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Drazilova S, Koky T, Macej M, Janicko M, Simkova D, Jarcuska P. The treatment of primary biliary cholangitis: from shadow to light. Therap Adv Gastroenterol 2024; 17:17562848241265782. [PMID: 39081664 PMCID: PMC11287753 DOI: 10.1177/17562848241265782] [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: 02/23/2024] [Accepted: 06/05/2024] [Indexed: 08/02/2024] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic disease characterized by the destruction of the small intrahepatic bile ducts, which can progress to liver cirrhosis. The gold standard in the treatment of PBC is ursodeoxycholic acid (UDCA), which is indicated in all patients with PBC because it improves not only biochemical parameters but also patients' survival. An important milestone in the identification of patients at risk is the assessment of biochemical response to UDCA. Patients who respond to treatment have a lower incidence of hepatic events and better prognosis than patients who do not. Several scoring systems can be used to assess the response and identify non-responders who will benefit from second-line treatment. Obeticholic acid (OCA) is currently the only approved second-line treatment for PBC, which is effective for non-responders to UDCA therapy or patients, who have not tolerated UDCA therapy. However, OCA is contraindicated in advanced liver cirrhosis and portal hypertension. Moreover, pruritus may be a limiting factor for the administration of OCA. Fibrates have shown promising data supporting their use in non-responders to UDCA because they improve the biochemical parameters and elastographic findings and have possible antipruritic effects. Therefore, the idea of a triple treatment seems interesting. Clinical research is focusing on several other groups of drugs: peroxisome proliferator-activated receptor (PPAR) δ- and α/δ agonists, non-steroidal farnesoid X receptor agonists, fibroblast growth factor 19 modulators, and inhibitors of nicotinamide adenine dinucleotide phosphate oxidase 1 and 4.
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Affiliation(s)
- Sylvia Drazilova
- 2nd Department of Internal Medicine, Faculty of Medicine and Louis Pasteur University Hospital, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Tomas Koky
- 2nd Department of Internal Medicine, Faculty of Medicine and Louis Pasteur University Hospital, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Marian Macej
- 2nd Department of Internal Medicine, Faculty of Medicine and Louis Pasteur University Hospital, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Martin Janicko
- 2nd Department of Internal Medicine, Faculty of Medicine and Louis Pasteur University Hospital, Pavol Jozef Safarik University, Kosice, Slovakia
| | - Dagmar Simkova
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine (IKEM), Prague 4, Czech Republic
| | - Peter Jarcuska
- 2nd Department of Internal Medicine, Faculty of Medicine and Louis Pasteur University Hospital, Pavol Jozef Safarik University, Trieda SNP 1, Kosice 040 11, Slovakia
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Yang F, Zhou L, Shen Y, Wang X, Fan X, Yang L. Multi-omics approaches for drug-response characterization in primary biliary cholangitis and autoimmune hepatitis variant syndrome. J Transl Med 2024; 22:214. [PMID: 38424613 PMCID: PMC10902991 DOI: 10.1186/s12967-024-05029-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 02/24/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) variant syndrome (VS) exhibit a complex overlap of AIH features with PBC, leading to poorer prognoses than those with PBC or AIH alone. The biomarkers associated with drug response and potential molecular mechanisms in this syndrome have not been fully elucidated. METHODS Whole-transcriptome sequencing was employed to discern differentially expressed (DE) RNAs within good responders (GR) and poor responders (PR) among patients with PBC/AIH VS. Subsequent gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted for the identified DE RNAs. Plasma metabolomics was employed to delineate the metabolic profiles distinguishing PR and GR groups. The quantification of immune cell profiles and associated cytokines was achieved through flow cytometry and immunoassay technology. Uni- and multivariable logistic regression analyses were conducted to construct a predictive model for insufficient biochemical response. The performance of the model was assessed by computing the area under the receiver operating characteristic (AUC) curve, sensitivity, and specificity. FINDINGS The analysis identified 224 differentially expressed (DE) mRNAs, 189 DE long non-coding RNAs, 39 DE circular RNAs, and 63 DE microRNAs. Functional pathway analysis revealed enrichment in lipid metabolic pathways and immune response. Metabolomics disclosed dysregulated lipid metabolism and identified PC (18:2/18:2) and PC (16:0/20:3) as predictors. CD4+ T helper (Th) cells, including Th2 cells and regulatory T cells (Tregs), were upregulated in the GR group. Pro-inflammatory cytokines (IFN-γ, TNF-α, IL-9, and IL-17) were downregulated in the GR group, while anti-inflammatory cytokines (IL-10, IL-4, IL-5, and IL-22) were elevated. Regulatory networks were constructed, identifying CACNA1H and ACAA1 as target genes. A predictive model based on these indicators demonstrated an AUC of 0.986 in the primary cohort and an AUC of 0.940 in the validation cohort for predicting complete biochemical response. CONCLUSION A combined model integrating genomic, metabolic, and cytokinomic features demonstrated high accuracy in predicting insufficient biochemical response in patients with PBC/AIH VS. Early recognition of individuals at elevated risk for insufficient response allows for the prompt initiation of additional treatments.
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Affiliation(s)
- Fan Yang
- Department of Gastroenterology and Hepatology and Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, #37 Guoxue Road, Chengdu, 610041, Sichuan, China
| | - Leyu Zhou
- Department of Gastroenterology and Hepatology and Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, #37 Guoxue Road, Chengdu, 610041, Sichuan, China
| | - Yi Shen
- Department of Gastroenterology and Hepatology and Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, #37 Guoxue Road, Chengdu, 610041, Sichuan, China
| | - Xianglin Wang
- Department of Gastroenterology and Hepatology and Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, #37 Guoxue Road, Chengdu, 610041, Sichuan, China
| | - Xiaoli Fan
- Department of Gastroenterology and Hepatology and Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, #37 Guoxue Road, Chengdu, 610041, Sichuan, China.
| | - Li Yang
- Department of Gastroenterology and Hepatology and Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, #37 Guoxue Road, Chengdu, 610041, Sichuan, China.
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Shen ZX, Wu DD, Xia J, Wang XB, Zheng X, Huang Y, Li BL, Meng ZJ, Gao YH, Qian ZP, Liu F, Lu XB, Shang J, Yan HD, Zheng YB, Gu WY, Zhang Y, Wei JY, Tan WT, Hou YX, Zhang Q, Xiong Y, Zou CC, Chen J, Huang ZB, Jiang XH, Luo S, Chen YY, Gao N, Liu CY, Yuan W, Mei X, Li J, Li T, Zhou XY, Deng GH, Chen JJ, Ma X, Li H. Prevalence and clinical characteristics of autoimmune liver disease in hospitalized patients with cirrhosis and acute decompensation in China. World J Gastroenterol 2022; 28:4417-4430. [PMID: 36159019 PMCID: PMC9453760 DOI: 10.3748/wjg.v28.i31.4417] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/19/2022] [Accepted: 07/25/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Autoimmune liver disease (AILD) has been considered a relatively uncommon disease in China, epidemiological data for AILD in patients with cirrhosis and acute decompensation (AD) is sparse. AIM To investigate the prevalence, outcome and risk factors for AILD in cirrhotic patients complicated with AD in China. METHODS We collected data from patients with cirrhosis and AD from two prospective, multicenter cohorts in hepatitis B virus endemic areas. Patients were regularly followed up at the end of 28-d, 90-d and 365-d, or until death or liver transplantation (LT). The primary outcome in this study was 90-d LT-free mortality. Acute-on-chronic liver failure (ACLF) was assessed on admission and during 28-d hospitalization, according to the diagnostic criteria of the European Association for the Study of the Liver (EASL). Risk factors for death were analyzed with logistic regression model. RESULTS In patients with cirrhosis and AD, the overall prevalence of AILD was 9.3% (242/2597). Prevalence of ACLF was significantly lower in AILD cases (14%) than those with all etiology groups with cirrhosis and AD (22.8%) (P < 0.001). Among 242 enrolled AILD patients, the prevalence rates of primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and PBC-AIH overlap syndrome (PBC/AIH) were 50.8%, 28.5% and 12.0%, respectively. In ACLF patients, the proportions of PBC, AIH and PBC/AIH were 41.2%, 29.4% and 20.6%. 28-d and 90-d mortality were 43.8% and 80.0% in AILD-related ACLF. The etiology of AILD had no significant impact on 28-d, 90-d or 365-d LT-free mortality in patients with cirrhosis and AD in both univariate and multivariate analysis. Total bilirubin (TB), hepatic encephalopathy (HE) and blood urea nitrogen (BUN) were independent risk factors for 90-d LT-free mortality in multivariate analysis. The development of ACLF during hospitalization only independently correlated to TB and international normalized ratio. CONCLUSION AILD was not rare in hospitalized patients with cirrhosis and AD in China, among which PBC was the most common etiology. 90-d LT-free mortality were independently associated with TB, HE and BUN.
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Affiliation(s)
- Zi-Xuan Shen
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
- Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Chinese Ministry of Health, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Dan-Dan Wu
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
- Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Chinese Ministry of Health, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Jie Xia
- Department of Infectious Diseases, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Xian-Bo Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100102, China
| | - Xin Zheng
- Department of Infectious Diseases, Institute of Infection and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Yan Huang
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Bei-Ling Li
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Zhong-Ji Meng
- Department of Infectious Disease, Taihe Hospital, Hubei University of Medicine, Shiyan 430418, Hubei Province, China
| | - Yan-Hang Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130031, Jilin Province, China
| | - Zhi-Ping Qian
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Centre, Fudan University, Shanghai 201508, China
| | - Feng Liu
- Tianjin Institute of Hepatology, Nankai University Second People’s Hospital, Tianjin 300102, China
- Department of Infectious Diseases and Hepatology, The Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
| | - Xiao-Bo Lu
- Infectious Disease Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang, China
| | - Jia Shang
- Department of Infectious Diseases, Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Hua-Dong Yan
- Department of Infectious Diseases, Hwamei Hospital, The Second Hospital of Ningbo, University of Chinese Academy of Sciences, Ningbo 315153, Zhejiang Province, China
| | - Yu-Bao Zheng
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
| | - Wen-Yi Gu
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
- Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Chinese Ministry of Health, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Yan Zhang
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
- Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Chinese Ministry of Health, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Jian-Yi Wei
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
- Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Chinese Ministry of Health, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Wen-Ting Tan
- Department of Infectious Diseases, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Yi-Xin Hou
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100102, China
| | - Qun Zhang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100102, China
| | - Yan Xiong
- Department of Infectious Diseases, Institute of Infection and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Cong-Cong Zou
- Department of Infectious Diseases, Institute of Infection and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Jun Chen
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Ze-Bing Huang
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Xiu-Hua Jiang
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Sen Luo
- Department of Infectious Disease, Taihe Hospital, Hubei University of Medicine, Shiyan 430418, Hubei Province, China
| | - Yuan-Yuan Chen
- Department of Infectious Disease, Taihe Hospital, Hubei University of Medicine, Shiyan 430418, Hubei Province, China
| | - Na Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130031, Jilin Province, China
| | - Chun-Yan Liu
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130031, Jilin Province, China
| | - Wei Yuan
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Centre, Fudan University, Shanghai 201508, China
| | - Xue Mei
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Centre, Fudan University, Shanghai 201508, China
| | - Jing Li
- Department of Infectious Diseases and Hepatology, The Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
| | - Tao Li
- Department of Infectious Diseases and Hepatology, The Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
| | - Xin-Yi Zhou
- Infectious Disease Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang, China
| | - Guo-Hong Deng
- Department of Infectious Diseases, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jin-Jun Chen
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xiong Ma
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
- Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Chinese Ministry of Health, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Hai Li
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
- Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Chinese Ministry of Health, Shanghai Jiao Tong University, Shanghai 200001, China
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Floreani A, Gabbia D, De Martin S. Update on the Pharmacological Treatment of Primary Biliary Cholangitis. Biomedicines 2022; 10:biomedicines10082033. [PMID: 36009580 PMCID: PMC9405864 DOI: 10.3390/biomedicines10082033] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/16/2022] [Accepted: 08/18/2022] [Indexed: 11/16/2022] Open
Abstract
Ursodeoxycholic acid (UDCA) is the first-line therapy used for the treatment of PBC. In recent years, new pharmacological agents have been proposed for PBC therapy to cure UDCA-non-responders. Obeticholic acid (OCA) is registered in many countries for PBC, and fibrates also seem to be effective in ameliorating biochemistry alteration and symptoms typical of PBC. Moreover, a variety of new agents, acting with different mechanisms of action, are under clinical evaluation for PBC treatment, including PPAR agonists, anti-NOX agents, immunomodulators, and mesenchymal stem cell transplantation. Since an insufficient amount of data is currently available about the effect of these novel approaches on robust clinical endpoints, such as transplant-free survival, their clinical approval needs to be supported by the consistent improvement of these parameters. The intensive research in this field will hopefully lead to a novel treatment landscape for PBC in the near future, with innovative therapies based on the combination of multiple agents acting on different pathogenetic mechanisms.
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Affiliation(s)
- Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35131 Padova, Italy
- IRCCS Negrar, 37024 Verona, Italy
| | - Daniela Gabbia
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy
- Correspondence:
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Gochanour EM, Kowdley KV. Investigational drugs in early phase development for primary biliary cholangitis. Expert Opin Investig Drugs 2020; 30:131-141. [PMID: 33249947 DOI: 10.1080/13543784.2021.1857364] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Introduction: With a large percentage of patients having an incomplete response or intolerance to current FDA approved medications, new therapies for the treatment of primary biliary cholangitis are in great demand. Areas covered: In this review, we assess currently available drugs as well as promising new therapies for the treatment of primary biliary cholangitis. A literature search was performed with the following search terms: 'PBC treatment,' 'PBC therapeutics,' 'PBC clinical trials,' and included original articles, meta-analyses, and systematic reviews from 1 January 1981, to 1 January 2020. ClinicalTrials.gov was accessed for data from ongoing trials. Expert opinion: Targeted drug therapies offer an alternative for patients who are unable to meet their therapeutic goals with either of the two currently approved treatment options. Specifically, new drugs targeting bile-acid regulation, immune-modulation, and fibrogenic pathways are currently in development with multiple agents showing encouraging early results with the ultimate goal of developing therapies that will achieve high rates of biochemical remission, will be well tolerated, and improve symptoms and quality of life in patients with primary biliary cholangitis. Based on a review of the current literature, PPAR agonists appear to be promising agents, along with FGF19 analogs and FXR agonists.
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Freedman BL, Danford CJ, Patwardhan V, Bonder A. Treatment of Overlap Syndromes in Autoimmune Liver Disease: A Systematic Review and Meta-Analysis. J Clin Med 2020; 9:jcm9051449. [PMID: 32414025 PMCID: PMC7291241 DOI: 10.3390/jcm9051449] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 04/30/2020] [Accepted: 05/07/2020] [Indexed: 12/13/2022] Open
Abstract
The treatment of overlap syndromes is guided by small observational studies whose data have never been synthesized in a rigorous, quantitative manner. We conducted a systematic review and meta-analysis to evaluate the efficacy of available treatments for these rare and morbid conditions. We searched the literature for studies comparing ≥2 therapies for autoimmune hepatitis (AIH)-primary biliary cholangitis (PBC), AIH-primary sclerosing cholangitis (PSC), PBC-PSC, AIH-PBC-PSC, autoimmune cholangitis (AIC), or autoimmune sclerosing cholangitis (ASC) with respect to various clinical outcomes, including biochemical improvement and transplant-free survival. A total of 28 studies met the inclusion criteria for AIH-PBC, AIH-PSC, AIC, and ASC. AIH-PBC patients tended to experience more biochemical improvement with ursodeoxycholic acid (UDCA) + [corticosteroids and/or antimetabolites], i.e., "combination therapy", than with corticosteroids ± azathioprine (RR = 4.00, 95% CI 0.93-17.18). AIH-PBC patients had higher transplant-free survival with combination therapy than with UDCA, but only when studies with follow-up periods ≤90 months were excluded (RR = 6.50, 95% CI 1.47-28.83). Combination therapy may therefore be superior to both UDCA and corticosteroids ± azathioprine for the treatment of AIH-PBC, but additional studies are needed to show this definitively and to elucidate optimal treatments for other overlap syndromes.
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Affiliation(s)
- Benjamin L. Freedman
- Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, USA;
| | - Christopher J. Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Dana 603, Boston, MA 02215, USA;
| | - Vilas Patwardhan
- Liver Center, Autoimmune and Cholestatic Liver Disease Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis St. Suite 8E, Boston, MA 02215, USA;
| | - Alan Bonder
- Liver Center, Autoimmune and Cholestatic Liver Disease Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis St. Suite 8E, Boston, MA 02215, USA;
- Correspondence: ; Tel.: +1-617-632-1070
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Shah RA, Kowdley KV. Current and potential treatments for primary biliary cholangitis. Lancet Gastroenterol Hepatol 2020; 5:306-315. [DOI: 10.1016/s2468-1253(19)30343-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 07/31/2019] [Accepted: 08/01/2019] [Indexed: 02/07/2023]
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Huang YQ. Recent advances in the diagnosis and treatment of primary biliary cholangitis. World J Hepatol 2016; 8:1419-1441. [PMID: 27957241 PMCID: PMC5124714 DOI: 10.4254/wjh.v8.i33.1419] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 07/26/2016] [Accepted: 08/29/2016] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC), formerly referred to as primary biliary cirrhosis, is an infrequent progressive intrahepatic cholestatic autoimmune illness that can evolve into hepatic fibrosis, hepatic cirrhosis, hepatic failure, and, in some cases, hepatocellular carcinoma. The disease itself is characterized by T-lymphocyte-mediated chronic non-suppurative destructive cholangitis and elevated serum levels of extremely specific anti-mitochondrial autoantibodies (AMAs). In this article, we will not only review epidemiology, risk factors, natural history, predictive scores, radiologic approaches (e.g., acoustic radiation force impulse imaging, vibration controlled transient elastography, and magnetic resonance elastography), clinical features, serological characteristics covering biochemical markers, immunoglobulins, infections markers, biomarkers, predictive fibrosis marker, specific antibodies (including AMAs such as AMA-M2), anti-nuclear autoantibodies [such as anti-multiple nuclear dot autoantibodies (anti-sp100, PML, NDP52, anti-sp140), anti-rim-like/membranous anti-nuclear autoantibodies (anti-gp210, anti-p62), anti-centromere autoantibodies, and some of the novel autoantibodies], histopathological characteristics of PBC, diagnostic advances, and anti-diastole of PBC. Furthermore, this review emphasizes the recent advances in research of PBC in terms of therapies, including ursodeoxycholic acid, budesonide, methotrexate, obeticholic acid, cyclosporine A, fibrates such as bezafibrate and fenofibrate, rituximab, mesenchymal stem cells transplant, and hepatic transplant. Currently, hepatic transplant remains the only optimal choice with acknowledged treatment efficiency for end-stage PBC patients.
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Effects of Omega-3 Fatty Acid in Nonalcoholic Fatty Liver Disease: A Meta-Analysis. Gastroenterol Res Pract 2016; 2016:1459790. [PMID: 27651787 PMCID: PMC5019889 DOI: 10.1155/2016/1459790] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 07/18/2016] [Indexed: 02/06/2023] Open
Abstract
A meta-analysis was conducted to assess the effect of omega-3 fatty acid supplementation (n-3 PUFAs) in lowering liver fat, liver enzyme (alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) levels), and blood lipids (triglyceride (TG), total cholesterol (TC), high density lipoprotein (HDL), and low density lipoprotein (LDL)) in patients with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). Methods. MEDLINE/PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL, Science Citation Index (ISI Web of Science), Chinese Biomedical Literature Database (CBM), and Chinese National Knowledge Infrastructure (CNKI) were searched for relevant randomized controlled trials on the effects of n-3 polyunsaturated fatty acids (PUFAs) in patients with NAFLD from inception to May 2015. Ten studies were included in this meta-analysis. Results. 577 cases of NAFLD/NASH in ten randomized controlled trials (RCTs) were included. The results of the meta-analysis showed that benefit changes in liver fat favored PUFA treatment, and it was also beneficial for GGT, but it was not significant on ALT, AST, TC, and LDL. Conclusions. In this meta-analysis, omega-3 PUFAs improved liver fat, GGT, TG, and HDL in patients with NAFLD/NASH. Therefore, n-3 PUFAs may be a new treatment option for NAFLD.
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Li S, Xia Y, Chen K, Li J, Liu T, Wang F, Lu J, Zhou Y, Guo C. Epigallocatechin-3-gallate attenuates apoptosis and autophagy in concanavalin A-induced hepatitis by inhibiting BNIP3. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:631-47. [PMID: 26929598 PMCID: PMC4760659 DOI: 10.2147/dddt.s99420] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Epigallocatechin-3-gallate (EGCG) is the most effective compound in green tea, and possesses a wide range of beneficial effects, including anti-inflammatory, antioxidant, antiobesity, and anticancer effects. In this study, we investigated the protective effects of EGCG in concanavalin A (ConA)-induced hepatitis in mice and explored the possible mechanisms involved in these effects. Methods Balb/C mice were injected with ConA (25 mg/kg) to induce acute autoimmune hepatitis, and EGCG (10 or 30 mg/kg) was administered orally twice daily for 10 days before ConA injection. Serum liver enzymes, proinflammatory cytokines, and other marker proteins were determined 2, 8, and 24 hours after the ConA administration. Results BNIP3 mediated cell apoptosis and autophagy in ConA-induced hepatitis. EGCG decreased the immunoreaction and pathological damage by reducing inflammatory factors, such as TNF-α, IL-6, IFN-γ, and IL-1β. EGCG also exhibited an antiapoptotic and antiautophagic effect by inhibiting BNIP3 via the IL-6/JAKs/STAT3 pathway. Conclusion EGCG attenuated liver injury in ConA-induced hepatitis by downregulating IL-6/JAKs/STAT3/BNIP3-mediated apoptosis and autophagy.
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Affiliation(s)
- Sainan Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Yujing Xia
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Jingjing Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Tong Liu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Fan Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
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Li J, Chen K, Li S, Feng J, Liu T, Wang F, Zhang R, Xu S, Zhou Y, Zhou S, Xia Y, Lu J, Zhou Y, Guo C. Protective effect of fucoidan from Fucus vesiculosus on liver fibrosis via the TGF-β1/Smad pathway-mediated inhibition of extracellular matrix and autophagy. Drug Des Devel Ther 2016; 10:619-30. [PMID: 26929597 PMCID: PMC4758785 DOI: 10.2147/dddt.s98740] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Liver fibrosis is a dynamic reversible pathological process in the development of chronic liver disease to cirrhosis. However, the current treatments are not administered for a long term due to their various side effects. Autophagy is initiated to decompose damaged or excess organelles, which had been found to alter the progression of liver fibrosis. In this article, we hypothesized that fucoidan from Fucus vesiculosus may attenuate liver fibrosis in mice by inhibition of the extracellular matrix and autophagy in carbon tetrachloride- and bile duct ligation-induced animal models of liver fibrosis. The results were determined using enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemical staining. Fucoidan from F. vesiculosus could inhibit the activation of hepatic stellate cells and the formation of extracellular matrix and autophagosomes, and its effect may be associated with the downregulation of transforming growth factor beta 1/Smads pathways. Fucoidan, as an autophagy and transforming growth factor beta 1 inhibitor, could be a promising potential therapeutic agent for liver fibrosis.
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Affiliation(s)
- Jingjing Li
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Sainan Li
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Jiao Feng
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Tong Liu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Fan Wang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Rong Zhang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Shizan Xu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Yuqing Zhou
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China
| | - Shunfeng Zhou
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China
| | - Yujing Xia
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
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Yin Q, Li J, Xia Y, Zhang R, Wang J, Lu W, Zhou Y, Zheng Y, Abudumijiti H, Chen R, Chen K, Li S, Liu T, Wang F, Lu J, Zhou Y, Guo C. Systematic review and meta-analysis: bezafibrate in patients with primary biliary cirrhosis. Drug Des Devel Ther 2015; 9:5407-19. [PMID: 26491252 PMCID: PMC4599574 DOI: 10.2147/dddt.s92041] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND AIM Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cirrhosis (PBC), but not all cases respond well. Evidence has shown that combination therapy of UDCA with bezafibrate significantly improved liver function. A meta-analysis was performed to assess the efficacy and safety of UDCA and bezafibrate combination therapy in the treatment of PBC. RESULTS Nine trials, with a total of 269 patients, were included in the analysis. The bias risk of these trials was high. Compared with UDCA alone, the combination with bezafibrate improved the Mayo risk score (mean difference [MD], 0.60; 95% confidence interval [CI], 0.25-0.95; P=0.0008) and liver biochemistry: alkaline phosphatase (MD, -238.21 IU/L; 95% CI, -280.83 to -195.60; P<0.00001); gamma-glutamyltransferase (MD, -38.23 IU/L; 95% CI, -50.16 to -25.85; P<0.00001); immunoglobulin M (MD, -128.63 IU/L; 95% CI, -151.55 to -105.71; P<0.00001); bilirubin (MD, -0.20 mg/dL; 95% CI, -0.33 to -0.07; P=0.002); triglycerides (MD, -26.84 mg/dL; 95% CI, -36.51 to -17.17; P<0.0001); total cholesterol (MD, -21.58 mg/dL; 95% CI, -30.81 to -12.34; P<0.0001), and serum alanine aminotransferase (MD, -10.24 IU/L; 95% CI, -12.65 to -78.5; P<0.00001). However, combination therapy showed no significant differences in the incidence of all-cause mortality or pruritus, and may have resulted in more adverse events (risk ratio [RR], 0.22; 95% CI, 0.07-0.67; P=0.008). CONCLUSION Combination therapy improved liver biochemistry and the prognosis of PBC, but did not improve clinical symptoms or incidence of death. Attention should be paid to adverse events when using bezafibrate.
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Affiliation(s)
- Qin Yin
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
- The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China
| | - Jingjing Li
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Yujing Xia
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Rong Zhang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Jianrong Wang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Wenxia Lu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
- The First Clinical Medical College of Nanjing Medical University, Nanjing, People’s Republic of China
| | - Yuqing Zhou
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
- The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China
| | - Yuanyuan Zheng
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Huerxidan Abudumijiti
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Rongxia Chen
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Sainan Li
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Tong Liu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Fan Wang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
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Zhang Y, Li S, He L, Wang F, Chen K, Li J, Liu T, Zheng Y, Wang J, Lu W, Zhou Y, Yin Q, Xia Y, Zhou Y, Lu J, Guo C. Combination therapy of fenofibrate and ursodeoxycholic acid in patients with primary biliary cirrhosis who respond incompletely to UDCA monotherapy: a meta-analysis. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:2757-66. [PMID: 26045661 PMCID: PMC4448927 DOI: 10.2147/dddt.s79837] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background Although the effectiveness of treatment with ursodeoxycholic acid (UDCA) and fenofibrate for primary biliary cirrhosis (PBC) has been suggested by small trials, a systematic review to summarize the evidence has not yet been carried out. Methods A meta-analysis of all long-term randomized controlled trials comparing the combination of UDCA and fenofibrate with UDCA monotherapy was performed via electronic searches. Results Six trials, which included 84 patients, were assessed. Combination therapy with UDCA and fenofibrate was more effective than UDCA monotherapy in improving alkaline phosphatase (mean difference [MD]: −90.44 IU/L; 95% confidence interval [CI]: −119.95 to −60.92; P<0.00001), gamma-glutamyl transferase (MD: −61.58 IU/L; 95% CI: −122.80 to −0.35; P=0.05), immunoglobulin M (MD: −38.45 mg/dL; 95% CI: −64.38 to −12.51; P=0.004), and triglycerides (MD: −0.41 mg/dL; 95% CI: −0.82 to −0.01; P=0.05). However, their effects on pruritus (odds ratio [OR]: 0.39; 95% CI: 0.09–1.78; P=0.23), total bilirubin (MD: −0.05 mg/dL; 95% CI: −0.21 to 0.12; P=0.58), and alanine aminotransferase (MD: −3.31 IU/L; 95% CI: −14.60 to 7.97; P=0.56) did not differ significantly. This meta-analysis revealed no significant differences in the incidence of adverse events (OR: 0.21; 95% CI: 0.03–1.25; P=0.09) between patients treated with combination therapy and those treated with monotherapy. Conclusion In this meta-analysis, combination therapy with UDCA and fenofibrate was more effective in reducing alkaline phosphatase than UDCA monotherapy, but it did not improve clinical symptoms. There did not appear to be an increase in adverse events with combination therapy.
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Affiliation(s)
- Yan Zhang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China ; Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Sainan Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Lei He
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Fan Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Jingjing Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Tong Liu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Yuanyuan Zheng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Jianrong Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China ; The First Clinical Medical College of Nanjing Medical University, Nanjing, People's Republic of China
| | - Wenxia Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China ; The First Clinical Medical College of Nanjing Medical University, Nanjing, People's Republic of China
| | - Yuqing Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China ; The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Qin Yin
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China ; The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Yujing Xia
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
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