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Mengchen Yu
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Ling Tong
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Huawen Xin
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Airong Yu
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
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Chang ML, Cheng JS, Le PH, Chen WT, Ku HP, Chien RN. Evolutionary relationship between antimitochondrial antibody positivity and primary biliary cholangitis in Taiwan: a 16-year hospital cohort study. Therap Adv Gastroenterol 2024; 17:17562848241241227. [PMID: 38560427 PMCID: PMC10981211 DOI: 10.1177/17562848241241227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 03/06/2024] [Indexed: 04/04/2024] Open
Abstract
Background How antimitochondrial antibody (AMA)-positive patients evolve to have primary biliary cholangitis (PBC) in viral hepatitis-endemic areas is unknown. Objectives We aimed to investigate this evolution in Taiwan. Design/methods A 16-year medical center-based cohort study of 2,095,628 subjects was conducted in Taiwan, an Asian country endemic to viral hepatitis. AMA-positive subjects were those with positive AMA with alkaline phosphatase (ALP) ⩽1.5 times the upper limit of normal (ULN), and PBC was defined as positive AMA with ALP >1.5 × ULN. Results AMA-positive subjects had a lower average age- and sex-adjusted prevalence than PBC patients (4.68/105 versus 11.61/105, p = 0.0002), but their incidence was comparable (0.99/105 versus 1.12/105, p = 0.36). The former group had a borderline significantly lower mean age (56.59 years versus 58.10 years, p = 0.06) and a lower female-to-male ratio (2.85:1 versus 5.44:1, p < 0.0001). Both AMA-positive subjects (prevalence change: 20.0%, p < 0.01; incidence change: -9.2%, p < 0.01) and PBC patients (prevalence change: 14.6%, p < 0.01; incidence change: -4.7%, p < 0.01) prevalence rate increased but the incidence rate decreased. Among the 423 AMA-positive subjects, 77 (18.2%) developed PBC, for a mean duration of 1.757 years. Compared with AMA-positive subjects, PBC patients had similar concurrent chronic hepatitis B (CHB) rates (2.7% versus 4.3%, p = 0.197) but lower chronic hepatitis C (CHC) rates (3.69% versus 15.60%, p < 0.01). Conclusion PBC was more prevalent than AMA-positive subjects, and PBC patients had a higher female-to-male ratio than AMA-positive subjects, of whom 18.2% developed PBC (mean lag: 1.757 years). Upward trends in prevalence rates and downward trends in incidence rates were noted for both AMA-positive subjects and PBC. CHB was rare, CHC was more prevalent among PBC patients than the general population, and CHC was less prevalent among PBC than among AMA-positive subjects.
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Affiliation(s)
- Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, No. 5, Fu Hsing Street, Kuei Shan, Taoyuan 333423, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jur-Shan Cheng
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Puo-Hsien Le
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Ting Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hsin-Ping Ku
- Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Chhatwal J, Tapper EB. Nonalcoholic Fatty Liver Disease Natural History: Role of Mathematical Modeling. Clin Gastroenterol Hepatol 2023; 21:280-282. [PMID: 35123079 DOI: 10.1016/j.cgh.2022.01.041] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023]
Affiliation(s)
- Jagpreet Chhatwal
- Massachusetts General Hospital, Institute for Technology Assessment, Harvard Medical School, Boston, Massachusetts
| | - Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
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Wang L, Sun K, Tian A, Liu Y, Zhang M, Zhou X, Han Y. Fenofibrate improves GLOBE and UK-PBC scores and histological features in primary biliary cholangitis. Minerva Med 2022; 113:974-982. [PMID: 33949176 DOI: 10.23736/s0026-4806.21.07316-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Fenofibrate (FF) has been suggested as a second-line therapy for primary biliary cholangitis (PBC) with suboptimal response to ursodeoxycholic acid (UDCA). But its long-term effect is unclear. METHODS From a retrospective cohort (N.=838), we enrolled 106 UDCA-refractory PBC patients, among them 62 received UDCA monotherapy (UDCA group) and 44 received FF combined with UDCA (UDCA+FF group). Changes of liver biochemistries and prognosis after treatment were determined. In addition, sequential liver biopsies were used to assess the effect of FF on histological parameters. RESULTS We found adding FF could significantly reduce serum levels of alkaline phosphatase (ALP), but for patients with pretreatment ALP≥1.67 upper limit of normal (ULN), the significant decline of serum ALP was only observed in the UDCA+FF group after 1 year of therapy. The mean GLOBE Score and the liver transplant-free survival predicted by GLOBE Score were both improved significantly in patients receiving UDCA+FF after 1 year of therapy. The liver-related death or liver transplant calculated using UK-PBC risk score was significantly reduced in patients receiving UDCA+FF after 1 year of therapy. Although there was no marked difference in the final histological analysis after 3 years of therapy, patients receiving UDCA+FF had improvements or stabilization in fibrosis (85.7%), and bile duct loss (78.6%) were more than that of patients receiving UDCA (70.6% and 76.5%, respectively). CONCLUSIONS Adding FF improves GLOBE and UK-PBC scores and is also associated with the improvements or stabilization of disease features, including fibrosis and ductular injury.
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Affiliation(s)
- Lu Wang
- Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, Air Force Medical University, Xi'an, China
| | - Keshuai Sun
- Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ai Tian
- Department of Hepatology, the 9th Hospital of Nan chang, Nan chang, China
| | - Yansheng Liu
- Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Miao Zhang
- Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xinmin Zhou
- Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ying Han
- Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China -
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Bittermann T. The Potential Synergy of Using Interventional and Observational Data to Study Clinically Meaningful, Long-term Outcomes in Rare Liver and Luminal Diseases. Gastroenterology 2022; 163:1491-1492. [PMID: 36181834 DOI: 10.1053/j.gastro.2022.09.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 09/26/2022] [Indexed: 12/02/2022]
Affiliation(s)
- Therese Bittermann
- Department of Medicine, Division of Gastroenterology & Hepatology and, Department of Biostatistics, Epidemiology & Informatics, University of Pennsylvania, Philadelphia, Pennsylvania.
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Murillo Perez CF, Fisher H, Hiu S, Kareithi D, Adekunle F, Mayne T, Malecha E, Ness E, van der Meer AJ, Lammers WJ, Trivedi PJ, Battezzati PM, Nevens F, Kowdley KV, Bruns T, Cazzagon N, Floreani A, Mason AL, Parés A, Londoño MC, Invernizzi P, Carbone M, Lleo A, Mayo MJ, Dalekos GN, Gatselis NK, Thorburn D, Verhelst X, Gulamhusein A, Janssen HLA, Smith R, Flack S, Mulcahy V, Trauner M, Bowlus CL, Lindor KD, Corpechot C, Jones D, Mells G, Hirschfield GM, Wason J, Hansen BE. Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls. Gastroenterology 2022; 163:1630-1642.e3. [PMID: 36150526 DOI: 10.1053/j.gastro.2022.08.054] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 07/19/2022] [Accepted: 08/30/2022] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (ie, alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The objective of this study was to evaluate time to first occurrence of liver transplantation or death in patients with OCA in the POISE trial and open-label extension vs comparable non-OCA-treated external controls. METHODS Propensity scores were generated for external control patients meeting POISE eligibility criteria from 2 registry studies (Global PBC and UK-PBC) using an index date selected randomly between the first and last date (inclusive) on which eligibility criteria were met. Cox proportional hazards models weighted by inverse probability of treatment assessed time to death or liver transplantation. Additional analyses (Global PBC only) added hepatic decompensation to the composite end point and assessed efficacy in patients with or without cirrhosis. RESULTS During the 6-year follow-up, there were 5 deaths or liver transplantations in 209 subjects in the POISE cohort (2.4%), 135 of 1381 patients in the Global PBC control (10.0%), and 281 of 2135 patients in the UK-PBC control (13.2%). The hazard ratios (HRs) for the primary outcome were 0.29 (95% CI, 0.10-0.83) for POISE vs Global PBC and 0.30 (95% CI, 0.12-0.75) for POISE vs UK-PBC. In the Global PBC study, HR was 0.20 (95% CI, 0.03-1.22) for patients with cirrhosis and 0.31 (95% CI, 0.09-1.04) for those without cirrhosis; HR was 0.42 (95% CI, 0.21-0.85) including hepatic decompensation. CONCLUSIONS Patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients.
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Affiliation(s)
- C Fiorella Murillo Perez
- Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Holly Fisher
- Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Shaun Hiu
- Newcastle University, Newcastle upon Tyne, United Kingdom
| | | | | | - Tracy Mayne
- Intercept Pharmaceuticals, Morristown, New Jersey
| | | | - Erik Ness
- Intercept Pharmaceuticals, Morristown, New Jersey
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Willem J Lammers
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | | | | | - Frederik Nevens
- University Hospital Katholieke Universiteit Leuven, Leuven, Belgium
| | | | - Tony Bruns
- Department of Gastroenterology and Hepatology, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
| | | | | | - Andrew L Mason
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Albert Parés
- Department of Medicine, Liver Unit, Hospital Clínic, University of Barcelona, The August Pi i Sunyer Biomedical Research Institute, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Barcelona, Spain; European Reference Network on Hepatological Diseases, Barcelona, Spain
| | - Maria-Carlota Londoño
- Department of Medicine, Liver Unit, Hospital Clínic, University of Barcelona, The August Pi i Sunyer Biomedical Research Institute, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Barcelona, Spain; European Reference Network on Hepatological Diseases, Barcelona, Spain
| | - Pietro Invernizzi
- European Reference Network on Hepatological Diseases, Barcelona, Spain; Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; San Gerardo Hospital, Monza, Italy
| | | | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Marlyn J Mayo
- Department of Medicine, Division of Digestive and Liver Disease, University of Texas, Southwestern Medical Center, Dallas, Texas
| | - George N Dalekos
- European Reference Network on Hepatological Diseases, Barcelona, Spain; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Nikolaos K Gatselis
- European Reference Network on Hepatological Diseases, Barcelona, Spain; Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Douglas Thorburn
- Royal Free London National Health Service Foundation Trust, London, United Kingdom
| | - Xavier Verhelst
- Department of Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Aliya Gulamhusein
- Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Rachel Smith
- Cambridge Liver Unit, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom
| | - Steve Flack
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Victoria Mulcahy
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | | | | | | | | | - David Jones
- Newcastle University, Newcastle upon Tyne, United Kingdom
| | - George Mells
- Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - James Wason
- Department of Biostatistics, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, the Netherlands, Toronto, Ontario, Canada; IHPME, University of Toronto, Toronto, Ontario, Canada.
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12
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Wang ZL, Jin R, Hao M, Xie YD, Liu ZC, Wang XX, Feng B. Treatment of ursodeoxycholic acid with glucocorticoids and immunosuppressants may improve the long-term survival rate in primary biliary cholangitis patients. Medicine (Baltimore) 2022; 101:e31395. [PMID: 36401422 PMCID: PMC9678505 DOI: 10.1097/md.0000000000031395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 09/28/2022] [Indexed: 12/05/2022] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease. The clinical effectiveness of ursodeoxycholic acid (UDCA) plus glucocorticoids and/or immunosuppressants remains controversial in PBC patients. The study aimed to compare the efficacy of monotherapy and combination therapy in patients with PBC and to assess the factors affecting the efficacy. In this retrospective study, 266 patients diagnosed with PBC were divided into monotherapy group (UDCA), double therapy group (UDCA plus glucocorticoids or immunosuppressants), and triple therapy group (UDCA plus glucocorticoids and immunosuppressants) according to different treatments. Demographic characteristics, immune parameters, biochemistry profiles, and other indicators were evaluated at baseline, 6 months, and 1 year following treatment. The prognosis was evaluated using the Paris II standard. The liver transplant-free survival at 3, 5, 10, and 15 years was predicted by GLOBE score. All statistical analyses were conducted using SPSS (version 24) software (SPSS Inc, Chicago, IL). The long-term survival rate of the triple therapy group was significantly improved compared with the monotherapy group (P = .005). In addition, multivariate analysis showed that abnormal platelet count, alkaline phosphatase, and albumin levels were risk factors for poor response. When IgG levels were elevated but below twice the upper limit of normal, the clinical benefit was not significant compared with monotherapy (P > .05). Compared with monotherapy and double therapy, triple therapy may improve the long-term survival rate of PBC patients. Abnormal platelet count, alkaline phosphatase, and albumin levels were associated with a poor prognosis.
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Affiliation(s)
- Zi-Long Wang
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University Hepatology Institute, Peking University People’s Hospital, Beijing, China
| | - Rui Jin
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University Hepatology Institute, Peking University People’s Hospital, Beijing, China
| | - Mei Hao
- Medical Information Center, Peking University People’s Hospital, Beijing, China
| | - Yan-Di Xie
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University Hepatology Institute, Peking University People’s Hospital, Beijing, China
| | - Zhi-Cheng Liu
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University Hepatology Institute, Peking University People’s Hospital, Beijing, China
| | - Xiao-Xiao Wang
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University Hepatology Institute, Peking University People’s Hospital, Beijing, China
| | - Bo Feng
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University Hepatology Institute, Peking University People’s Hospital, Beijing, China
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13
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Yuan Z, Wang J, Zhang H, Miao Y, Tang Q, Yuan Z, Nong C, Duan Z, Zhang L, Jiang Z, Yu Q. Triptolide increases resistance to bile duct ligation-induced liver injury and fibrosis in mice by inhibiting RELB. Front Nutr 2022; 9:1032722. [PMID: 36313114 PMCID: PMC9608656 DOI: 10.3389/fnut.2022.1032722] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/28/2022] [Indexed: 12/04/2022] Open
Abstract
Cholestasis is a common, chronic liver disease that may cause fibrosis and cirrhosis. Tripterygium wilfordii Hook.f (TWHF) is a species in the Euonymus family that is commonly used as a source of medicine and food in Eastern and Southern China. Triptolide (TP) is an epoxy diterpene lactone of TWHF, as well as the main active ingredient in TWHF. Here, we used a mouse model of common bile duct ligation (BDL) cholestasis, along with cultured human intrahepatic biliary epithelial cells, to explore whether TP can relieve cholestasis. Compared with the control treatment, TP at a dose of 70 or 140 μg/kg reduced the serum levels of the liver enzymes alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in mice; hematoxylin and eosin staining also showed that TP reduced necrosis in tissues. Both in vitro and in vivo analyses revealed that TP inhibited cholangiocyte proliferation by reducing the expression of RelB. Immunohistochemical staining of CK19 and Ki67, as well as measurement of Ck19 mRNA levels in hepatic tissue, revealed that TP inhibited the BDL-induced ductular reaction. Masson 3 and Sirius Red staining for hepatic hydroxyproline showed that TP alleviated BDL-induced hepatic fibrosis. Additionally, TP substantially inhibited BDL-induced hepatic inflammation. In summary, TP inhibited the BDL-induced ductular reaction by reducing the expression of RelB in cholangiocytes, thereby alleviating liver injury, fibrosis, and inflammation.
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Affiliation(s)
- Zihang Yuan
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Jie Wang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Haoran Zhang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Yingying Miao
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Qianhui Tang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Ziqiao Yuan
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Cheng Nong
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Zhicheng Duan
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Luyong Zhang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China,Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhenzhou Jiang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China,Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, China,*Correspondence: Zhenzhou Jiang,
| | - Qinwei Yu
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China,Qinwei Yu,
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14
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Zhou Y, Zhou Y, Li Y, Sun W, Wang Z, Chen L, He Y, Niu X, Chen J, Yao G. Targeted bile acid profiles reveal the liver injury amelioration of Da-Chai-Hu decoction against ANIT- and BDL-induced cholestasis. Front Pharmacol 2022; 13:959074. [PMID: 36059946 PMCID: PMC9437253 DOI: 10.3389/fphar.2022.959074] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/18/2022] [Indexed: 11/26/2022] Open
Abstract
Multiple types of liver diseases, particularly cholestatic liver diseases (CSLDs) and biliary diseases, can disturb bile acid (BA) secretion; however, BA accumulation is currently seen as an important incentive of various types of liver diseases’ progression. Da-Chai-Hu decoction (DCHD) has long been used for treating cholestatic liver diseases; however, the exact mechanisms remain unclear. Currently, our study indicates that the liver damage and cholestasis status of the α-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis and bile duct ligation (BDL)-induced extrahepatic cholestasis, following DCHD treatment, were improved; the changes of BA metabolism post-DCHD treatment were investigated by targeted metabolomics profiling by UPLC-MS/MS. DCHD treatment severely downregulated serum biochemical levels and relieved inflammation and the corresponding pathological changes including necrosis, inflammatory infiltration, ductular proliferation, and periductal fibrosis in liver tissue. The experimental results suggested that DCHD treatment altered the size, composition, and distribution of the BAs pool, led the BAs pool of the serum and liver to sharply shrink, especially TCA and TMCA, and enhanced BA secretion into the gallbladder and the excretion of BAs by the urinary and fecal pathway; the levels of BAs synthesized by the alternative pathway were increased in the liver, and the conjugation of BAs and the pathway of BA synthesis were actually affected. In conclusion, DCHD ameliorated ANIT- and BDL-induced cholestatic liver injury by reversing the disorder of BAs profile.
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Affiliation(s)
- YueHua Zhou
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - YunZhong Zhou
- Institute of Pharmaceutical Preparation Research, Jinghua Pharmaceutical Group Co., Ltd., Jiangsu, China
| | - YiFei Li
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wei Sun
- Center for Drug Safety Evaluation and Research, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - ZhaoLong Wang
- Institute of Pharmaceutical Preparation Research, Jinghua Pharmaceutical Group Co., Ltd., Jiangsu, China
| | - Long Chen
- Experimental Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ye He
- Institute of Pharmaceutical Preparation Research, Jinghua Pharmaceutical Group Co., Ltd., Jiangsu, China
| | - XiaoLong Niu
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jialiang Chen
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guangtao Yao
- Shanghai Innovation Center of TCM Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Center for Drug Safety Evaluation and Research, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Guangtao Yao,
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15
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Wang J, Yuan Z, Zhang H, Wu Q, Miao Y, Xu Y, Yu Q, Huang X, Zhang Z, Huang X, Tang Q, Zhang L, Jiang Z. Obeticholic acid aggravates liver injury by up-regulating the liver expression of osteopontin in obstructive cholestasis. Life Sci 2022; 307:120882. [PMID: 35963300 DOI: 10.1016/j.lfs.2022.120882] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 07/25/2022] [Accepted: 08/08/2022] [Indexed: 10/15/2022]
Abstract
AIMS Obeticholic acid (OCA) was approved for the treatment of primary biliary cholangitis (PBC) patients, as it can significantly improve the level of serum alkaline phosphatase. However, OCA-induced liver injury in PBC patients puts them at risk of acute chronic liver failure, thus limiting the clinical application of OCA. Osteopontin (OPN), an extracellular cell matrix molecule, is highly induced in many cholestatic liver diseases. Herein we explored whether liver injury exacerbation by OCA was related to OPN. MAIN METHODS Bile duct ligation (BDL) mice were treated with OCA (40 mg/kg) to evaluate its effect on liver injury and OPN involvement. Enzyme-linked immunosorbent assay, western blot, immunohistochemistry, and other assays were used to detect OPN levels in serum and liver. Immunohistochemistry, and immunofluorescence, among other assays, were used to evaluate the extent of ductular reaction. The extent of fibrosis was also determined using various assays, such as immunohistochemistry, quantitative real-time PCR (qPCR), and hydroxyproline assays. KEY FINDINGS OPN was overexpressed in the liver of BDL mice treated with OCA. OCA induced overexpression of OPN exacerbated ductular reaction, fibrosis, and liver inflammation, and reduced hepatocyte proliferation. SIGNIFICANCE Upon liver injury, OCA upregulates the expression of OPN in the liver and accelerates disease progression. This mechanism helps explain the risk of liver damage associated with OCA.
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Affiliation(s)
- Jie Wang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Zihang Yuan
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Haoran Zhang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Qipeng Wu
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Yingying Miao
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Yunxia Xu
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Qinwei Yu
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaofei Huang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Ziling Zhang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Xinliang Huang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Qianhui Tang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Luyong Zhang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhenzhou Jiang
- New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China.
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16
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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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17
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Xu XW, Zhu Y, Song JZ, Zou GQ, Zhao Z, Zheng QL, Cao LJ, Wang GJ, Wang H, Hao HP. Selective Photoaffinity Probe for Monitoring Farnesoid X Receptor Expression in Cultured Cells. Anal Chem 2022; 94:10722-10729. [DOI: 10.1021/acs.analchem.2c01206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Xiao-Wei Xu
- State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 210009, Nanjing, China
| | - Ya Zhu
- State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 210009, Nanjing, China
| | - Jiang-Zhou Song
- State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 210009, Nanjing, China
| | - Gui-Qing Zou
- State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 210009, Nanjing, China
| | - Zhou Zhao
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 210009, Nanjing, China
| | - Qiu-Ling Zheng
- State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 210009, Nanjing, China
| | - Li-Juan Cao
- State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 210009, Nanjing, China
| | - Guang-Ji Wang
- State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 210009, Nanjing, China
| | - Hong Wang
- State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 210009, Nanjing, China
| | - Hai-Ping Hao
- State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 210009, Nanjing, China
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18
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Chang ML, Chen WT, Chan TM, Lin CY, Chang MY, Chen SC, Chien RN. Anti-Mitochondrial Antibody Titers Decrease Over Time in Primary Biliary Cholangitis Patients With Ursodeoxycholic Acid Therapeutic Response: A Cohort Study Followed Up to 28 Years. Front Immunol 2022; 13:869018. [PMID: 35663951 PMCID: PMC9160714 DOI: 10.3389/fimmu.2022.869018] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 04/19/2022] [Indexed: 11/24/2022] Open
Abstract
Background How anti-mitochondrial antibody (AMA) and liver biochemistry levels change in primary biliary cholangitis (PBC) patients treated with ursodeoxycholic acid (UDCA) remains unclear. Methods A 28-year cohort of 157 PBC patients was conducted. Patients with alkaline phosphatase (Alk-p) levels >1.67 × upper limit of normal after 1 year of UDCA treatment were considered nonresponders. Results At baseline, of 157 (mean age: 54.41 years), 136 (86.6%) were female, 51 (32.5%) had cirrhosis, and 128 (81.5%) had detectable AMAs (immunoglobulin G). UDCA nonresponders (n=61) were younger and had higher Alk-p and total bilirubin levels and cirrhosis rates than UDCA responders (n=84). Alk-p levels and cirrhosis were negatively associated with UDCA response. Regardless of cirrhosis and UDCA response, most PBC patients had decreased Alk-p and γ-glutamyltransferase levels at last follow-up (up to 28.73 years) compared with baseline levels. Patients with baseline cirrhosis (2.78 ± 2.56 vs. 6.84 ± 9.00 mg/dL, p=0.024) and UDCA nonresponders (2.54 ± 2.19 vs. 4.51 ± 6.99 mg/dL, p=0.006) had increased total bilirubin levels while patients without cirrhosis (AST: 91.5 ± 84.5 vs. 58.9 ± 43.7 U/L, p<0.001; ALT: 107.3 ± 122.5 vs. 50.7 ± 36.8 U/L, p<0.001) and UDCA responders (AST: 83.8 ± 101.3 vs. 45.58 ± 38.42 U/L, p=0.014; ALT: 95.10 ± 144.6 vs. 39.12 ± 30.65 U/L, p=0.009) had decreased aminotransferase levels. Only UDCA responders had decreased AMA titers from 1 year after UDCA treatment (p=0.028) until the last follow-up (p<0.001). Conclusions UDCA responders exhibited decreased AMA titers 1 year after treatment. Regardless of UDCA response, PBC patients showed improved cholestatic features, but only UDCA responders and patients without baseline cirrhosis exhibited attenuated hepatobiliary damage following UDCA treatment.
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Affiliation(s)
- Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Ting Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Tien-Ming Chan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Division of Rheumatology, Allergy, and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Cheng-Yu Lin
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ming-Yu Chang
- Division of Pediatrics, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Shiang-Chi Chen
- Department of Nursing, Taipei Medical University, Taipei, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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19
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Yamaguchi M, Asano T, Arisaka T, Mashima H, Irisawa A, Tamano M. Effects of pemafibrate on primary biliary cholangitis with dyslipidemia. Hepatol Res 2022; 52:522-531. [PMID: 35072975 DOI: 10.1111/hepr.13747] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 01/11/2022] [Accepted: 01/20/2022] [Indexed: 02/08/2023]
Abstract
AIM The purpose of this study was to examine the effect of pemafibrate (PEM) in primary biliary cholangitis (PBC) patients with dyslipidemia. METHODS Patients who were diagnosed with PBC between June 2018 and December 31, 2020 were included in the study if they also had dyslipidemia and their alkaline phosphatase (ALP) or gamma-glutamyl transferase (GGT) levels remained above the normal range despite taking 600 mg/day ursodeoxycholic acid (UDCA) for at least 6 months. Patients who were treated with UDCA alone were administered PEM as an add-on (PEM-add group), and patients who were treated with UDCA and bezafibrate (BEZ) for at least 6 months were given PEM instead of BEZ (PEM-switch group). Clinical parameters were compared in all patients, and the levels of ALP, GGT, the estimated glomerular filtration rate (eGFR), and creatinine (Cr) were compared between the PEM-add and PEM-switch groups. Improvement in cholangitis was also evaluated. RESULTS In the PEM-add group, both ALP and GGT improved in 40 of 46 patients (87.0%). In the PEM-switch group, both ALP and GGT improved in 15 of 29 patients (51.7%). In the PEM-switch group, however, significant improvement was seen in eGFR and Cr. CONCLUSIONS Administration of PEM is effective in PBC patients with dyslipidemia who are refractory to UDCA monotherapy. In patients using both UDCA and BEZ, there was an advantage in switching to PEM if they had renal damage; however, improvement of ALP and GGT occurred in about 50%.
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Affiliation(s)
- Mayumi Yamaguchi
- Department of Gastroenterology, Dokkyo Medical University Saitama Medical Center, Minami-Koshigaya, Koshigaya, Japan
| | - Takeharu Asano
- Department of Gastroenterology, Jichi Medical University Saitama Medical Center, Amanuma, Omiya-ku, Japan
| | - Takahiro Arisaka
- Department of Gastroenterology, Dokkyo Medical University, Kitakobayashi, Mibu, Japan
| | - Hirosato Mashima
- Department of Gastroenterology, Jichi Medical University Saitama Medical Center, Amanuma, Omiya-ku, Japan
| | - Atsushi Irisawa
- Department of Gastroenterology, Dokkyo Medical University, Kitakobayashi, Mibu, Japan
| | - Masaya Tamano
- Department of Gastroenterology, Dokkyo Medical University Saitama Medical Center, Minami-Koshigaya, Koshigaya, Japan
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20
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Kim W. Chronic Liver Disease. SEX/GENDER-SPECIFIC MEDICINE IN THE GASTROINTESTINAL DISEASES 2022:209-227. [DOI: 10.1007/978-981-19-0120-1_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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21
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Montano-Loza AJ, Allegretti JR, Cheung A, Ebadi M, Jones D, Kerkar N, Levy C, Rizvi S, Vierling JM, Alvarez F, Bai W, Gilmour S, Gulamhusein A, Guttman O, Hansen BE, MacParland S, Mason A, Onofrio F, Santamaria P, Stueck A, Swain M, Vincent C, Ricciuto A, Hirschfield G. Single Topic Conference on Autoimmune Liver Disease from the Canadian Association for the Study of the Liver. CANADIAN LIVER JOURNAL 2021; 4:401-425. [PMID: 35989897 PMCID: PMC9235119 DOI: 10.3138/canlivj-2021-0006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 02/09/2021] [Indexed: 11/20/2022]
Abstract
Autoimmune liver disease (AILD) spans a spectrum of chronic disorders affecting the liver parenchyma and biliary system. Three main categories of AILD are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). This review condenses the presentation and discussions of the Single Topic Conference (STC) on AILD that was held in Ottawa, Ontario, in November 2019. We cover generalities regarding disease presentation and clinical diagnosis; mechanistic themes; treatment paradigms; clinical trials, including approaches and challenges to new therapies; and looking beyond traditional disease boundaries. Although these diseases are considered autoimmune, the etiology and role of environmental triggers are poorly understood. AILDs are progressive and chronic conditions that affect survival and quality of life. Advances have been made in PBC treatment because second-line treatments are now available (obeticholic acid, bezafibrate); however, a significant proportion still present suboptimal response. AIH treatment has remained unchanged for several decades, and data suggest that fewer than 50% of patients achieve a complete response and as many as 80% develop treatment-related side effects. B-cell depletion therapy to treat AIH is in an early stage of development and has shown promising results. An effective treatment for PSC is urgently needed. Liver transplant remains the best option for patients who develop decompensated cirrhosis or hepatocellular carcinoma within specific criteria, but recurrent AILD might occur. Continued efforts are warranted to develop networks for AILD aimed at assessing geo-epidemiological, clinical, and biochemical differences to capture the new treatment era in Canada.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| | - Jessica R Allegretti
- Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Angela Cheung
- Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Maryam Ebadi
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| | - David Jones
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Nanda Kerkar
- Division of Gastroenterology, Hepatology and Nutrition, Golisano Children’s Hospital at Strong, University of Rochester Medical Center, New York, USA
| | - Cynthia Levy
- Schiff Center for Liver Diseases, University of Miami, Miami, Florida, USA
| | - Sumera Rizvi
- Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | | | - Fernando Alvarez
- Department of Pediatrics, Hôpital Sainte-Justine, University of Montreal, Montreal, Quebec, Canada
| | - Wayne Bai
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| | - Susan Gilmour
- Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada
| | - Aliya Gulamhusein
- Ajmera Family Transplant Centre, Toronto General Research Institute, Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Orlee Guttman
- Division of Gastroenterology, Hepatology and Nutrition, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada
| | - Bettina E Hansen
- Ajmera Family Transplant Centre, Toronto General Research Institute, Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Sonya MacParland
- Ajmera Family Transplant Centre, Toronto General Research Institute, Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Andrew Mason
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| | - Fernanda Onofrio
- Ajmera Family Transplant Centre, Toronto General Research Institute, Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Pere Santamaria
- Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Ashley Stueck
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Mark Swain
- Calgary Liver Unit, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Catherine Vincent
- Department of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Amanda Ricciuto
- Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Gideon Hirschfield
- Toronto Centre for Liver Disease, University Health Network & Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
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22
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Gerussi A, Restelli U, Croce D, Bonfanti M, Invernizzi P, Carbone M. Cost of illness of Primary Biliary Cholangitis - a population-based study. Dig Liver Dis 2021; 53:1167-1170. [PMID: 32830065 DOI: 10.1016/j.dld.2020.07.029] [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: 07/02/2020] [Revised: 07/21/2020] [Accepted: 07/22/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND The economic burden of Primary Biliary Cholangitis (PBC) has not been investigated at population-level. Aim of this study was to estimate the cost of illness of PBC in Lombardy, Italy. METHODS Individuals with PBC were identified through ICD-9-CM code 571.6 and/or medical exemption code 008.571.6, from the Banca Dati Assistito of Lombardy. Only health services (outpatient, inpatient activities and drugs) related to PBC were considered to estimate direct medical costs in 2017. RESULTS We identified 970 adult patients (83.5% females) with a mean age of 61 years. Global annual costs were equal to € 913,763 (€ 942 per patient), with € 459,506 (50.3%, € 474 per patient) deriving from hospitalizations (mostly due to liver transplantation, 30.5%, and cirrhosis complications, 20.6%). Costs from outpatient activities were € 109,090 (11.9%, € 112 per patient). CONCLUSIONS This study provides an overview of the costs attributed to PBC care and management, mainly related to hospitalizations for cirrhosis complications, which is necessary for assuring cost-effective introduction of novel therapies. Additional studies focused on indirect cost, e.g. overall loss of productivity, are warranted.
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Affiliation(s)
- Alessio Gerussi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Umberto Restelli
- Center for Health Economics, Social and Health Care Management, LIUC - Università Cattaneo, Castellanza (Varese), Italy; School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Davide Croce
- Center for Health Economics, Social and Health Care Management, LIUC - Università Cattaneo, Castellanza (Varese), Italy
| | - Marzia Bonfanti
- Center for Health Economics, Social and Health Care Management, LIUC - Università Cattaneo, Castellanza (Varese), Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy.
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23
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Hu C, Li Y, Liu Y, Lai Y, Ding L. A Sensitive HPLC-MS/MS Method for Determination of Obeticholic Acid in Human Plasma: Application to a Pharmacokinetic Study in Healthy Volunteers. J Chromatogr Sci 2021; 60:545-550. [PMID: 34313291 DOI: 10.1093/chromsci/bmab098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Indexed: 11/14/2022]
Abstract
A rapid and sensitive LC-MS/MS method was developed and fully validated for the determination of obeticholic acid in human plasma. Glimepiride was used as internal standard. For this method, liquid-liquid extraction was performed to extract analyte from the plasma samples. Chromatographic separation was performed on a C18 (2.1 × 50 mm, 2.7 μm, Agilent) column with isocratic elution using water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid at a flow rate of 0.4 mL/min. The mass detection was performed in negative mode. The precursor-product ion pairs for MRM were m/z 465.3 → 419.3 for obeticholic acid and m/z 489.3 → 224.8 for the IS. The method exhibited great linearity over the concentration range of 0.150-100 ng/mL for obeticholic acid. The sensitivity, linearity, accuracy, precision, recovery, matrix effect and stability of this method were all within the acceptable limits. The method was successfully validated and applied to the pharmacokinetic studies in healthy Chinese volunteers after a single oral dose administration of obeticholic acid tablets of 10 mg, and the pharmacokinetic characteristics of obeticholic acid in human were reported for the first time.
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Affiliation(s)
- Can Hu
- College of Pharmacy and Chemistry, Dali University, Dali 671000, China
- Nanjing Clinical Tech Laboratories Inc., Nanjing 211000, China
| | - Ya Li
- Nanjing Clinical Tech Laboratories Inc., Nanjing 211000, China
| | - Yujie Liu
- Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd, Nanjing 210009, China
| | - Yong Lai
- College of Pharmacy and Chemistry, Dali University, Dali 671000, China
| | - Li Ding
- Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
- Nanjing Clinical Tech Laboratories Inc., Nanjing 211000, China
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24
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Abstract
Cholestatic liver disease is a disease that causes liver damage and fibrosis owing to bile stasis. It is represented by primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), but the pathophysiological pathways that cause bile stasis in both diseases are different. The pathogenesis of the disease is still unclear, although autoimmune mechanisms have been postulated and partially elucidated. Although the disease may progress slowly with only mild liver dysfunction, it may progress to liver cirrhosis or liver failure, which require liver transplantation. As a medical treatment, ursodeoxycholic acid is widely used for PBC and has proved to be very effective against disease progression in cases of PBC. On the other hand, its efficacy is limited in cases of PSC, and the research and development of various drugs are underway. Furthermore, the clinical course of both diseases is quite variable, making the design of clinical trials fairly difficult. In this review, we present the general natural history of PBC and PSC, and provide information on the latest drug therapies currently available and those that are under investigation.
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25
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Clinical Management of Primary Biliary Cholangitis-Strategies and Evolving Trends. Clin Rev Allergy Immunol 2021; 59:175-194. [PMID: 31713023 DOI: 10.1007/s12016-019-08772-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PBC is a chronic progressive autoimmune disorder involving the destruction of intrahepatic small bile ducts, cholestasis, fibrosis, and ultimately cirrhosis if left untreated. It is largely driven by the autoimmune response, but bile acids and the intestinal microbiota are implicated in disease progression as well. The only drugs licensed for PBC are UDCA and OCA. UDCA as a first-line and OCA as a second-line therapy are safe and effective, but the lack of response in a significant portion of patients and inadequate control of symptoms such as fatigue and pruritus remain as concerns. Liver transplantation is an end-stage therapy for many patients refractory to UDCA, which gives excellent survival rates but also moderate to high recurrence rates. The limited options for FDA-approved PBC therapies necessitate the development of alternative approaches. Currently, a wide variety of experimental drugs exist targeting immunological and physiological aspects of PBC to suppress inflammation. Immunological therapies include drugs targeting immune molecules in the B cell and T cell response, and specific cytokines and chemokines implicated in inflammation. Drugs targeting bile acids are also noteworthy as bile acids can perpetuate hepatic inflammation and lead to fibrosis over time. These include FXR agonists, ASBT inhibitors, and PPAR agonists such as bezafibrate and fenofibrate. Nonetheless, many of these drugs can only delay disease progression and fail to enhance patients' quality of life. Nanomedicine shows great potential for treatment of autoimmune diseases, as it provides a new approach that focuses on tolerance induction rather than immunosuppression. Tolerogenic nanoparticles carrying immune-modifying agents can be engineered to safely and effectively target the antigen-specific immune response in autoimmune diseases. These may work well with PBC especially, given the anatomical features and immunological specificity of the disease. Nanobiological therapy is thus an area of highly promising research for future treatment of PBC.
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Li H, Guan Y, Han C, Zhang Y, Liu Q, Wei W, Ma Y. The pathogenesis, models and therapeutic advances of primary biliary cholangitis. Biomed Pharmacother 2021; 140:111754. [PMID: 34044277 DOI: 10.1016/j.biopha.2021.111754] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 12/30/2022] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune disease characterized by the destruction of intrahepatic small bile ducts and the presence of antimitochondrial antibody (AMA), eventually progresses to liver fibrosis and cirrhosis. Genetic predisposition and environmental factors are involved in the occurrence of PBC, and the epitopes exposure and the imbalance of autoimmune tolerance are the last straw. The apoptosis of biliary epithelial cell (BEC) leads to the release of autoantigen epitopes, which activate the immune system, and the disorder of innate and adaptive immunity eventually leads to the start of disease. Animal models have unique advantages in investigating the pathogenesis and drug exploitation of PBC. Multiple models have been reported, and spontaneous model and induced model have been widely used in relevant research of PBC in recent years. Currently, the only drugs licensed for PBC are ursodesoxycholic acid (UDCA) and obeticholic acid (OCA). In the last few years, as the learned more about the pathogenesis of PBC, more and more targets have been discovered, and multiple targeted drugs are being in developed. In this review, the pathogenesis, murine models and treatment strategies of PBC were summarized, and the current research status was discussed to provide insights for the further study of PBC.
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Affiliation(s)
- Hao Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Yanling Guan
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Chenchen Han
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Yu Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Qian Liu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China.
| | - Yang Ma
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, China.
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Chen CJ, Cheng JS, Wang HE, Huang CW, Hu JH, Chen WT, Chang MY, Ku HP, Lin CY, Chien RN, Chang ML. Identification of the Representative Primary Biliary Cholangitis Cohort in Taiwan: A Comparison of Four Nationwide Cohorts. J Clin Med 2021; 10:jcm10112226. [PMID: 34063859 PMCID: PMC8196594 DOI: 10.3390/jcm10112226] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 05/12/2021] [Accepted: 05/19/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND/PURPOSE The rates and outcomes of primary biliary cholangitis (PBC) in Taiwan remain unclear. METHODS A nationwide population-based cohort study (Taiwan National Health Insurance Research Database, 2002-2015) was conducted. Data from four PBC cohorts with various definitions were compared (cohort 1 (C1): ICD-9-CM (571.6); C2: alkaline phosphatase (Alk-P) and antimitochondrial antibody (AMA) measurements; C3: Alk-p and AMA measurements and ursodeoxycholic acid (UDCA) treatment; C4: ICD-9-CM (571.6), Alk-p and AMA measurements and UDCA treatment). RESULTS The average prevalence rate ranged from 9.419/105 (C4) to 307.658/105 (C2), and the female-to-male ratio ranged from 1.192 (C1) to 3.66 (C4). Prevalence rates increased over time in all cohorts. The average incidence rates ranged from 1.456/105 (C4) to 66.386/105 (C2). Incidence rates decreased over time in C1 (-9.09%, p < 0.0001) and C4 (-6.68%, p < 0.0001) and remained steady in the others. C4 had the lowest prevalence and incidence rates and highest female-to-male ratio. Cirrhosis rates ranged from 7.21% (C2) to 39.34% (C4), hepatoma rates ranged from 2.77%(C2) to 6.66%(C1), liver transplantation (LT) rates ranged from 1.07% (C2) to 6.77% (C4), and mortality rates ranged from 18.24% (C2) to 47.36% (C1). C4 had the highest LT (6.77%), osteoporosis (13.87%) and dyslipidemia rates (17.21%). CONCLUSIONS Based on the reported ranges of reasonable rates, female predominance and characteristic outcomes, C4 was the most representative Taiwanese PBC cohort, with average prevalence and incidence rates of 9.419/105 and 1.456/105, respectively, and a female-to-male ratio of 3.66. In a 14-year period, cirrhosis, hepatoma, LT, and mortality were noted in 39.34%, 5.52%, 6.77%, and 34.22% of C4 patients, respectively.
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Affiliation(s)
- Cheng-Jen Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; (C.-J.C.); (H.-E.W.); (C.-W.H.); (W.-T.C.); (H.-P.K.); (C.-Y.L.); (R.-N.C.)
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
| | - Jur-Shan Cheng
- Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan;
- Department of Emergency Medicine, Chang Gung Memorial Hospital, Keelung 204, Taiwan
| | - Haw-En Wang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; (C.-J.C.); (H.-E.W.); (C.-W.H.); (W.-T.C.); (H.-P.K.); (C.-Y.L.); (R.-N.C.)
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
| | - Chun-Wen Huang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; (C.-J.C.); (H.-E.W.); (C.-W.H.); (W.-T.C.); (H.-P.K.); (C.-Y.L.); (R.-N.C.)
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
| | - Jing-Hong Hu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Yunlin 638, Taiwan;
| | - Wei-Ting Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; (C.-J.C.); (H.-E.W.); (C.-W.H.); (W.-T.C.); (H.-P.K.); (C.-Y.L.); (R.-N.C.)
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
| | - Ming-Yu Chang
- Division of Pediatric Neurologic Medicine, Chang Gung Children’s Hospital, Taoyuan 333423, Taiwan;
- Division of Pediatrics, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Hsin-Ping Ku
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; (C.-J.C.); (H.-E.W.); (C.-W.H.); (W.-T.C.); (H.-P.K.); (C.-Y.L.); (R.-N.C.)
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
| | - Cheng-Yu Lin
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; (C.-J.C.); (H.-E.W.); (C.-W.H.); (W.-T.C.); (H.-P.K.); (C.-Y.L.); (R.-N.C.)
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; (C.-J.C.); (H.-E.W.); (C.-W.H.); (W.-T.C.); (H.-P.K.); (C.-Y.L.); (R.-N.C.)
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
| | - Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; (C.-J.C.); (H.-E.W.); (C.-W.H.); (W.-T.C.); (H.-P.K.); (C.-Y.L.); (R.-N.C.)
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
- Liver Research Unit, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, No. 5, Fu Hsing Street, Kuei Shan, Taoyuan 333423, Taiwan
- Correspondence: ; Tel.: +886-3-328-1200-8107; Fax: +886-3-327-2236
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Mandorfer M, Simbrunner B. Prevention of First Decompensation in Advanced Chronic Liver Disease. Clin Liver Dis 2021; 25:291-310. [PMID: 33838851 DOI: 10.1016/j.cld.2021.01.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 10/20/2020] [Indexed: 01/31/2023]
Abstract
The first occurrence of decompensation constitutes a watershed moment in the natural history of chronic liver disease; it denotes a point of no return in a relevant proportion of patients. Preventive strategies may profoundly decrease cirrhosis-related morbidity and mortality. Removing the primary etiologic factor and cofactors, is key; however, a considerable proportion of patients require additional etiology-independent treatment strategies that target important pathomechanisms promoting decompensation (ie, portal hypertension and systemic inflammation). This article explains the importance of preventing first decompensation and summarizes the evidence for etiologic and etiology-independent (most important, nonselective beta-blockers and statins) therapies.
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Affiliation(s)
- Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria.
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
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Li Y, Chen L, Li L, Sottas C, Petrillo SK, Lazaris A, Metrakos P, Wu H, Ishida Y, Saito T, Golden-Mason L, Rosen HR, Wolff JJ, Silvescu CI, Garza S, Cheung G, Huang T, Fan J, Culty M, Stiles B, Asahina K, Papadopoulos V. Cholesterol-binding translocator protein TSPO regulates steatosis and bile acid synthesis in nonalcoholic fatty liver disease. iScience 2021; 24:102457. [PMID: 34013171 PMCID: PMC8113880 DOI: 10.1016/j.isci.2021.102457] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 02/19/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023] Open
Abstract
Translocator protein (TSPO, 18 kDa) levels increase in parallel with the evolution of simple steatosis (SS) to nonalcoholic steatohepatitis (NASH) in nonalcoholic fatty liver disease (NAFLD). However, TSPO function in SS and NASH is unknown. Loss of TSPO in hepatocytes in vitro downregulated acetyl-CoA acetyltransferase 2 and increased free cholesterol (FC). FC accumulation induced endoplasmic reticulum stress via IRE1A and protein kinase RNA-like ER kinase/ATF4/CCAAT-enhancer-binding protein homologous protein pathways and autophagy. TSPO deficiency activated cellular adaptive antioxidant protection; this adaptation was lost upon excessive FC accumulation. A TSPO ligand 19-Atriol blocked cholesterol binding and recapitulated many of the alterations seen in TSPO-deficient cells. These data suggest that TSPO deficiency accelerated the progression of SS. In NASH, however, loss of TSPO ameliorated liver fibrosis through downregulation of bile acid synthesis by reducing CYP7A1 and CYP27A1 levels and increasing farnesoid X receptor expression. These studies indicate a dynamic and complex role for TSPO in the evolution of NAFLD.
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Affiliation(s)
- Yuchang Li
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
| | - Liting Chen
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
| | - Lu Li
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
| | - Chantal Sottas
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
| | - Stephanie K. Petrillo
- Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada
- Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada
| | - Anthoula Lazaris
- Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada
- Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada
| | - Peter Metrakos
- Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada
- Department of Surgery, McGill University, Montreal, QC H3G 1A4, Canada
| | - Hangyu Wu
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
| | - Yuji Ishida
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- Research & Development Department, PhoenixBio, Co., Ltd, Higashi-Hiroshima, Hiroshima, Japan
| | - Takeshi Saito
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- University of Southern California Research Center for Liver Diseases, Los Angeles, CA 90089, USA
| | - Lucy Golden-Mason
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- University of Southern California Research Center for Liver Diseases, Los Angeles, CA 90089, USA
| | - Hugo R. Rosen
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- University of Southern California Research Center for Liver Diseases, Los Angeles, CA 90089, USA
| | | | | | - Samuel Garza
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
| | - Garett Cheung
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
| | - Tiffany Huang
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
| | - Jinjiang Fan
- Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada
- Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
| | - Martine Culty
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
| | - Bangyan Stiles
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
| | - Kinji Asahina
- University of Southern California Research Center for Liver Diseases, Los Angeles, CA 90089, USA
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA 90089, USA
| | - Vassilios Papadopoulos
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA
- Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada
- Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
- Corresponding author
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Kulkarni AV, Tevethia HV, Arab JP, Candia R, Premkumar M, Kumar P, Sharma M, Reddy DN, Padaki NR. Efficacy and safety of obeticholic acid in liver disease-A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2021; 45:101675. [PMID: 33722778 DOI: 10.1016/j.clinre.2021.101675] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 02/17/2021] [Accepted: 03/03/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Currently, there is no pharmacotherapy for non-alcoholic steatohepatitis (NASH), a common liver disorder. In contrast, primary biliary cholangitis (PBC) is a chronic cholestatic liver disease for which ursodeoxycholic acid (UDCA) is the drug of choice. However, 50% of PBC patients may not respond to UDCA. Obeticholic acid (OCA) is emerging as a vital pharmacotherapy for these chronic disorders. We aimed to analyse the safety and efficacy of OCA. METHODS We performed an extensive search of electronic databases from 01/01/2000 to 31/03/2020. We included randomized controlled trials of OCA in patients with NASH, PBC, and primary sclerosing cholangitis (PSC). We assessed the histological improvement in NASH, reduction in alkaline phosphatase (≤1.67 ULN) in PBC, and the adverse effects of OCA. RESULTS Seven RCTs (n = 2834) were included. Of the total RCTs, there were three on both NASH and PBC and one on PSC. OCA improved NASH fibrosis [OR: 1.95 (1.47-2.59; p < 0.001)]. With the 10 mg OCA dose, the odds of improvement was 1.61 (1.03-2.51; p = 0.03), while with the 25 mg dose, it was 2.23 (1.55-3.18; p < 0.001). However, 25 mg OCA led to significant adverse events and discontinuation of the drug [2.8 (1.42-3.02); p < 0.001)] compared with 10 mg OCA [0.95 (0.6-1.5); p = 0.84] in NASH patients. In PBC patients, the response to 5 mg OCA was better than with the higher doses [5 mg: 7.66 (3.12-18.81; p < 0.001), 10 mg: 5.18 (2-13.41; p = 0.001), 25 mg: 2.36 (0.94-5.93; p = 0.06), 50 mg: 4.08 (1.05-15.78; p = 0.04)]. The risk of pruritus was lowest with 5 mg OCA. CONCLUSIONS Lower doses of OCA are effective and safe in NASH and cholestatic liver disease. While 10 mg OCA is effective for NASH fibrosis regression, only 5 mg OCA is required for PBC.
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Affiliation(s)
- Anand V Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India.
| | | | - Juan Pablo Arab
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Roberto Candia
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | | | - Pramod Kumar
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Mithun Sharma
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - D Nageshwar Reddy
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Nagaraja Rao Padaki
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
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Rice S, Albani V, Minos D, Fattakhova G, Mells GF, Carbone M, Flack S, Varvaropoulou N, Badrock J, Spicer A, Sandford RN, Shirley MDF, Coughlan D, Hirschfield G, Taylor-Robinson SD, Vale L, Jones DEJ. Effects of Primary Biliary Cholangitis on Quality of Life and Health Care Costs in the United Kingdom. Clin Gastroenterol Hepatol 2021; 19:768-776.e10. [PMID: 32562892 DOI: 10.1016/j.cgh.2020.06.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 05/08/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS There have been few high-quality studies of the costs, preference-based health-related quality of life (HRQoL) and cost effectiveness of treatments for primary biliary cholangitis (PBC). We aimed to estimate the marginal effects of PBC complications and symptoms, accounting for treatment, on HRQoL and the annual cost of health care in the United Kingdom (UK). These are essential components for evaluation of cost effectiveness and this information will aid in evaluation of new treatments. METHODS Questionnaires were mailed to 4583 participants in the UK-PBC research cohort and data were collected on HRQoL and use of the National Health Service (NHS) in the UK from 2015 through 2016. HRQoL was measured using the EQ-5D-5L instrument. The annual cost of resource use was calculated using unit costs obtained from NHS sources. We performed econometric analyses to determine the effects of treatment, symptoms, complications, liver transplantation status, and patient characteristics on HRQoL and annual costs. RESULTS In an analysis of data from 2240 participants (over 10% of all UK PBC patients), we found that PBC symptoms have a considerable effect on HRQoL. Ursodeoxycholic acid therapy was associated with significantly higher HRQoL regardless of response status. Having had a liver transplant and ascites were also independently associated with reduced HRQoL. Having had a liver transplant (US$4294) and esophageal varices (US$3401) were the factors with the two greatest mean annual costs to the NHS. Symptoms were not independently associated with cost but were associated with reduction in HRQoL for patients, indicating the lack of effective treatments for PBC symptoms. CONCLUSIONS In an analysis of data from 2240 participants in the UK PBC, we found that HRQoL and cost estimates provide greater insight into the relative importance of PBC-related symptoms and complications. These findings provide estimates for health technology assessments of new treatments for PBC.
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Affiliation(s)
- Stephen Rice
- Health Economics Group, Institute of Health and Society, Newcastle University, Newcastle upon Tyne.
| | - Viviana Albani
- Health Economics Group, Institute of Health and Society, Newcastle University, Newcastle upon Tyne
| | - Dimitrios Minos
- Department of Political Economy, King's College London, London
| | - Gulnar Fattakhova
- Health Economics Group, Institute of Health and Society, Newcastle University, Newcastle upon Tyne
| | - George F Mells
- Department of Medical Genetics, Cambridge Biomedical Campus, University of Cambridge, Cambridge
| | - Marco Carbone
- Department of Medical Genetics, Cambridge Biomedical Campus, University of Cambridge, Cambridge
| | - Steven Flack
- Department of Medical Genetics, Cambridge Biomedical Campus, University of Cambridge, Cambridge
| | - Nikoletta Varvaropoulou
- Department of Medical Genetics, Cambridge Biomedical Campus, University of Cambridge, Cambridge
| | - Jonathan Badrock
- Department of Medical Genetics, Cambridge Biomedical Campus, University of Cambridge, Cambridge
| | - Ann Spicer
- Department of Medical Genetics, Cambridge Biomedical Campus, University of Cambridge, Cambridge
| | - Richard N Sandford
- Department of Medical Genetics, Cambridge Biomedical Campus, University of Cambridge, Cambridge
| | | | - Diarmuid Coughlan
- Health Economics Group, Institute of Health and Society, Newcastle University, Newcastle upon Tyne
| | - Gideon Hirschfield
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham; Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
| | | | - Luke Vale
- Health Economics Group, Institute of Health and Society, Newcastle University, Newcastle upon Tyne
| | - David E J Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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Vuppalanchi R, González-Huezo MS, Payan-Olivas R, Muñoz-Espinosa LE, Shaikh F, Pio Cruz-Lopez JL, Parmar D. A Multicenter, Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of Saroglitazar in Patients With Primary Biliary Cholangitis. Clin Transl Gastroenterol 2021; 12:e00327. [PMID: 33769355 PMCID: PMC7997082 DOI: 10.14309/ctg.0000000000000327] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 02/08/2021] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Patients with primary biliary cholangitis (PBC) without biochemical response to ursodeoxycholic acid (UDCA) are at increased risk of liver-related mortality. Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual PPAR agonistic properties (α/γ). There is a strong mechanistic rationale for studying saroglitazar in PBC because PPARα is a molecular target of fibrates that showed improvements in liver tests in patients with PBC. METHODS In this 16-week, open-label, phase 3 study, 37 patients were screened across 3 clinical centers to enroll 7 patients. All patients received daily dose of saroglitazar 4 mg for 16 weeks in addition to their ongoing treatment with UDCA. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at week 16 as compared to baseline. RESULTS Mean age of the study population was 51.1 ± 10.0 years, all patients were female of Mexican descent, and mean body mass index was 25.5± = 4.8 kg/m2. Six (85.7%) patients reported taking ursodiol at baseline and continued throughout the study with a mean daily dosage of 417 mg. Among these, the daily dosage of UDCA 500 mg in 4 and 250 mg in 2 subjects, respectively. The mean baseline ALP level was 230 ± 103 U/L. The primary efficacy endpoint, mean change (reduction) from baseline in ALP concentration at week 16 based on the modified intent-to-treat population was -94 ± 53 U/L (P = 0.003), corresponding to a reduction of 48 ± 23%. Treatment with saroglitazar 4 mg resulted in a rapid and sustained decrease of ALP levels at week 4 (-84 ± 47 U/L, P = 0.003). Six patients who completed the study achieved mean ALP reduction of at least 40% at week 4 and all subsequent visits. DISCUSSION Although the study was terminated because of lack of enrollment, saroglitazar daily for 16 weeks resulted in rapid and sustained improvements in ALP with an acceptable safety profile in patients with PBC.
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Affiliation(s)
- Raj Vuppalanchi
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
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Abstract
Primary biliary cholangitis (PBC) causes chronic and persistent cholestasis in the liver, eventually resulting in cirrhosis and hepatic failure without appropriate treatment. PBC mainly develops in middle-aged women, but it is also common in young women and men. PBC is considered a model of autoimmune disease because of the presence of disease-specific autoantibodies, that is, antimitochondrial antibodies (AMAs), intense infiltration of mononuclear cells into the bile ducts, and a high prevalence of autoimmune diseases such as comorbidities. Histologically, PBC is characterized by degeneration and necrosis of intrahepatic biliary epithelial cells surrounded by a dense infiltration of mononuclear cells, coined as chronic non-suppurative destructive cholangitis, which leads to destructive changes and the disappearance of small- or medium-sized bile ducts. Since 1990, early diagnosis with the detection of AMAs and introduction of ursodeoxycholic acid as first-line treatment has greatly altered the clinical course of PBC, and liver transplantation-free survival of patients with PBC is now comparable to that of the general population.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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Yu K, Li P, Xu T, Xu J, Wang K, Chai J, Zhao D, Liu Y, Wang Y, Ma J, Fan L, Guo S, Li Z, Li M, Wang Z. Decreased infiltration of CD4 + Th1 cells indicates a good response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis. Pathol Res Pract 2020; 217:153291. [PMID: 33249399 DOI: 10.1016/j.prp.2020.153291] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/10/2020] [Accepted: 11/11/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is characterized by nonsuppurative destructive cholangitis and is thought to be an autoimmune disorder. Currently, ursodeoxycholic acid (UDCA) is the only FDA approved first-line therapy for PBC, but up to nearly one-third of patients do not achieve a complete response to this treatment. Adaptive immune cells, including T cells and B cells, have been found in the portal tracts and the bile duct epithelium and play a role in the pathogenesis of PBC, but the importance of these cells for evaluating the therapeutic response to UDCA in PBC has not yet been studied. METHODS In this study, we collected liver puncture biopsy specimens from 34 matched patients with PBC before and after UDCA treatment and investigated the relationship between the infiltration of adaptive immune cells and the treatment response to UDCA. The extent of immune cell infiltration was determined by immunohistochemical analysis. Responses were defined based on Paris-I criteria. RESULTS After 1 year of treatment, 25/34 patients responded to UDCA treatment according to Paris-I criteria (responders), and 9/34 patients were nonresponders. Immunohistochemical analysis showed that UDCA responders exhibited significantly less CD4+ T cell infiltration after UDCA treatment than before (50.4 ± 7.5/HPF vs 30.0 ± 7.9/HPF, P = 0.002). In contrast, UDCA nonresponders exhibited significantly more CD4+ T cell infiltration after UDCA treatment than before (32.2 ± 8.0/HPF vs 75.0 ± 13.9/HPF, P = 0.045). Moreover, patients who exhibited a reduction in CD4+ T cell infiltration after UDCA treatment had a higher response rate than those that exhibited an increase in CD4+ T cell infiltration (85.7 % vs 53.8 %, P = 0.041). However, CD3+ T cell, CD8+ T cell, and CD20+ B cell infiltration was not significantly different before and after treatment in either UDCA responders or nonresponders. Furthermore, we found that the number of infiltrating T-bet+ Th1 cells was much lower after UDCA treatment than before in responders (10.5 ± 5.7/HPF vs. 5.16 ± 4.0/HPF, P = 0.0214) but much higher in nonresponders after treatment than before (1.89±1.2/HPF vs. 12.3±5.4/HPF, P = 0.043). However, there was no difference in the extent of GATA3+ Th2 or FOXP3+ Treg infiltration before and after treatment in either UDCA responders or nonresponders. CONCLUSION Collectively, our results suggest that a decrease in the number of liver-infiltrating CD4+ Th1 cells is associated with a good response of PBC patients to UDCA treatment. Immunohistochemical analysis of CD4 and T-bet in PBC liver specimens may be a potential approach for evaluating the therapeutic response to UDCA.
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Affiliation(s)
- Kangjie Yu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Peifeng Li
- Department of Pathology, The 960th Hospital of PLA, Jinan 250000, China
| | - Tianqi Xu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Junpeng Xu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Kaijing Wang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Jia Chai
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Danhui Zhao
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Yixiong Liu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Yingmei Wang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Jing Ma
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Linni Fan
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Shuangping Guo
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Zengshan Li
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
| | - Mingyang Li
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
| | - Zhe Wang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
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Alvaro D, Carpino G, Craxi A, Floreani A, Moschetta A, Invernizzi P. Primary biliary cholangitis management: controversies, perspectives and daily practice implications from an expert panel. Liver Int 2020; 40:2590-2601. [PMID: 32757367 DOI: 10.1111/liv.14627] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 07/24/2020] [Accepted: 07/26/2020] [Indexed: 02/13/2023]
Abstract
Primary biliary cholangitis (PBC) is a rare progressive immune-mediated liver disease that, if not adequately treated, may culminate in end-stage disease and need for transplantation. According to current guidelines, PBC is diagnosed in the presence of antimitochondrial antibodies (AMA) or specific antinuclear antibodies, and of a cholestatic biochemical profile, while biopsy is recommended only in selected cases. All patients receive ursodeoxycholic acid (UDCA) in first line; the only registered second-line therapy is obeticholic acid (OCA) for UDCA-inadequate responders. Despite the recent advances in understanding PBC pathogenesis and developing new treatments, many grey areas remain. Six Italian experts selected the following topics as the most urgent to address in PBC management: diagnosis and natural history of PBC: as a portion of the subjects with isolated AMA, normal alkaline phosphatase (ALP) levels and no symptoms of liver disease could have PBC by histology, defining how to manage and follow this population is crucial; role of liver biopsy: recent evidence suggests that biopsy may provide relevant information for risk stratification and prediction of UDCA response, possibly facilitating personalized approaches; risk stratification: the tools for risk stratification are well established, but some issues (eg bile acid dosage in routine practice) remain controversial; and therapy: those in more advanced stages of development are nuclear receptor modulators and fibrates, but more data are needed to plan personalized strategies. In this manuscript, for each topic, current evidence, controversies and future perspectives are summarized with the possible implications for clinical practice.
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Affiliation(s)
- Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Division of Health Sciences, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Antonio Craxi
- Gastroenterology and Liver Unit, PROMISE, University of Palermo, Palermo, Italy
| | - Annarosa Floreani
- Studioso Senior University of Padova and, Scientific Consultant IRCCS Negrar, Verona, Italy.,Scientific Consultant IRCCS Negrar, Verona, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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Sahu R, Mishra R, Majee C. An insight into primary biliary cholangitis and its recent advances in treatment: semi-synthetic analogs to combat ursodeoxycholic-acid resistance. Expert Rev Gastroenterol Hepatol 2020; 14:985-998. [PMID: 32674617 DOI: 10.1080/17474124.2020.1797485] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease which on progression causes cirrhosis; various studies also suggested that several diseases can co-exist in patients. In existing depiction of disease PBC, apart from entire use of ursodeoxycholic acid (UDCA), several patients need to step forward to liver-transplantation or death due to resistance or non-responder with UDCA monotherapy. AREAS COVERED To overcome this non-respondent treatment, novel bile acid semi-synthetic analogs have been identified which shows their potency against for farnesoid X receptor and transmembrane G protein-coupled receptor-5 which are identified as target for many developing analogs which have desirable pharmacokinetic profiles. EXPERT OPINION A range of studies suggests that adding semisynthetic analogs in therapeutic regime improves liver biochemistries in patients with suboptimal response to UDCA. Thus, the aspire of this review is to abridge and compare therapeutic value and current markets affirm of various bile acids semi-synthetic analogs which certainly are having promising effects in PBC monotherapy or in pooled treatment with UDCA for PBC.
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Affiliation(s)
- Rakesh Sahu
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute) , Greater Noida, India
| | - Rakhi Mishra
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute) , Greater Noida, India
| | - Chandana Majee
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute) , Greater Noida, India
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Huang C, Xing X, Xiang X, Fan X, Men R, Ye T, Yang L. MicroRNAs in autoimmune liver diseases: from diagnosis to potential therapeutic targets. Biomed Pharmacother 2020; 130:110558. [PMID: 32781357 DOI: 10.1016/j.biopha.2020.110558] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 07/21/2020] [Accepted: 07/26/2020] [Indexed: 02/08/2023] Open
Abstract
Autoimmune liver diseases (AILDs) are a group of liver disorders composed of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) characterized by chronic hepatic and biliary inflammation. Although several genetic factors, such as HLA alleles, TNFA, and CTLA-4, have been reported in the pathogenesis of AILDs, many details remain unknown. In recent years, microRNAs (miRNAs) have emerged as crucial components in the diagnosis and therapeutic applications of various autoimmune diseases, including systemic lupus erythematosus (SLE), glomerulonephritis, and AILDs. MiRNAs comprise a class of small, noncoding molecules of 19--25 nucleotides that modulate multiple genes by suppressing or degrading target mRNAs. Altered miRNA profiles have been identified in serum, immune cells, and live tissues from AILD patients. Elevated serum miR-21 and miR-122 levels in AIH patients as well as decreased miR-200c levels in PSC patients indicate their diagnostic utility. Highly expressed miR-122 and miR-378f as well as downregulated miR-4311 and miR-4714-3p in serum samples from refractory PBC patients suggest their potential to evaluate treatment efficacy. Moreover, miRNAs have been reported to participate in AILD development. Increased miR-506 levels may impair bile secretion in PBC by inhibiting Cl-/HCO3-anion exchanger 2 (AE2) and type III inositol 1,4,5-trisphosphate receptor-3 (InsP3R3). Additionally, different miRNA mimics or antagonists, such as atagomiR-155 and miR-223 mimics, have been widely applied in experimental AILD murine models with great efficacy. Here, we provide an overview of miRNAs in AILDs, aiming to summarize their potential roles in diagnosis and therapeutic interventions, and we discuss the challenges and future applications of miRNAs in clinical practice.
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Affiliation(s)
- Chen Huang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xian Xing
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xinyu Xiang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoli Fan
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Ruoting Men
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Tinghong Ye
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
| | - Li Yang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China.
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Phaw NA, Dyson JK, Jones D. Emerging drugs for the treatment of primary biliary cholangitis. Expert Opin Emerg Drugs 2020; 25:101-112. [PMID: 32253941 DOI: 10.1080/14728214.2020.1751814] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Primary biliary cholangitis (PBC) is a progressive inflammatory autoimmune cholestatic liver disease. Without treatment, it may result in fibrosis and eventually end stage liver disease. In addition to the disease burden, the symptom impact on the quality of life for PBC patients is significant. Ursodeoxycholic acid, and the second-line therapy, Obeticholic acid, are the only available licensed treatments. Although there has been rapid development of novel therapies in recent years for the treatment of PBC, there are very few symptoms directed therapies. AREA COVERED This literature review aims to review the current treatment landscape in PBC and to explore how the next few years may unfold in the field. The current guidelines and emerging therapies in phase 2, 3 and 4 clinical trials have been included. EXPERT OPINION The currently available therapies are effective, but their use has limitations and challenges and there is still significant unmet need. Although there have been promising therapeutic interventions in recent years, further research into personalizing therapeutic strategies with available treatments and new agents is needed.
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Affiliation(s)
- Naw April Phaw
- Institute of Translational and Clinical Research, Newcastle University , Newcastle-upon-Tyne, UK.,Hepatology Department, Newcastle Hospital NHS Foundation Trust , Newcastle-upon-Tyne, UK
| | - Jessica Katharine Dyson
- Institute of Translational and Clinical Research, Newcastle University , Newcastle-upon-Tyne, UK.,Hepatology Department, Newcastle Hospital NHS Foundation Trust , Newcastle-upon-Tyne, UK
| | - David Jones
- Institute of Translational and Clinical Research, Newcastle University , Newcastle-upon-Tyne, UK.,Hepatology Department, Newcastle Hospital NHS Foundation Trust , Newcastle-upon-Tyne, UK.,NIHR Newcastle Biomedical Research Centre, Newcastle University , Newcastle-upon-Tyne, UK
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Galoosian A, Hanlon C, Zhang J, Holt EW, Yimam KK. Clinical Updates in Primary Biliary Cholangitis: Trends, Epidemiology, Diagnostics, and New Therapeutic Approaches. J Clin Transl Hepatol 2020; 8:49-60. [PMID: 32274345 PMCID: PMC7132015 DOI: 10.14218/jcth.2019.00049] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/21/2019] [Accepted: 01/01/2020] [Indexed: 12/12/2022] Open
Abstract
Primary biliary cholangitis, formerly known as primary biliary cirrhosis, is a chronic, autoimmune, and cholestatic disease ameliorating the biliary epithelial system causing fibrosis and end-stage liver disease, over time. Patients range from an asymptomatic phase early in the disease course, to symptoms of decompensated cirrhosis later in its course. This review focuses on the current consensus on the epidemiology, diagnosis, and management of patients with primary biliary cholangitis. We also discuss established medical management as well as novel and investigational therapeutics in the pipeline for management of PBC.
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Affiliation(s)
- Artin Galoosian
- Department of Medicine, California Pacific Medical Center, San Francisco, CA, USA
| | - Courtney Hanlon
- Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Julia Zhang
- Department of Medicine, California Pacific Medical Center, San Francisco, CA, USA
| | - Edward W. Holt
- Department of Transplant, Division of Hepatology, California Pacific Medical Center, San Francisco, CA, USA
| | - Kidist K. Yimam
- Director of the Autoimmune Liver Disease Program, Department of Transplant, Division of Hepatology, California Pacific Medical Center, San Francisco, CA, USA
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Chang C, Tanaka A, Bowlus C, Gershwin ME. The use of biologics in the treatment of autoimmune liver disease. Expert Opin Investig Drugs 2020; 29:385-398. [PMID: 32102572 DOI: 10.1080/13543784.2020.1733527] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Autoimmune liver diseases include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and juvenile autoimmune hepatitis (JAIH). The pathophysiologic features of each disease vary, but generally include presence of autoantibodies, cytokine abnormalities, and/or T and B cell autoreactivity.Areas covered: This article compares conventional therapy with newer biologics available for treatment of autoimmune liver diseases. Conventional therapy involves the use of immunosuppressive agents, or other treatment modalities for specific autoimmune liver diseases such as ursodeoxycholic acid and fibrates for PBC. Biologics were developed to target the production of autoantibodies by B cells, the presence of proinflammatory cytokines, adhesion molecules or T and B cell activation.Expert opinion: Despite the promise of biologics being able to target specific cellular and humoral pathways, results have been generally poor, and safety has not been as expected. Cases of autoimmune hepatitis have also developed with the use of these biologicals. Reasons for the lack of success of biologics in treating autoimmune liver disease has led to a reevaluation of our understanding of underlying pathogenesis, demonstrating that while our knowledge of the immunity has improved over the past two decades, it is far from complete.
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Affiliation(s)
- Christopher Chang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.,Division of Pediatric Immunology and Allergy, Joe DiMaggio Children's Hospital, Hollywood, FL, USA
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Christopher Bowlus
- Division of Gastroenterology, University of California at Davis, Davis, CA, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
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Ma X, Jiang Y, Zhang W, Wang J, Wang R, Wang L, Wei S, Wen J, Li H, Zhao Y. Natural products for the prevention and treatment of cholestasis: A review. Phytother Res 2020; 34:1291-1309. [PMID: 32026542 DOI: 10.1002/ptr.6621] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 12/26/2019] [Accepted: 01/13/2020] [Indexed: 12/16/2022]
Abstract
Cholestasis is a common manifestation of decreased bile flow in various liver diseases. It results in fibrosis and even cirrhosis without proper treatment. It is believed that a wide range of factors, including transporter dysfunction, oxidative stress, inflammatory damage, and immune disruption, can cause cholestasis. In recent years, natural products have drawn much attention for specific multiple-target activities in diseases. Many attempts have been made to investigate the anticholestatic effects of natural products with advanced technology. This review summarizes recent studies on the biological activities and mechanisms of recognized compounds for cholestasis treatment. Natural products, including various flavonoids, phenols, acids, quinones, saponins, alkaloids, glycosides, and so on, function as comprehensive regulators via ameliorating oxidative stress, inflammation, and apoptosis, restoring bile acid balance with hepatic transporters, and adjusting immune disruption. Moreover, in this progress, nuclear factor erythroid 2-related factor 2, reactive oxygen species production, heme oxygenase-1, NF-κB, cholesterol 7 alpha-hydroxylase, and farnesoid X receptors are thought as main targets for the activity of natural products. Therefore, this review presents the detailed mechanisms that include multiple targets and diverse signalling pathways. Natural products are the valuable when seeking novel therapeutic agents to treat cholestatic liver diseases.
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Affiliation(s)
- Xiao Ma
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yinxiao Jiang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenwen Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiabo Wang
- China Military Institute of Chinese Medicine, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Ruilin Wang
- China Military Institute of Chinese Medicine, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Lifu Wang
- China Military Institute of Chinese Medicine, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Shizhang Wei
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jianxia Wen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.,Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Haotian Li
- Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yanling Zhao
- Department of Pharmacy, Fifth Medical Center of PLA General Hospital, Beijing, China
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Zhou J, Cui S, He Q, Guo Y, Pan X, Zhang P, Huang N, Ge C, Wang G, Gonzalez FJ, Wang H, Hao H. SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis. Nat Commun 2020; 11:240. [PMID: 31932588 PMCID: PMC6957516 DOI: 10.1038/s41467-019-14138-6] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023] Open
Abstract
Farnesoid X receptor (FXR) is a promising target for nonalcoholic steatohepatitis (NASH) and fibrosis. Although various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models, the response rate and efficacies in clinical trials were not optimum. Here we report that prophylactic but not therapeutic administration of obeticholic acid (OCA) prevents hepatic stellate cell (HSC) activation and fibrogenesis. Activated HSCs show limited response to OCA and other FXR agonists due to enhanced FXR SUMOylation. SUMOylation inhibitors rescue FXR signaling and thereby increasing the efficacy of OCA against HSC activation and fibrosis. FXR upregulates Perilipin-1, a direct target gene of FXR, to stabilize lipid droplets and thereby prevent HSC activation. Therapeutic coadministration of OCA and SUMOylation inhibitors drastically impedes liver fibrosis induced by CCl4, bile duct ligation, and more importantly NASH. In conclusion, we propose a promising therapeutic approach by combining SUMOylation inhibitors and FXR agonists for liver fibrosis.
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Affiliation(s)
- Jiyu Zhou
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Shuang Cui
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Qingxian He
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Yitong Guo
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Xiaojie Pan
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Pengfei Zhang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Ningning Huang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
| | - Chaoliang Ge
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, 230022, Hefei, China
| | - Guangji Wang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China.
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Hong Wang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China.
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 210009, Nanjing, China.
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Honda A, Tanaka A, Kaneko T, Komori A, Abe M, Inao M, Namisaki T, Hashimoto N, Kawata K, Takahashi A, Ninomiya M, Kang JH, Arakawa M, Yamagiwa S, Joshita S, Umemura T, Sato K, Kaneko A, Kikuchi K, Itakura J, Nomura T, Kakisaka K, Fujii H, Kawada N, Takikawa Y, Masaki T, Ohira H, Mochida S, Yoshiji H, Iimuro S, Matsuzaki Y, Takikawa H. Bezafibrate Improves GLOBE and UK-PBC Scores and Long-Term Outcomes in Patients With Primary Biliary Cholangitis. Hepatology 2019; 70:2035-2046. [PMID: 30737815 DOI: 10.1002/hep.30552] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 02/02/2019] [Indexed: 12/11/2022]
Abstract
In Japan, bezafibrate (BF) is a second-line agent for primary biliary cholangitis (PBC) that is refractory to ursodeoxycholic acid (UDCA) treatment. From a retrospective cohort (n = 873) from the Japan PBC Study Group, we enrolled 118 patients who had received UDCA monotherapy for at least 1 year followed by combination therapy with UDCA+BF for at least 1 year. GLOBE and UK-PBC scores after UDCA monotherapy (i.e., immediately before UDCA+BF combination therapy) were compared with those after 1 year of UDCA+BF combination therapy. The real outcomes of enrolled patients estimated by Kaplan-Meier analysis were compared with the predicted outcomes calculated using GLOBE and UK-PBC scores. In addition, the hazard ratio of BF treatment was calculated using propensity score analysis. The mean GLOBE score before the combination therapy was 0.504 ± 0.080, which improved significantly to 0.115 ± 0.085 (P < 0.0001) after 1 year of combination therapy. The real liver transplant-free survival of enrolled patients was significantly better than that predicted by GLOBE score before introducing BF. Combination therapy did not significantly improve the real rates of liver transplantation or liver-related death compared with those predicted by UK-PBC risk score before introducing BF, but the predicted risk was significantly reduced by the addition of BF (P < 0.0001). Cox regression analysis with inverse probability of treatment weighting showed that the addition of BF significantly reduced the hazard of liver transplant or liver-related death in patients who, after 1 year of UDCA monotherapy, had normal serum bilirubin (adjusted hazard ratio 0.09, 95% confidence interval 0.01-0.60, P = 0.013). Conclusion: Addition of BF to UDCA monotherapy improves not only GLOBE and UK-PBC scores but also the long-term prognosis of PBC patients, especially those with early-stage PBC.
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Affiliation(s)
- Akira Honda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Tetsuji Kaneko
- Teikyo Academic Research Center, Teikyo University, Tokyo, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Nagasaki, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Mie Inao
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Naoaki Hashimoto
- Department of Gastroenterology, Tokyo Teishin Hospital, Tokyo, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Jong-Hon Kang
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Mie Arakawa
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | - Satoshi Yamagiwa
- Department of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Satoru Joshita
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeji Umemura
- Division of Hepatology and Gastroenterology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ken Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Akira Kaneko
- Department of Gastroenterology, NTT West Osaka Hospital, Osaka, Japan
| | - Kentaro Kikuchi
- The Fourth Department of Internal Medicine, Teikyo University Mizonokuchi Hospital, Kanagawa, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Nara, Japan
| | - Satoshi Iimuro
- Teikyo Academic Research Center, Teikyo University, Tokyo, Japan
| | - Yasushi Matsuzaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Hajime Takikawa
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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Goossens JF, Bailly C. Ursodeoxycholic acid and cancer: From chemoprevention to chemotherapy. Pharmacol Ther 2019; 203:107396. [DOI: 10.1016/j.pharmthera.2019.107396] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 07/16/2019] [Indexed: 12/12/2022]
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Factors Associated With Potential Progressive Course of Primary Biliary Cholangitis: Data From Real-world US Database. J Clin Gastroenterol 2019; 53:693-698. [PMID: 30148766 DOI: 10.1097/mcg.0000000000001120] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Although relatively, primary biliary cholangitis (PBC) is an important cause of nonalcoholic chronic liver disease which may lead to liver transplantation. PBC patients with alkaline phosphatase (ALP) ≥1.5× the upper limit of normal (ULN) tend to have a more aggressive course. The study was designed to identify factors associated with ALP≥1.5×ULN or cirrhosis in PBC and to evaluate concomitant health care resource utilization. METHODS We used a large real-world database that contained comprehensive and continuous electronic medical recored/claims data from over 500 health care practices or systems from the United States. RESULTS Of 195 million patients included in the database, 36,317 were adults with PBC. After applying exclusion criteria, 15,875 patients comprised the final PBC cohort (63.0±13.5 y, 78% female, 71% privately insured, 5% covered by Medicaid, 57% with other autoimmune diseases, 46% with cirrhosis); 6083 (38%) had ALP≥1.5×ULN. Patients with ALP≥1.5×ULN were more frequently female, less covered by Medicaid, had more pruritus, cirrhosis, and other autoimmune diseases (P<0.05). In multivariate analysis, older age, female gender, the presence of other autoimmune diseases, and having compensated or decompensated cirrhosis were independently associated with having ALP≥1.5×ULN in PBC (P<0.05). In contrast, being male was associated with higher risk of cirrhosis in PBC [odds ratio 2.3 (95% confidence interval, 2.1-2.5)]. Patients with ALP≥1.5×ULN and/or with cirrhosis also incurred substantially more health care resource utilization (P<0.05). CONCLUSIONS Many clinical, sociodemographic, and economic factors are associated with a potentially more aggressive profile of PBC with elevated ALP. These data may inform clinicians to implement management strategies to optimize care of these patients.
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Abstract
Cholestatic liver diseases encompass a broad spectrum of pathologies, with the core injury occurring at the level of cholangiocytes and progressing to hepatic fibrosis and liver dysfunction. Primary biliary cholangitis and primary sclerosing cholangitis are the most significant progressive cholangiopathies in adults. Although rare, they commonly evolve to liver failure and need for liver transplantation. Despite recent advances in the basic knowledge of these cholangiopathies, the pathogenesis is still elusive. Targeted treatments to prevent disease progression and to preclude malignancy are not yet available. This review will address the general clinical features of both diseases, analyze their commonalities and differences, and provide a state-of-the art overview of the currently available therapeutics.
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Wei Z, Zhao D, Zhang Y, Chen Y, Zhang S, Li Q, Zeng P, Li X, Zhang W, Duan Y, Han J, Yang X. Rosiglitazone ameliorates bile duct ligation-induced liver fibrosis by down-regulating NF-κB-TNF-α signaling pathway in a PPARγ-dependent manner. Biochem Biophys Res Commun 2019; 519:854-860. [PMID: 31561855 DOI: 10.1016/j.bbrc.2019.09.084] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 09/19/2019] [Indexed: 12/12/2022]
Abstract
Liver fibrosis is a major cause of morbidity and mortality worldwide. One of its therapeutic targets is peroxisome proliferator-activated receptor γ (PPARγ), with its ligands including rosiglitazone being tested in pre-clinical and clinical studies. However, the effects of rosiglitazone on bile duct ligation (BDL)-induced liver fibrosis and the involved mechanisms remain unknown. Herein, we used floxed control (PPARγfl/fl) and hepatocyte-specific PPARγ deficient (HepPPARγ KO) mice to conduct BDL to induce liver fibrosis and treated the animals with rosiglitazone. After one week of BDL, mice in BDL group displayed liver injury evidenced by increased collagen content, fibrosis area, necrosis area and apoptotic cells, and elevated alkaline phosphatase and alanine transaminase activities in serum. Interestingly, rosiglitazone ameliorated BDL-induced liver injury in PPARγfl/fl mice but not in HepPPARγ KO mice. Mechanistically, rosiglitazone reduced BDL-induced collagen content by downregulating fibrotic related genes including transforming growth factor β1, α-smooth muscle actin and collagen type I α1, and decreased inflammation cytokine tumor necrosis factor α level by inhibiting phosphorylation of nuclear factor-κB in a PPARγ-dependent manner. Based on findings above, we demonstrated that rosiglitazone can ameliorate BDL-induced liver fibrosis in mice and confirmed its critical functions on fibrosis by regulating NF-κB-TNF-α pathway in a PPARγ-dependent manner.
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Affiliation(s)
- Zhuo Wei
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China; Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Dan Zhao
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Ye Zhang
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Yuanli Chen
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Shuang Zhang
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Qi Li
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Peng Zeng
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Xiaoju Li
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Wenwen Zhang
- Tianjin Key Lab of Human Development and Reproductive Regulation, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
| | - Yajun Duan
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Jihong Han
- College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China; Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Xiaoxiao Yang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
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48
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Lin CY, Cheng YT, Chang ML, Chien RN. The extrahepatic events of Asian patients with primary biliary cholangitis: A 30-year cohort study. Sci Rep 2019; 9:7577. [PMID: 31110209 PMCID: PMC6527707 DOI: 10.1038/s41598-019-44081-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Accepted: 05/09/2019] [Indexed: 12/16/2022] Open
Abstract
The extrahepatic complications of primary biliary cholangitis (PBC) in Asian patients remain elusive. A 30-year cohort study of 150 Taiwanese PBC patients treated with ursodeoxycholic acid (UDCA) was conducted. Patients with alkaline phosphatase levels >1.67 × ULN after 1-year treatment were considered suboptimal responders. At baseline, of 150 patients (mean age: 53.75 years), 128 (85.3%) were females, and 34 (22.8%) had cirrhosis. The cumulative incidences of various incident events were all-cause mortality or liver transplantation: 46.7%; extrahepatic mortality: 24.5%; extrahepatic malignancies: 8.1%; hypertension: 46.2%; dyslipidemia: 44.1%; diabetes: 30.6%; hyperuricemia: 11.2%; acute coronary syndrome: 3.1%; cerebral vascular accident (CVA): 8.9%; autoimmune diseases: 16%; and osteoporosis: 20.9%. The 5- to 20-year cumulative incidences for all-cause mortality or liver transplantation and extrahepatic mortality were 16.2–41.3% and 3.1–11.9%, respectively. Baseline associations were age and alpha-fetoprotein levels with extrahepatic mortality, 80% due to sepsis; age with extrahepatic malignancies and hypertension; gender and hyperuricemia with CVA; and UDCA response with autoimmune disease. Conclusions: Sepsis accounted for most extrahepatic mortality in PBC patients, and the longer the follow-up was, the higher the extrahepatic/all-cause mortality ratio. Baseline age is crucial for incident extrahepatic events and only CVA shows gender-dimorphism; the association between UDCA response and autoimmune disease requires further investigation.
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Affiliation(s)
- Cheng-Yu Lin
- Liver Research Center, Division of Gastroenterology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ya-Ting Cheng
- Liver Research Center, Division of Gastroenterology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ming-Ling Chang
- Liver Research Center, Division of Gastroenterology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan. .,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| | - Rong-Nan Chien
- Liver Research Center, Division of Gastroenterology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan. .,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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49
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Tanaka A. Emerging novel treatments for autoimmune liver diseases. Hepatol Res 2019; 49:489-499. [PMID: 30969002 DOI: 10.1111/hepr.13347] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/26/2019] [Accepted: 04/07/2019] [Indexed: 12/17/2022]
Abstract
The etiology of autoimmune liver diseases, such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), still remains largely unknown and no therapeutic agents that are able to "cure" these diseases have been developed. Although corticosteroids for AIH and ursodeoxycholic acid for PBC have been shown to significantly improve liver transplantation (LT)-free survival and are recommended as first-line drugs, treatment strategies for patients who show incomplete response to these drugs have not yet been fully established. No drug is significantly associated with long LT-free survival in PSC patients. Nevertheless, with progress in genetics, immunology, and cellular biology, several new compounds or antibodies are expected to have an effect on autoimmune liver diseases and several drugs are under consideration for clinical use. Although most clinical trials have been carried out in the USA or Europe, some are, or will be, undertaken in Japan in the future. In this review, the current standard-of-care of autoimmune liver diseases will be summarized, together with emerging novel treatments relevant to clinical practice in Japan.
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50
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Eaton JE, Gores GJ. Long-term outcomes with obeticholic acid in primary biliary cholangitis: reassuring, but still an itch we need to scratch. Lancet Gastroenterol Hepatol 2019; 4:417-418. [PMID: 30922872 DOI: 10.1016/s2468-1253(19)30084-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 02/21/2019] [Indexed: 12/12/2022]
Affiliation(s)
- John E Eaton
- Division of Gastroenterology & Hepatology, Medicine, Mayo Clinic, Rochester, MN, USA
| | - Gregory J Gores
- Division of Gastroenterology & Hepatology, Medicine, Mayo Clinic, Rochester, MN, USA; Division of Physiology, Mayo Clinic, Rochester, MN, USA.
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