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Rigopoulou EI, Lygoura V, Gabeta S, Gatselis N, Giannoulis G, Dalekos GN. Increased IgG Levels at Diagnosis Are Associated With Worse Prognosis of Patients With Primary Biliary Cholangitis. Liver Int 2025; 45:e70074. [PMID: 40125888 DOI: 10.1111/liv.70074] [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: 11/30/2024] [Revised: 02/09/2025] [Accepted: 03/17/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUND AND AIM A proportion of patients with primary biliary cholangitis (PBC) have increased IgG (I-IgG) levels at baseline, though not fulfilling the criteria of autoimmune hepatitis/PBC variant. Our aim was to evaluate whether I-IgG has prognostic significance in non-cirrhotic PBC patients. METHODS Retrospective analysis of prospectively collected data from 675 PBC patients (592 non-cirrhotic) with available IgG levels at first evaluation was performed. RESULTS Among non-cirrhotic patients, 97 with I-IgG were more frequently females (p < 0.05), having a higher frequency of concurrent autoimmune diseases (p = 0.01) and a higher frequency of PBC-specific ANA (p < 0.001), sp100 (p < 0.001) and gp210 (p = 0.029) compared to 495 with normal IgG (N-IgG). Patients with I-IgG were older (p < 0.001) and had lower albumin (p < 0.001) and higher AST (p < 0.001), ALT (p = 0.005), ALP (p = 0.006), γGT (p = 0.038) and IgM (p < 0.001) compared to those with N-IgG. I-IgG patients had a higher probability of cirrhosis development (Breslow p < 0.001; log-rank p = 0.05) and liver-related death (Breslow p = 0.034; log-rank p < 0.05) compared to N-IgG patients. IgG > 1.5xULN was the highest risk factor for cirrhosis development (HR = 9.507, 95% CI: 1.221-74.038, p = 0.032) and liver-related death (HR = 27.140, 95% CI: 3.111-236.783; p = 0.003); IgG normalisation after 1 year of UDCA treatment had a favourable effect on disease outcome. Ν-IgG was associated with a higher probability of liver stiffness regression (p = 0.025). CONCLUSIONS This long-term study demonstrates that I-IgG levels characterise a subgroup of non-cirrhotic PBC patients with faster disease progression and increased probability of liver-related death. Normalisation of IgG levels during UDCA treatment seems to improve prognosis and therefore, these patients could benefit from stricter follow-up and earlier add-on second-line treatments.
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Affiliation(s)
- Eirini I Rigopoulou
- 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
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Vassiliki Lygoura
- 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
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Stella Gabeta
- 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
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Nikolaos Gatselis
- 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
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - George Giannoulis
- 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
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
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Zhao J, Yue P, Mi N, Li M, Fu W, Zhang X, Gao L, Bai M, Tian L, Jiang N, Lu Y, Ma H, Dong C, Zhang Y, Zhang H, Zhang J, Ren Y, Suzuki A, Wong PF, Tanaka K, Rerknimitr R, Junger HH, Cheung TT, Melloul E, Demartines N, Leung JW, Yao J, Yuan J, Lin Y, Schlitt HJ, Meng W. Biliary fibrosis is an important but neglected pathological feature in hepatobiliary disorders: from molecular mechanisms to clinical implications. MEDICAL REVIEW (2021) 2024; 4:326-365. [PMID: 39135601 PMCID: PMC11317084 DOI: 10.1515/mr-2024-0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/06/2024] [Indexed: 08/15/2024]
Abstract
Fibrosis resulting from pathological repair secondary to recurrent or persistent tissue damage often leads to organ failure and mortality. Biliary fibrosis is a crucial but easily neglected pathological feature in hepatobiliary disorders, which may promote the development and progression of benign and malignant biliary diseases through pathological healing mechanisms secondary to biliary tract injuries. Elucidating the etiology and pathogenesis of biliary fibrosis is beneficial to the prevention and treatment of biliary diseases. In this review, we emphasized the importance of biliary fibrosis in cholangiopathies and summarized the clinical manifestations, epidemiology, and aberrant cellular composition involving the biliary ductules, cholangiocytes, immune system, fibroblasts, and the microbiome. We also focused on pivotal signaling pathways and offered insights into ongoing clinical trials and proposing a strategic approach for managing biliary fibrosis-related cholangiopathies. This review will offer a comprehensive perspective on biliary fibrosis and provide an important reference for future mechanism research and innovative therapy to prevent or reverse fibrosis.
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Affiliation(s)
- Jinyu Zhao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ping Yue
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningning Mi
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Matu Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Wenkang Fu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xianzhuo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Long Gao
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Mingzhen Bai
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Liang Tian
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Ningzu Jiang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yawen Lu
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Haidong Ma
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Chunlu Dong
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yong Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hengwei Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Jinduo Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yanxian Ren
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Azumi Suzuki
- Department of Gastroenterology, Hamamatsu Medical Center, Hamamatsu, Japan
| | - Peng F. Wong
- Department of Vascular Surgery, The James Cook University Hospital, Middlesbrough, UK
| | - Kiyohito Tanaka
- Department of Gastroenterology, Kyoto Second Red Cross Hospital, Kyoto, Japan
| | - Rungsun Rerknimitr
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn, Bangkok, Thailand
- Excellence Center for Gastrointestinal Endoscopy, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Henrik H. Junger
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Tan T. Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Emmanuel Melloul
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Nicolas Demartines
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne (UNIL), Lausanne, Switzerland
| | - Joseph W. Leung
- Division of Gastroenterology and Hepatology, UC Davis Medical Center and Sacramento VA Medical Center, Sacramento, CA, USA
| | - Jia Yao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Jinqiu Yuan
- Clinical Research Center, Big Data Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yanyan Lin
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hans J. Schlitt
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Wenbo Meng
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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Stoelinga AE, Biewenga M, Drenth JP, Verhelst X, van der Meer AJ, de Boer YS, Bouma G, de Vries ES, Verdonk RC, van der Berg AP, Brouwer JT, Vanwolleghem T, Lammers W, Beuers U, Sarasqueta AF, Verheij J, Roskams T, Crobach S, Tushuizen ME, van Hoek B. Diagnostic criteria and long-term outcomes in AIH-PBC variant syndrome under combination therapy. JHEP Rep 2024; 6:101088. [PMID: 38974367 PMCID: PMC11225825 DOI: 10.1016/j.jhepr.2024.101088] [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: 11/17/2023] [Revised: 03/22/2024] [Accepted: 03/27/2024] [Indexed: 07/09/2024] Open
Abstract
Background & Aims Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) can co-exist in AIH-PBC, requiring combined treatment with immunosuppression and ursodeoxycholic acid (UDCA). The Paris criteria are commonly used to identify these patients; however, the optimal diagnostic criteria are unknown. We aimed to evaluate the use and clinical relevance of both Paris and Zhang criteria. Methods Eighty-three patients with a clinical suspicion of AIH-PBC who were treated with combination therapy were included. Histology was re-evaluated. Characteristics and long-term outcomes were retrospectively compared to patients with AIH and PBC. Results Seventeen (24%) patients treated with combination therapy fulfilled the Paris criteria. Fifty-two patients (70%) fulfilled the Zhang criteria. Patients who met Paris and Zhang criteria more often had inflammation and fibrosis on histology compared to patients only meeting the Zhang criteria. Ten-year liver transplant (LT)-free survival was 87.3% (95% CI 78.9-95.7%) in patients with AIH-PBC. This did not differ in patients in or outside the Paris or Zhang criteria (p = 0.46 and p = 0.40, respectively) or from AIH (p = 0.086). LT-free survival was significantly lower in patients with PBC and severe hepatic inflammation - not receiving immunosuppression - compared to those with AIH-PBC (65%; 95% CI 52.2-77.8% vs. 87%; 95% CI 83.2-90.8%; hazard ratio 0.52; p = 0.043). Conclusions In this study, patients with AIH-PBC outside Paris or Zhang criteria were frequently labeled as having AIH-PBC and were successfully treated with combination therapy with similar outcomes. LT-free survival was worse in patients with PBC and hepatic inflammation than in those treated as having AIH-PBC. More patients may benefit from combination therapy. Impact and implications This study demonstrated that patients with AIH-PBC variant syndrome treated with combined therapy consisting of immunosuppressants and ursodeoxycholic acid often do not fulfill the Paris criteria. They do however have comparable response to therapy and long-term outcomes as patients who do fulfill the diagnostic criteria. Additionally, patients with PBC and additional signs of hepatic inflammation have poorer long-term outcomes compared to patients treated as having AIH-PBC. These results implicate that a larger group of patients with features of both AIH and PBC may benefit from combined treatment. With our results, we call for improved consensus among experts in the field on the diagnosis and management of AIH-PBC variant syndrome.
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Affiliation(s)
- Anna E.C. Stoelinga
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Maaike Biewenga
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Joost P.H. Drenth
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre – location VUmc, Amsterdam, the Netherlands
- European Reference Network RARE-LIVER, Germany
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, UZ Gent, Gent, Belgium
- European Reference Network RARE-LIVER, Germany
| | - Adriaan J.P. van der Meer
- Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, the Netherlands
- European Reference Network RARE-LIVER, Germany
| | - Ynto S. de Boer
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre – location VUmc, Amsterdam, the Netherlands
- European Reference Network RARE-LIVER, Germany
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre – location VUmc, Amsterdam, the Netherlands
- European Reference Network RARE-LIVER, Germany
| | - Elsemieke S. de Vries
- Department of Gastroenterology and Hepatology, Isala clinics, Zwolle, the Netherlands
| | - Robert C. Verdonk
- Department of Gastroenterology and Hepatology, Sint Antonius hospital, Nieuwegein, the Netherlands
| | - Aad P. van der Berg
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, Groningen, the Netherlands
- European Reference Network RARE-LIVER, Germany
| | - Johannes T. Brouwer
- Department of Gastroenterology and Hepatology, Reinier de Graaf Gasthuis, Delft, the Netherlands
| | - Thomas Vanwolleghem
- Department of Gastroenterology and Hepatology, UZ Antwerpen, Antwerpen, Belgium
- European Reference Network RARE-LIVER, Germany
| | - Wim Lammers
- Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, the Netherlands
- European Reference Network RARE-LIVER, Germany
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre – location AMC, Amsterdam, the Netherlands
- European Reference Network RARE-LIVER, Germany
| | - Arantza Farina Sarasqueta
- Department of Pathology, Amsterdam University Medical Centre – location AMC, Amsterdam, the Netherlands
| | - Joanne Verheij
- Department of Pathology, Amsterdam University Medical Centre – location AMC, Amsterdam, the Netherlands
| | | | - Stijn Crobach
- Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Maarten E. Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
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Luo X, Lu LG. Progress in the Management of Patients with Cholestatic Liver Disease: Where Are We and Where Are We Going? J Clin Transl Hepatol 2024; 12:581-588. [PMID: 38974958 PMCID: PMC11224908 DOI: 10.14218/jcth.2023.00519] [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: 11/20/2023] [Revised: 03/27/2024] [Accepted: 04/11/2024] [Indexed: 07/09/2024] Open
Abstract
Cholestatic liver disease is a group of diseases in which bile acid accumulates in the liver for various reasons, resulting in abnormal liver biochemical indicators and histological damage. Cholestasis can be divided into intrahepatic cholestasis and extrahepatic cholestasis, which will contribute to liver damage and progress to liver fibrosis and cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis are the two most typical cholestatic liver diseases. Ursodeoxycholic acid is currently the first-line treatment for PBC, while obeticholic acid, budesonide and fibrates have also shown good potential in the treatment of PBC. There are currently no official drugs approved to treat primary sclerosing cholangitis, and the use of ursodeoxycholic acid may have certain clinical benefits. At present, progress has been made in new treatment directions for cholestatic liver disease, including fibroblast growth factor 19, cholestyramine, S-adenosyl-L-methionine, steroid drugs, farnesoid X receptor agonists, and more. Considerable progress has been made in the management of cholestatic liver disease but there are still many opportunities and challenges. In this review, we summarized the recommended guidelines for the management of cholestatic disease and the progress of new drug research and development, in order to provide an important reference for the clinical practice of cholestatic liver disease.
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Affiliation(s)
- Xin Luo
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lun-Gen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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van Hooff MC, Werner E, van der Meer AJ. Treatment in primary biliary cholangitis: Beyond ursodeoxycholic acid. Eur J Intern Med 2024; 124:14-21. [PMID: 38307734 DOI: 10.1016/j.ejim.2024.01.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 01/17/2024] [Accepted: 01/19/2024] [Indexed: 02/04/2024]
Abstract
Primary biliary cholangitis (PBC) is a rare cholestatic immune-mediated liver disease. The clinical course varies from mild to severe, with a substantial group of patients developing cirrhosis within a decade. These patients are at risk of hepatocellular carcinoma, decompensation and liver failure. First line Ursodeoxycholic acid (UDCA) treatment improves the cholestatic surrogate markers, and was recently associated with a favorable survival free of liver transplantation, even in case of an incomplete biochemical response. However, despite adequate UDCA therapy, patients remain at risk of liver disease progression. Therefore, on-treatment multifactor-based risk stratification is necessary to identify patients in need of additional therapy. This requires a personalized approach; especially as recent studies suggest that complete biochemical normalization as most stringent response criterion might be preferred in selected patients to optimize their outcome. Today, stricter biochemical goals might actually be reachable with the addition of farnesoid X receptor or peroxisome proliferator-activated receptor agonists, or, in highly-selected cases, use of corticosteroids. Randomized controlled trials showed improvements in the key biochemical surrogate markers with the addition of these drugs, which have also been associated with improved clinical outcome. Considering this evolving PBC landscape, with more versatile treatment options and treatment goals, this review recapitulates the recent insight in UDCA therapy, the selection of patients with a residual risk of liver disease progression and the results of the currently available second line treatment options.
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Affiliation(s)
- M C van Hooff
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, NA building, Floor 6, Rotterdam 3015 GD, the Netherlands
| | - E Werner
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, NA building, Floor 6, Rotterdam 3015 GD, the Netherlands
| | - A J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, NA building, Floor 6, Rotterdam 3015 GD, the Netherlands.
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Wang R, Lin Q, Lu Z, Wen H, Hu F, You J, He Y, Fang Y, Bian Z, Hou Q, Ju Z, Wang Y, Lian M, Xiao X, Sheng L, Guo C, Hua J, Tang R, You Z, Chen X, Gershwin ME, Huang Z, Wang Q, Miao Q, Ma X. Immunosuppression induces regression of fibrosis in primary biliary cholangitis with moderate-to-severe interface hepatitis. J Autoimmun 2024; 143:103163. [PMID: 38301505 DOI: 10.1016/j.jaut.2023.103163] [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: 10/16/2023] [Revised: 12/10/2023] [Accepted: 12/13/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND In patients with primary biliary cholangitis (PBC) treated with ursodeoxycholic acid (UDCA), the presence of moderate-to-severe interface hepatitis is associated with a higher risk of liver transplantation and death. This highlights the need for novel treatment approaches. In this study, we aimed to investigate whether combination therapy of UDCA and immunosuppressant (IS) was more effective than UDCA monotherapy. METHODS We conducted a multicenter study involving PBC patients with moderate-to-severe interface hepatitis who underwent paired liver biopsies. Firstly, we compared the efficacy of the combination therapy with UDCA monotherapy on improving biochemistry, histology, survival rates, and prognosis. Subsequently we investigated the predictors of a beneficial response. RESULTS This retrospective cohort study with prospectively collected data was conducted in China from January 2009 to April 2023. Of the 198 enrolled patients, 32 underwent UDCA monotherapy, while 166 received combination therapy, consisting of UDCA combined with prednisolone, prednisolone plus mycophenolate mofetil (MMF), or prednisolone plus azathioprine (AZA). The monotherapy group was treated for a median duration of 37.6 months (IQR 27.5-58.1), and the combination therapy group had a median treatment duration of 39.3 months (IQR 34.5-48.8). The combination therapy showed a significantly greater efficacy in reducing fibrosis compared to UDCA monotherapy, with an 8.3-fold increase in the regression rate (from 6.3% to 52.4%, P < 0.001). Other parameters, including biochemistry, survival rates, and prognosis, supported its effectiveness. Baseline IgG >1.3 × ULN and ALP <2.4 × ULN were identified as predictors of regression following the combination therapy. A predictive score named FRS, combining these variables, accurately identified individuals achieving fibrosis regression with a cut-off point of ≥ -0.163. The predictive value was validated internally and externally. CONCLUSION Combination therapy with IS improves outcomes in PBC patients with moderate-to-severe interface hepatitis compared to UDCA monotherapy. Baseline IgG and ALP are the most significant predictors of fibrosis regression. The new predictive score, FRS, incorporating baseline IgG and ALP, can effectively identify individuals who would benefit from the combination therapy.
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Affiliation(s)
- Rui Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qiuxiang Lin
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Zhonghua Lu
- Department of Liver Disease, Affiliated Wuxi Fifth Hospital of Jiangnan University, Wuxi, China
| | - Haoyu Wen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Fangqin Hu
- Division of Hepatology, The Affiliated Hospital of Shaoxing University, Shaoxing, China
| | - Jia You
- Department of Hepatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Yonghong He
- Cholestatic Liver Diseases Center, Department of Gastroenterology, Southwest Hospital of Army Medical University, Chongqing, China
| | - Yuan Fang
- Department of Hepatopathy, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Zhaolian Bian
- Department of Gastroenterology and Hepatology, Nantong Third People's Hospital, The Third Affiliated Hospital of Nantong University, Nantong, China
| | - Qiuchen Hou
- Department of Liver Disease, Affiliated Wuxi Fifth Hospital of Jiangnan University, Wuxi, China
| | - Zhaoxia Ju
- Department of Liver Disease, Affiliated Wuxi Fifth Hospital of Jiangnan University, Wuxi, China
| | - Yanyan Wang
- Department of Gastroenterology and Hepatology, Nantong Third People's Hospital, The Third Affiliated Hospital of Nantong University, Nantong, China
| | - Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Li Sheng
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Canjie Guo
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jing Hua
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Zhengrui You
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Xiaoyu Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Zuxiong Huang
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China; Division of Infectious Diseases, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China; Institute of Aging & Tissue Regeneration, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Medford A, Childs J, Little A, Chakraborty S, Baiocchi L, Alpini G, Glaser S. Emerging Therapeutic Strategies in The Fight Against Primary Biliary Cholangitis. J Clin Transl Hepatol 2023; 11:949-957. [PMID: 37408803 PMCID: PMC10318288 DOI: 10.14218/jcth.2022.00398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/29/2022] [Accepted: 01/04/2023] [Indexed: 07/03/2023] Open
Abstract
The liver has a vital role in many metabolic and regulatory processes in the body. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a chronic cholestatic autoimmune disease of the intrahepatic bile ducts associated with loss of tolerance to mitochondrial antigens. At this time there is no definitive cure for PBC; however, ursodeoxycholic acid (UDCA) has been shown to reduce injury when administered as the first line of treatment. Additional therapeutics can be given concurrently or as an alternative to UDCA to manage the symptoms and further curb disease progression. Currently, a liver transplant is the only potentially curative option when the patient has developed end-stage liver disease or intractable pruritus. This review aims to delineate the pathogenesis of primary biliary cholangitis and shed light on current therapeutic strategies in the treatment of PBC.
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Affiliation(s)
- Abigail Medford
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX, USA
| | - Jonathan Childs
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX, USA
| | - Ashleigh Little
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX, USA
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX, USA
| | | | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX, USA
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8
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Levy C, Manns M, Hirschfield G. New Treatment Paradigms in Primary Biliary Cholangitis. Clin Gastroenterol Hepatol 2023; 21:2076-2087. [PMID: 36809835 DOI: 10.1016/j.cgh.2023.02.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/28/2023] [Accepted: 02/03/2023] [Indexed: 02/24/2023]
Abstract
Primary biliary cholangitis (PBC) is an archetypal autoimmune disease. Chronic lymphocytic cholangitis is associated with interface hepatitis, ductopenia, cholestasis, and progressive biliary fibrosis. People living with PBC are frequently symptomatic, experiencing a quality-of-life burden dominated by fatigue, itch, abdominal pain, and sicca complex. Although the female predominance, specific serum autoantibodies, immune-mediated cellular injury, as well as genetic (HLA and non-HLA) risk factors, identify PBC as autoimmune, to date treatment has focused on cholestatic consequences. Biliary epithelial homeostasis is abnormal and contributes to disease. The impact of cholangiocyte senescence, apoptosis, and impaired bicarbonate secretion enhances chronic inflammation and bile acid retention. First-line therapy is a non-specific anti-cholestatic agent, ursodeoxycholic acid. For those with residual cholestasis biochemically, obeticholic acid is introduced, and this semisynthetic farnesoid X receptor agonist adds choleretic, anti-fibrotic, and anti-inflammatory activity. Future PBC licensed therapy will likely include peroxisome proliferator activated receptor (PPAR) pathway agonists, including specific PPAR-delta agonism (seladelpar), as well as elafibrinor and saroglitazar (both with broader PPAR agonism). These agents dovetail the clinical and trial experience for off-label bezafibrate and fenofibrate use. Symptom management is essential, and encouragingly, PPAR agonists reduce itch; IBAT inhibition (eg, linerixibat) also appears promising for pruritus. For those where liver fibrosis is the target, NOX inhibition is being evaluated. Earlier stage therapies in development include therapy to impact immunoregulation in patients, as well other approaches to treating pruritus (eg, antagonists of MrgprX4). Collectively the PBC therapeutic landscape is exciting. Therapy goals are increasingly proactive and individualized and aspire to rapidly achieve normal serum tests and quality of life with prevention of end-stage liver disease.
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Affiliation(s)
- Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, Florida.
| | | | - Gideon Hirschfield
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Canada
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9
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You H, Duan W, Li S, Lv T, Chen S, Lu L, Ma X, Han Y, Nan Y, Xu X, Duan Z, Wei L, Jia J, Zhuang H, Chinese Society of Hepatology, Chinese Medical Association. Guidelines on the Diagnosis and Management of Primary Biliary Cholangitis (2021). J Clin Transl Hepatol 2023; 11:736-746. [PMID: 36969891 PMCID: PMC10037524 DOI: 10.14218/jcth.2022.00347] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/02/2022] [Accepted: 11/20/2022] [Indexed: 03/29/2023] Open
Abstract
In 2015, the Chinese Society of Hepatology and the Chinese Society of Gastroenterology published a consensus on primary biliary cholangitis (PBC). In the past years, numerous clinical studies have been published in the field of PBC. To guide the clinical diagnosis and management of PBC patients, the Chinese Society of Hepatology invited a panel of experts to assess the new clinical evidence and formulate the current guidelines.
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Affiliation(s)
- Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Shuxiang Li
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Tingting Lv
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Sha Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Lungen Lu
- Department of Gastroenterology, First People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiong Ma
- Department of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Han
- Department of Gastroenterology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yuemin Nan
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiaoyuan Xu
- Department of Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, Beijing, China
- Correspondence to: Jidong Jia, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing 100050, China. ORCID: https://orcid.org/0000-0002-4673-8890. Tel: +86-10-63139816, Fax: +86-10-63139246, E-mail: ; Xiaoyuan Xu, Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China. ORCID: https://orcid.org/0000-0002-1759-4330. Tel/Fax: +86-10-83575787, E-mail:
| | - Zhongping Duan
- Artificial Liver Center, Beijing You-An Hospital, Capital Medical University, Beijing, China
| | - Lai Wei
- Hepatobiliary Pancreatic Center, Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
- Correspondence to: Jidong Jia, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing 100050, China. ORCID: https://orcid.org/0000-0002-4673-8890. Tel: +86-10-63139816, Fax: +86-10-63139246, E-mail: ; Xiaoyuan Xu, Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China. ORCID: https://orcid.org/0000-0002-1759-4330. Tel/Fax: +86-10-83575787, E-mail:
| | - Hui Zhuang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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10
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Bhan I, Schaefer EA, Bradley WR, Rodriguez-Lopez JM, Crowley JC, Hutchison B. Case 4-2023: A 56-Year-Old Man with Abnormal Results on Liver Testing. N Engl J Med 2023; 388:544-554. [PMID: 36780679 DOI: 10.1056/nejmcpc2201249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Affiliation(s)
- Irun Bhan
- From the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Harvard Medical School - both in Boston
| | - Esperance A Schaefer
- From the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Harvard Medical School - both in Boston
| | - William R Bradley
- From the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Harvard Medical School - both in Boston
| | - Josanna M Rodriguez-Lopez
- From the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Harvard Medical School - both in Boston
| | - Jerome C Crowley
- From the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Harvard Medical School - both in Boston
| | - Bailey Hutchison
- From the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Harvard Medical School - both in Boston
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11
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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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12
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Liu CH, Bowlus CL. Treatment of Primary Biliary Cholangitis: First-Line and Second-Line Therapies. Clin Liver Dis 2022; 26:705-726. [PMID: 36270725 DOI: 10.1016/j.cld.2022.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune disease of the interlobular bile ducts leading to secondary damage of hepatocytes and may progress to cirrhosis and liver failure. The first-line treatment is ursodeoxycholic acid; up to 40% of patients do not have an adequate response and remain at risk of disease progression. Obeticholic acid has been conditionally approved for the treatment of PBC as add-on therapy and bezafibrate has shown similar efficacy in this group of patients. Several new therapies are in development and may further add to the treatment options available to patients with PBC.
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Affiliation(s)
- Chung-Heng Liu
- Drexel University College of Medicine, 2900 W Queen Ln, Philadelphia, PA 19129 USA
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, 4150 V Street, PSSB 3500, Sacramento, CA 95817, USA.
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13
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Mayo MJ. Mechanisms and molecules: What are the treatment targets for primary biliary cholangitis? Hepatology 2022; 76:518-531. [PMID: 35152430 DOI: 10.1002/hep.32405] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/05/2022] [Accepted: 02/08/2022] [Indexed: 12/22/2022]
Abstract
Treatment of primary biliary cholangitis (PBC) with ursodeoxycholic acid (UDCA) is not always sufficient to prevent progression to hepatic decompensation and/or need for liver transplant. Adjuvant therapy with obeticholic acid may provide additional biochemical improvements in some patients, but it is not well-tolerated by patients with significant itch or advanced cirrhosis. Thus, new and creative approaches to treating patients with PBC are important to identify. This review discusses major potential therapeutic targets in PBC and provides examples of some specific agents currently in development for the treatment of PBC. Targets are broadly classified into those which strive to modify bile, inflammation, cell survival, or fibrosis. In bile, shrinking the size of the bile acid pool or modifying the quality of the bile by making it more hydrophilic or enriched in phosphatidylcholine may ameliorate cholestatic injury. Biliary epithelial cell survival may be extended by fortifying the bicarbonate umbrella or improving cell membrane integrity. Autoimmunity and cholangitis have the potential to be improved via regulation of the immune system. Targeting cytokines, immune checkpoints, and anti-mitochondrial antibodies are examples of a more focused immunosuppression approach. Stem cell therapy and lymphocyte trafficking inhibition are more novel methods of broad immune regulation. Anti-fibrotic therapies are also potentially useful for preventing progression of PBC. The nuclear hormone receptors, farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) regulate many of these pathways: cholestasis, inflammation, and fibrosis, which is why they are being enthusiastically pursued as potential therapeutic targets in PBC.
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Affiliation(s)
- Marlyn J Mayo
- Internal Medicine, University of Texas Southwestern University, Dallas, Texas, USA
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Park JW, Kim JH, Kim SE, Jung JH, Jang MK, Park SH, Lee MS, Kim HS, Suk KT, Kim DJ. Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics. Biomedicines 2022; 10:1288. [PMID: 35740310 PMCID: PMC9220082 DOI: 10.3390/biomedicines10061288] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/24/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023] Open
Abstract
Cholangiopathies encompass various biliary diseases affecting the biliary epithelium, resulting in cholestasis, inflammation, fibrosis, and ultimately liver cirrhosis. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most important progressive cholangiopathies in adults. Much research has broadened the scope of disease biology to genetic risk, epigenetic changes, dysregulated mucosal immunity, altered biliary epithelial cell function, and dysbiosis, all of which interact and arise in the context of ill-defined environmental triggers. An in-depth understanding of the molecular pathogenesis of these cholestatic diseases will help clinicians better prevent and treat diseases. In this review, we focus on the main underlying mechanisms of disease initiation and progression, and novel targeted therapeutics beyond currently approved treatments.
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Affiliation(s)
- Ji-Won Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jung-Hee Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sung-Eun Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Jang Han Jung
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Myoung-Kuk Jang
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Sang-Hoon Park
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Myung-Seok Lee
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
| | - Hyoung-Su Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Ki Tae Suk
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon-si 24252, Korea; (J.-W.P.); (J.-H.K.); (S.-E.K.); (J.H.J.); (M.-K.J.); (S.-H.P.); (M.-S.L.); (H.-S.K.); (K.T.S.)
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 200-010, Korea
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15
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Wang ZL, Song KM, Jin R, Xie YD, Wang YQ, Liu ZC, Feng B. Combination therapy of ursodeoxycholic acid and glucocorticoid and (or) immunosuppressant in patients with primary biliary cholangitis: A meta-analysis. Medicine (Baltimore) 2022; 101:e28987. [PMID: 35244071 PMCID: PMC8896518 DOI: 10.1097/md.0000000000028987] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 02/08/2022] [Accepted: 02/12/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND/OBJECTIVES Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune cholestasis liver disease. There were many studies comparing a combination of glucocorticoids and/or immunosuppressants to a single UDCA therapy in PBC patients, while the literature demonstrated divergent finds. To evaluate the effectiveness of ursodeoxycholic acid (UDCA) combined with glucocorticoids and (or) immunosuppressants on biochemistry, immunology, histology, clinical symptoms, and adverse reactions of PBC from the perspective of evidence-based medicine. MATERIALS AND METHODS PubMed, web of science, the Cochrane Library, EMBASE databases were searched to collect clinical randomized trials and self-control studies of UDCA combined with glucocorticoids and (or) immunosuppressants and UDCA monotherapy in the treatment of PBC. The retrieval time is from the establishment of the database to August 2020. Two reviewers independently screened literature, extracted data and evaluated the bias of included studies. Revman 5.3 software was used for meta-analysis. RESULTS Six studies including 201 patients were included. The meta-analysis found that the combination therapy can improve some biochemical indexes, immunological indexes, and clinical symptoms of patients with PBC. However, combination therapy has no significant improvement in other biochemical indicators which respond to liver and bile duct damage, such as ALT, GGT, and ALB. Besides, the improvement of liver histology is limited, and the incidence of adverse events is higher. CONCLUSION Overall, the combination therapy showed no improvement in key biochemical parameters and limited improvement in liver pathology. Besides, the side effects were more serious. Therefore, in the current treatment regimen, it is not recommended for PBC patients.
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Affiliation(s)
- Zi-Long Wang
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing, China
| | - Kai-Min Song
- The Fifth Clinical Medical College of Shanxi Medical University, Jinzhong, Shanxi, China
| | - Rui Jin
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing, China
| | - Yan-Di Xie
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing, China
| | - Yu-Qiong Wang
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Zhi-Cheng Liu
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing, China
| | - Bo Feng
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing, China
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16
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Cariello M, Gadaleta RM, Moschetta A. The gut-liver axis in cholangiopathies: focus on bile acid based pharmacological treatment. Curr Opin Gastroenterol 2022; 38:136-143. [PMID: 35034082 PMCID: PMC10826921 DOI: 10.1097/mog.0000000000000807] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW This review analyses the main features of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and provides an overview of the currently available (bile acid) bile acid related treatments. RECENT FINDINGS In PBC, biliary injury is the consequence of a dysregulated intrahepatic and systemic immune response. Given the close association between PSC and inflammatory bowel disease (IBD), the microbiota represents an important factor in the development of PSC. Bile acid based pharmacological treatments could represent promising therapeutic strategies in the management of cholangiopathies. SUMMARY Cholangiopathies include a spectrum of diseases resulting in cholestasis, an impairment of bile flow in the biliary tree, leading to biliary obstruction and damage as well as liver inflammation and fibrosis. PSC and PBC are highly heterogeneous cholangiopathies and progressive disorders with defined pathophysiological mechanisms. Curative treatments have not been established, and although their prevalence is low, they are a frequent indication for liver transplantation in the advanced stages of cholangiopathies. These diseases still present with unmet therapeutic strategies, also taking into account that on average 30-40% of patients undergoing liver transplantation will have recurrence of the original illness.
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Affiliation(s)
- Marica Cariello
- INBB, National Institute for Biostructures and Biosystems, Rome
| | - Raffaella M. Gadaleta
- Department of Interdisciplinary Medicine, ‘Aldo Moro’ University of Bari, Bari, Italy
| | - Antonio Moschetta
- INBB, National Institute for Biostructures and Biosystems, Rome
- Department of Interdisciplinary Medicine, ‘Aldo Moro’ University of Bari, Bari, Italy
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17
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You H, Ma X, Efe C, Wang G, Jeong SH, Abe K, Duan W, Chen S, Kong Y, Zhang D, Wei L, Wang FS, Lin HC, Yang JM, Tanwandee T, Gani RA, Payawal DA, Sharma BC, Hou J, Yokosuka O, Dokmeci AK, Crawford D, Kao JH, Piratvisuth T, Suh DJ, Lesmana LA, Sollano J, Lau G, Sarin SK, Omata M, Tanaka A, Jia J. APASL clinical practice guidance: the diagnosis and management of patients with primary biliary cholangitis. Hepatol Int 2022; 16:1-23. [PMID: 35119627 PMCID: PMC8843914 DOI: 10.1007/s12072-021-10276-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 11/08/2021] [Indexed: 12/14/2022]
Affiliation(s)
- Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Xiong Ma
- Department of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, Mainland, China
| | - Cumali Efe
- Department of Gastroenterology, Gazi Yaşargil Education and Research Hospital, Diyarbakir, Turkey
| | - Guiqiang Wang
- Department of Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, Beijing, Mainland, China
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, South Korea
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Sha Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland, China
| | - Dong Zhang
- Experimental and Translational Research Center, Beijing Clinical Research Institute, Beijing, Mainland, China
| | - Lai Wei
- Hepatobiliary Pancreatic Center, Tsinghua Changgung Hospital, Tsinghua University, Beijing, Mainland, China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of PLA General Hospial, Beijing, Mainland, China
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jin Mo Yang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, St. Vincent’s Hospital, The Catholic University of Korea, Suwon, South Korea
| | - Tawesak Tanwandee
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Rino A. Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Diana A. Payawal
- Department of Medicine, Fatima University Medical Center, Manila, Philippines
| | | | - Jinlin Hou
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Mainland, China
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - A. Kadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Darrell Crawford
- School of Medicine, University of Queensland, Brisbane, Australia
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand
| | - Dong Jin Suh
- Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, South Korea
| | | | - Jose Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - George Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong SAR, China
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Tokyo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
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18
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Gao W, Li Z, Chu H, Yuan H, Hu L, Yao L, Zhang L, Wang W, Lin R, Yang L. Ursodeoxycholic Acid in Liver Cirrhosis: A Chinese Perspective. PHARMACOTHERAPY FOR LIVER CIRRHOSIS AND ITS COMPLICATIONS 2022:81-111. [DOI: 10.1007/978-981-19-2615-0_6] [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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19
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Kuebler JF, Madadi-Sanjani O, Pfister ED, Baumann U, Fortmann D, Leonhardt J, Ure BM, Manns MP, Taubert R, Petersen C. Adjuvant Therapy with Budesonide Post-Kasai Reduces the Need for Liver Transplantation in Biliary Atresia. J Clin Med 2021; 10:jcm10245758. [PMID: 34945055 PMCID: PMC8704494 DOI: 10.3390/jcm10245758] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 11/26/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Based on the hypothesis that autoimmunological factors coregulate the pathomechanism in biliary atresia (BA), adjuvant therapy with steroids has become routine, although its efficacy has never been proven. In 2010, a study on the advantages of budesonide compared to prednisolone in autoimmune hepatitis gave rise to experimental therapy using budesonide as an adjuvant BA treatment. Ninety-five BA patients prospectively received a budesonide 2 mg/dose rectal foam daily for three months (SG). A case-matched control group (CG: 81) was retrospectively recruited. The outcome measures were survival with native liver (SNL), determined at six months and two years after the Kasai procedure. The follow-up rate was 100%. At six months, SNL was statistically not different but became so after two years (SG: 54%; CG: 32%; p < 0.001). No steroid-related side effects were observed, except for eight patients with finally caught-up growth retardation. This study demonstrates for the first time a significantly longer survival with native liver in patients with BA after adjuvant therapy. However, indication, dosage, and duration of any budesonide application is not given in neonates with BA. Hence, we suggest extending the postoperative use of budesonide in a multicenter observational study with a clearly defined follow-up protocol, particularly in terms of potentially underestimated side effects.
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Affiliation(s)
- Joachim F. Kuebler
- Department of Pediatric Surgery, Hannover Medical School, 30625 Hannover, Germany; (J.F.K.); (O.M.-S.); (D.F.); (B.M.U.)
| | - Omid Madadi-Sanjani
- Department of Pediatric Surgery, Hannover Medical School, 30625 Hannover, Germany; (J.F.K.); (O.M.-S.); (D.F.); (B.M.U.)
| | - Eva D. Pfister
- Department of Paediatric Gastroenterology and Hepatology, Hannover Medical School, 30625 Hannover, Germany; (E.D.P.); (U.B.)
| | - Ulrich Baumann
- Department of Paediatric Gastroenterology and Hepatology, Hannover Medical School, 30625 Hannover, Germany; (E.D.P.); (U.B.)
| | - David Fortmann
- Department of Pediatric Surgery, Hannover Medical School, 30625 Hannover, Germany; (J.F.K.); (O.M.-S.); (D.F.); (B.M.U.)
| | - Johannes Leonhardt
- Clinic for Pediatric Surgery, Klinikum Braunschweig, 38118 Braunschweig, Germany;
| | - Benno M. Ure
- Department of Pediatric Surgery, Hannover Medical School, 30625 Hannover, Germany; (J.F.K.); (O.M.-S.); (D.F.); (B.M.U.)
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (M.P.M.); (R.T.)
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (M.P.M.); (R.T.)
| | - Claus Petersen
- Department of Pediatric Surgery, Hannover Medical School, 30625 Hannover, Germany; (J.F.K.); (O.M.-S.); (D.F.); (B.M.U.)
- Correspondence: ; Tel.: +49-511-532-9047; Fax: +49-511-532-9059
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20
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Montano-Loza AJ, Corpechot C. Definition and Management of Patients With Primary Biliary Cholangitis and an Incomplete Response to Therapy. Clin Gastroenterol Hepatol 2021; 19:2241-2251.e1. [PMID: 32629125 DOI: 10.1016/j.cgh.2020.06.062] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 06/23/2020] [Accepted: 06/25/2020] [Indexed: 02/07/2023]
Abstract
Primary biliary cholangitis (PBC) is an immune-mediated chronic liver disease characterized by biliary epithelial injury, cholestasis, and progressive fibrosis that can lead to cirrhosis and requirement for liver transplantation. All patients with PBC should receive initial treatment with ursodeoxycholic acid (UDCA), and odds for response are based on characteristics at baseline. It is important to have clear definitions of patients at risk for a poor response to therapy, of biochemical markers of an incomplete response, and standardized management. Patients typically are assessed after 12 months of treatment with UDCA for biochemical markers of response. However, evaluation at 6 months has been proposed for patients with more severe disease or symptoms (such as pruritus or fatigue). Markers of response to therapy include reduced serum levels of alkaline phosphatase and bilirubin (Paris-2, Toronto, GLOBE, and so forth); patients with high levels of total and conjugated bilirubin or levels of alkaline phosphatase more than 1.5-fold the upper limit of normal should be considered for second-line therapy. Patients with adequate biochemical responses can continue UDCA monotherapy. Incomplete responders should be considered for second-line therapies with obeticholic acid (licensed) or fibrates (unlicensed) in addition to continued treatment with UDCA. Patients with PBC should be followed up for life.
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Affiliation(s)
- Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
| | - Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris, European Reference Network Rare-Liver, Saint-Antoine Research Center, Sorbonne University, Paris, France.
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21
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Thérien A, Cieślak A, Verreault M, Perreault M, Trottier J, Gobeil S, Vohl MC, Barbier O. Omega-3 Polyunsaturated Fatty Acid: A Pharmaco-Nutraceutical Approach to Improve the Responsiveness to Ursodeoxycholic Acid. Nutrients 2021; 13:nu13082617. [PMID: 34444777 PMCID: PMC8400581 DOI: 10.3390/nu13082617] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/13/2021] [Accepted: 07/20/2021] [Indexed: 12/13/2022] Open
Abstract
Ursodeoxycholic acid (UDCA) is the first line therapy for the treatment of cholestatic and autoimmune liver diseases. Its clinical use is currently limited by a significant proportion of non-responder patients. Polyunsaturated fatty acids (n-3 PUFAs) possess important anti-inflammatory properties and protect liver cells against bile acid (BA)-induced toxicity. The present study was designed to rapidly evaluate whether combining n-3 PUFAs (i.e., eicosapentaenoic [EPA] and docosahexaenoic [DHA] acids) to UDCA would provide additional benefits when compared to the drug alone. The parameters evaluated were (i) the expression of genes governing BA synthesis, transport, and metabolism; (ii) the prevention of BA-induced apoptosis and endoplasmic reticulum (ER)-stress; and (iii) the control of BA- and LPS-dependent inflammation. In the absence of n-3 PUFAs, most of the parameters investigated were unaffected by UDCA or were only altered by the higher dose (500 µM) of the drug. By contrast, in the presence of EPA/DHA (50/50 µM), all parameters showed a strongly improved response and the lowest UDCA dosage (50 µM) provided equal or better benefits than the highest dose used alone. For example, the combination EPA/DHA + UDCA 50 µM caused comparable down-regulation of the CYP7A1 gene expression and of the BA-induced caspase 3 activity as observed with UDCA 500 µM. In conclusion, these results suggest that the addition of n-3 PUFAs to UDCA may improve the response to the drug, and that such a pharmaco-nutraceutical approach could be used in clinic to open the narrow therapeutic dose of UDCA in cholestatic liver diseases.
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Affiliation(s)
- Ariane Thérien
- CHU de Québec Research Center, Québec, QC G1V 4G2, Canada; (A.T.); (A.C.); (M.V.); (M.P.); (J.T.); (S.G.)
- Faculty of Pharmacy, Université Laval, Québec, QC G1V 0A6, Canada
| | - Anna Cieślak
- CHU de Québec Research Center, Québec, QC G1V 4G2, Canada; (A.T.); (A.C.); (M.V.); (M.P.); (J.T.); (S.G.)
- Faculty of Pharmacy, Université Laval, Québec, QC G1V 0A6, Canada
| | - Mélanie Verreault
- CHU de Québec Research Center, Québec, QC G1V 4G2, Canada; (A.T.); (A.C.); (M.V.); (M.P.); (J.T.); (S.G.)
| | - Martin Perreault
- CHU de Québec Research Center, Québec, QC G1V 4G2, Canada; (A.T.); (A.C.); (M.V.); (M.P.); (J.T.); (S.G.)
- Faculty of Medicine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Jocelyn Trottier
- CHU de Québec Research Center, Québec, QC G1V 4G2, Canada; (A.T.); (A.C.); (M.V.); (M.P.); (J.T.); (S.G.)
| | - Stéphane Gobeil
- CHU de Québec Research Center, Québec, QC G1V 4G2, Canada; (A.T.); (A.C.); (M.V.); (M.P.); (J.T.); (S.G.)
- Faculty of Medicine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Marie-Claude Vohl
- Centre Nutrition, Santé et Société (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Université Laval, Québec, QC G1V 0A6, Canada;
| | - Olivier Barbier
- CHU de Québec Research Center, Québec, QC G1V 4G2, Canada; (A.T.); (A.C.); (M.V.); (M.P.); (J.T.); (S.G.)
- Faculty of Pharmacy, Université Laval, Québec, QC G1V 0A6, Canada
- Centre Nutrition, Santé et Société (NUTRISS), Institute of Nutrition and Functional Foods (INAF), Université Laval, Québec, QC G1V 0A6, Canada;
- Correspondence:
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22
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Mawardi M, Alalwan A, Fallatah H, Abaalkhail F, Hasosah M, Shagrani M, Alghamdi MY, Alghamdi AS. Cholestatic liver disease: Practice guidelines from the Saudi Association for the Study of Liver diseases and Transplantation. Saudi J Gastroenterol 2021; 27:S1-S26. [PMCID: PMC8411950 DOI: 10.4103/sjg.sjg_112_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/26/2021] [Accepted: 05/16/2021] [Indexed: 11/04/2022] Open
Abstract
Cholestatic liver diseases (CLDs) are a group of diseases characterized by jaundice and cholestasis as the main presentation with different complications, which have considerable impact on the liver and can lead to end-stage liver disease, cirrhosis, and liver-related complications. In the last few years, tremendous progress has been made in understanding the pathophysiology, diagnosis, and treatment of patients with these conditions. However, several aspects related to the management of CLDs remain deficient and unclear. Due to the lack of recommendations that can help in the management, treatment of those conditions, the Saudi Association for the Study of Liver diseases and Transplantation (SASLT) has created a task force group to develop guidelines related to CLDs management in order to provide a standard of care for patients in need. These guidelines provide general guidance for health care professionals to optimize medical care for patients with CLDs for both adult and pediatric populations, in association with clinical judgments to be considered on a case-by-case basis. These guidelines describe common CLDs in Saudi Arabia, with recommendations on the best approach for diagnosis and management of different diseases based on the Grading of Recommendation Assessment (GRADE), combined with a level of evidence available in the literature.
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Affiliation(s)
- Mohammad Mawardi
- Department of Medicine, Gastroenterology Section, King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia
| | - Abduljaleel Alalwan
- Department of Hepatobiliary Sciences and Liver Transplantation, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Hind Fallatah
- Department of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Faisal Abaalkhail
- Department of Medicine, Gastroenterology Section, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Mohammed Hasosah
- Department of Pediatrics, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Mohammad Shagrani
- Department of Liver and Small Bowel Transplantation, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Mohammed Y Alghamdi
- Department of Medicine, Gastroenterology Unit, King Fahd Military Complex, Dhahran, Saudi Arabia
| | - Abdullah S Alghamdi
- Department of Medicine, Gastroenterology Unit, King Fahad General Hospital, Jeddah, Saudi Arabia
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23
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The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities. J Clin Med 2021; 10:jcm10081763. [PMID: 33919600 PMCID: PMC8073106 DOI: 10.3390/jcm10081763] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/12/2021] [Accepted: 04/15/2021] [Indexed: 02/07/2023] Open
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are two chronic cholestatic liver diseases affecting bile ducts that may progress to biliary cirrhosis. In the past few years, the increasing knowledge in the pathogenesis of both diseases led to a growing number of clinical trials and possible new targets for therapy. In this review, we provide an update on the treatments in clinical use and summarize the new drugs in trials for PBC and PSC patients. Farnesoid X Receptor (FXR) agonists and Pan-Peroxisome Proliferator-Activated Receptor (PPAR) agonists are the most promising agents and have shown promising results in both PBC and PSC. Fibroblast Growth Factor 19 (FGF19) analogues also showed good results, especially in PBC, while, although PBC and PSC are autoimmune diseases, immunosuppressive drugs had disappointing effects. Since the gut microbiome could have a potential role in the pathogenesis of PSC, recent research focused on molecules that could change the microbiome, with good results. The near future of the medical management of these diseases may include new treatments or a combination of multiple drugs targeting different signaling pathways at different stages of the diseases.
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Hirschfield GM, Beuers U, Kupcinskas L, Ott P, Bergquist A, Färkkilä M, Manns MP, Parés A, Spengler U, Stiess M, Greinwald R, Pröls M, Wendum D, Drebber U, Poupon R. A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA. J Hepatol 2021; 74:321-329. [PMID: 32950590 DOI: 10.1016/j.jhep.2020.09.011] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 08/03/2020] [Accepted: 09/02/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS In patients with primary biliary cholangitis (PBC), the efficacy of budesonide, a synthetic corticosteroid displaying high first-pass metabolism, is unresolved. In a placebo-controlled, double-blind trial, we evaluated the added-value of budesonide in those with PBC and ongoing risk of progressive disease despite ursodeoxycholic acid (UDCA) treatment. METHODS We evaluated 62 patients with PBC who had histologically confirmed hepatic inflammatory activity, according to the Ishak score, and an alkaline phosphatase (ALP) >1.5× upper limit of normal (ULN), after at least 6 months of UDCA therapy. Participants were randomly assigned 2:1 to receive budesonide (9 mg/day) or placebo once daily, for 36 months, with UDCA treatment (12-16 mg/kg body weight/day) maintained. Primary efficacy was defined as improvement of liver histology with respect to inflammation and no progression of fibrosis. Secondary outcomes included changes in biochemical markers of liver injury. RESULTS Recruitment challenges resulted in a study that was underpowered for the primary efficacy analysis. Comparing patients with paired biopsies only (n = 43), the primary histologic endpoint was not met (p >0.05). The proportion of patients with ALP <1.67×ULN, a ≥15% decrease in ALP and normal bilirubin was higher in the budesonide group than in the placebo group at 12, 24, and 36 months (p <0.05, each). In contrast to placebo, budesonide reduced mean ALP and 35% of budesonide-treated patients achieved normalisation of ALP (placebo 9%; p = 0.023). Serious adverse events occurred in 10 patients receiving budesonide and 7 patients receiving placebo. CONCLUSION Budesonide add-on therapy was not associated with improved liver histology in patients with PBC and insufficient response to UDCA; however, improvements in biochemical markers of disease activity were demonstrated in secondary analyses. LAY SUMMARY Around one-third of patients with primary biliary cholangitis (PBC) needs additional medical therapy alongside ursodeoxycholic acid (UDCA) treatment. In this clinical trial, the addition of the corticosteroid budesonide did not improve liver histology; there were however relevant improvements in liver blood tests. CLINICALTRIALS. GOV NUMBER NCT00746486.
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Affiliation(s)
- Gideon M Hirschfield
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Limas Kupcinskas
- Department of Gastroenterology & Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Peter Ott
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Annika Bergquist
- Department of Gastroenterology & Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Martti Färkkilä
- Helsinki University and Helsinki University Hospital, Clinic of Gastroenterology, Helsinki, Finland
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Albert Parés
- Liver Unit, Hospital Clínic, IDIBAPS, University of Barcelona, CIBERehd, Barcelona, Spain
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Michael Stiess
- Research and Development, Dr. Falk Pharma GmbH, Freiburg, Germany
| | - Roland Greinwald
- Research and Development, Dr. Falk Pharma GmbH, Freiburg, Germany
| | - Markus Pröls
- Research and Development, Dr. Falk Pharma GmbH, Freiburg, Germany
| | - Dominique Wendum
- Service d'Anatomie et Cytologie Pathologiques Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75571 Paris cedex 12; Sorbonne Université, INSERM UMR_S938, Centre de Recherche Saint-Antoine(CRSA), 75012 Paris, France
| | - Uta Drebber
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Raoul Poupon
- Service d'Hépatologie, Centre national de référence des maladies inflammatoires du foie et des voies biliaires, Hôpital Saint-Antoine, Paris, France
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25
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Qian JD, Yao TT, Wang Y, Wang GQ. Treatment of primary biliary cholangitis with ursodeoxycholic acid, prednisolone and immunosuppressants in patients not responding to ursodeoxycholic acid alone and the prognostic indicators. Clin Res Hepatol Gastroenterol 2020; 44:874-884. [PMID: 32305248 DOI: 10.1016/j.clinre.2020.03.026] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/14/2020] [Accepted: 03/23/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIM We reviewed the medical records of primary biliary cholangitis patients who were diagnosed by liver biopsy and treated with the corresponding treatment. We evaluated the therapeutic effect and long-term prognostic indicators. METHODS This observational cohort study enrolled 80 eligible patients diagnosed by liver biopsy between December 2013 and December 2018 in our department. UDCA monotherapy or UDCA added to prednisolone and immunosuppressant triple therapy was prescribed to patients. We analyzed and compared the demographic characteristics, biochemistry profiles, immune parameters, and noninvasive liver fibrosis assessments at baseline as well as the treatment efficacy, long-term outcomes and adverse effects at baseline and at each visit between the two groups. The indicators that could affect prognosis were assessed. RESULTS Thirty-eight primary biliary cholangitis patients received UDCA monotherapy (group A), and another 42 patients received UDCA, prednisolone and immunosuppressant triple therapy (group B). After therapy, all patients showed significant improvements in liver biochemical parameters, immune indicators, and noninvasive fibrosis indicators (Fibrosis-4 (FIB-4), aspartate aminotransferase-to-platelet ratio index (APRI)), all P values<0.0001. The Mayo score also decreased significantly after treatment (P=0.022). Triple therapy was more effective, and there was a significant difference between the two groups. In addition, multivariate analysis showed that anti-gp210 antibody positivity; antimitochondrial antibody (AMA) negativity; high alkaline phosphatase (ALP), total bilirubin (TBIL) and globulin levels; and a severe degree of fibrosis at baseline were independent predictors of a poor prognosis. CONCLUSIONS Triple therapy was a treatment option for UDCA-refractory PBC patients. Anti-gp210 antibody positivity; AMA negativity; high ALP, TBIL and globulin levels; and a severe degree of fibrosis at baseline were associated with a poor prognosis.
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Affiliation(s)
- Jian-Dan Qian
- Department of Infectious Diseases and the Center for Liver Diseases, Peking University First Hospital, 100034 Beijing, China.
| | - Tian-Tian Yao
- Department of Infectious Diseases and the Center for Liver Diseases, Peking University First Hospital, 100034 Beijing, China.
| | - Yan Wang
- Department of Infectious Diseases and the Center for Liver Diseases, Peking University First Hospital, 100034 Beijing, China.
| | - Gui-Qiang Wang
- Department of Infectious Diseases and the Center for Liver Diseases, Peking University First Hospital, 100034 Beijing, China; The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, 310003 Hangzhou, Zhejiang Province, China; Peking University International Hospital, 102206 Beijing, China.
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Bari K, Shah SA, Kaiser TE, Cohen RM, Anwar N, Kleesattel D, Sherman KE. Safety and Efficacy of Budesonide for Liver Transplant Immune Suppression: Results of a Pilot Phase 2a Trial. Liver Transpl 2020; 26:1430-1440. [PMID: 32602616 PMCID: PMC7606621 DOI: 10.1002/lt.25837] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/04/2020] [Accepted: 06/19/2020] [Indexed: 02/06/2023]
Abstract
Despite adverse effects like hyperglycemia, new-onset diabetes after transplant (NODAT), and infectious complications, corticosteroid use remains an important part of liver transplantation (LT) immune suppression. Budesonide, a synthetic corticosteroid, undergoes extensive first-pass hepatic metabolism with only 10% systemic bioavailability, providing an opportunity for an improved toxicity-therapeutic ratio. Although effective in the treatment of autoimmune hepatitis, the effects of budesonide for LT immune suppression are unknown. We conducted a single-center phase 2a trial to study the safety and efficacy of budesonide immunosuppressive therapy. From July 2017 to November 2018, 20 patients undergoing a first LT received budesonide tapering doses (from 9 to 3 mg) for 12 weeks. Patients were compared with matched control patients who received prednisone from the same time period. Additionally, both groups received calcineurin inhibitors and mycophenolate mofetil. Outcome measures at week 24 included rates of biopsy-proven acute cellular rejection (ACR), NODAT (hemoglobin A1c >6.4%), and infectious complications. In the budesonide arm, 1 patient developed ACR at week 5 and was removed from the study. Another patient stopped the study drug at week 8 due to persistent nausea. Rates of ACR were similar between the budesonide and control groups (5% versus 5%, P = 1.00). Three patients in the control group developed NODAT versus none in the budesonide group (15% versus 0%; P = 0.23). There were 6 infections in the control group compared with none in the budesonide group (30% versus 0; P = 0.02). These pilot data suggest that budesonide has the potential to be a safe and effective alternative to prednisone for LT immune suppression while reducing steroid-induced infections and NODAT. Randomized controlled trials are required to validate these findings.
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Affiliation(s)
- Khurram Bari
- University of Cincinnati, Division of Digestive Diseases, Department of Medicine, Cincinnati, Ohio
| | - Shimul A. Shah
- University of Cincinnati, Division of Transplant Surgery, Department of Surgery, Cincinnati, Ohio
| | - Tiffany E. Kaiser
- University of Cincinnati, Division of Digestive Diseases, Department of Medicine, Cincinnati, Ohio
| | - Robert M Cohen
- University of Cincinnati, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cincinnati, Ohio
| | - Nadeem Anwar
- University of Cincinnati, Division of Digestive Diseases, Department of Medicine, Cincinnati, Ohio
| | - David Kleesattel
- University of Cincinnati, Department of Internal Medicine, Cincinnati, Ohio
| | - Kenneth E. Sherman
- University of Cincinnati, Division of Digestive Diseases, Department of Medicine, Cincinnati, Ohio
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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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28
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Mago S, Wu GY. Primary Sclerosing Cholangitis and Primary Biliary Cirrhosis Overlap Syndrome: A Review. J Clin Transl Hepatol 2020; 8:336-346. [PMID: 33083257 PMCID: PMC7562796 DOI: 10.14218/jcth.2020.00036] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 07/21/2020] [Accepted: 07/24/2020] [Indexed: 12/12/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are slow progressive diseases which have been increasing in prevalence. The pathogeneses of PBC and PSC are incompletely understood but the underlying mechanisms appear to be fundamentally autoimmune in origin. Although PBC and PSC appear to be separate entities, overlap has been described. Diagnosis depends on a combination of serological markers, imaging, and pathological criteria. The mainstay of treatment has been ursodeoxycholic acid and in some cases of extrahepatic biliary obstruction and overlap disorder, endoscopic retrograde cholangiopancreatography has been useful.
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Affiliation(s)
- Sheena Mago
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
- Correspondence to: Sheena Mago, Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA. E-mail:
| | - George Y. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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Yao TT, Qian JD, Wang GQ. Efficacy of ursodeoxycholic acid combined with prednisolone and immunosuppressant triple therapy in the treatment of refractory primary biliary cholangitis. Med Clin (Barc) 2020; 155:165-170. [PMID: 32600985 DOI: 10.1016/j.medcli.2020.03.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 03/18/2020] [Accepted: 03/22/2020] [Indexed: 01/26/2023]
Abstract
BACKGROUND AND AIM To explore the efficacy treatment regimen in refractory PBC. METHODS Triple treatment including ursodeoxycholic acid, prednisolone and immunosuppressant was prescribed to 47 refractory patients. Biochemistries, immune parameters, non-invasive liver fibrosis assessments were measured during follow-up. RESULTS Triple therapy resulted in significant decrease in ALP, GGT, ALT, AST, TBIL, ALB, IgG, IgM, APRI, FIB-4 and S-INDEX. The biochemical cumulative normalization rates of ALP and other biochemical parameters were higher in long-term follow-up. Poor outcome was observed in patients with lower ALB, higher TBIL, PT, sp100 positivity and advanced liver pathology at baseline. Osteoporosis and bone fracture were observed in 15% patients. CONCLUSIONS Triple therapy is associated with marked decrease and normalization of ALP and other parameters. ALB, TBIL, PT, sp100 and pathology were related with poor outcome. Osteoporosis should be closely monitored.
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Affiliation(s)
- Tian-Tian Yao
- Department of Infectious Diseases, Peking University First Hospital, 8 Xishiku Street, Beijing 100034, P.R., China
| | - Jian-Dan Qian
- Department of Infectious Diseases, Peking University First Hospital, 8 Xishiku Street, Beijing 100034, P.R., China
| | - Gui-Qiang Wang
- Department of Infectious Diseases, Peking University First Hospital, 8 Xishiku Street, Beijing 100034, P.R., China.
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30
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Aguilar MT, Chascsa DM. Update on Emerging Treatment Options for Primary Biliary Cholangitis. Hepat Med 2020; 12:69-77. [PMID: 32547264 PMCID: PMC7259454 DOI: 10.2147/hmer.s205431] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 04/29/2020] [Indexed: 12/12/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a rare autoimmune cholestatic liver disease that may progress to fibrosis or cirrhosis. Treatment options are currently limited. Ursodeoxycholic acid (UDCA) remains first-line therapy and has been proven to normalize serum biochemistries, halt histologic disease progression, and lead to patient survival comparable to the general population. Obeticholic acid (OCA) was recently approved as adjunct therapy in PBC patients with inadequate response or intolerance to UDCA. However, OCA has been associated with worsening pruritus in clinical studies which may limit its use in this patient population. Several studies are currently underway to address the lack of treatment options for PBC. Of these, fibrates, which have been used in Japan for over a decade, have produced promising results. Furthermore, as currently approved therapies for PBC do not address the potentially debilitating clinical symptoms of PBC such as pruritus and fatigue, supplemental therapy is often required for symptom control.
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Affiliation(s)
- Maria T Aguilar
- Department of Gastroenterology & Hepatology, Mayo Clinic, Scottsdale, AZ, USA
| | - David M Chascsa
- Department of Gastroenterology & Hepatology, Mayo Clinic, Phoenix, AZ, USA
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Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with non-suppurative destruction of the intrahepatic bile ducts. The interplay of genetics and environmental triggers contributes to the onset of the disease and subsequently results in cholestasis and progressive fibrosis. Recently, genome-wide association studies (GWAS) have identified multiple genes influencing the susceptibility to PBC in HLA and non-HLA loci. However, it is estimated that the known risk variants merely account for no more than 20% of the heritability of PBC and causes of the remaining heritability remain uncertain. Increasing evidence suggests that the presence of epigenetic abnormalities may explain the "missing heritability" that cannot be captured by GWAS. Among these epigenetic mechanisms, DNA methylation, histone modification, and noncoding RNAs (i.e. miRNA and lncRNA) are involved in the pathogenesis of PBC. Additionally, telomere dysregulation in biliary epithelial cells (BECs) may play a role in disease onset, whereas a deficiency in sex chromosome and skewed gene expression in the X chromosome may to some extent explain the female dominance in PBC.
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32
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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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33
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Gerussi A, Lucà M, Cristoferi L, Ronca V, Mancuso C, Milani C, D'Amato D, O'Donnell SE, Carbone M, Invernizzi P. New Therapeutic Targets in Autoimmune Cholangiopathies. Front Med (Lausanne) 2020; 7:117. [PMID: 32318580 PMCID: PMC7154090 DOI: 10.3389/fmed.2020.00117] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 03/18/2020] [Indexed: 12/12/2022] Open
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune cholangiopathies characterized by limited treatment options. A more accurate understanding of the several pathways involved in these diseases has fostered the development of novel and promising targeted drugs. For PBC, the characterization of the role of farnesoid X receptor (FXR) and perixosome-proliferator activated receptor (PPAR) has paved the way to several clinical trials including different molecules with choleretic and antinflammatory action. Conversely, different pathogenetic models have been proposed in PSC such as the "leaky gut" hypothesis, a dysbiotic microbiota or a defect in mechanisms protecting against bile acid toxicity. Along these theories, new treatment approaches have been developed, ranging from drugs interfering with trafficking of lymphocytes from the gut to the liver, fecal microbiota transplantation or new biliary acids with possible immunomodulatory potential. Finally, for both diseases, antifibrotic agents are under investigation. In this review, we will illustrate current understanding of molecular mechanisms in PBC and PSC, focusing on actionable biological pathways for which novel treatments are being developed.
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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
| | - Martina Lucà
- 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
| | - Laura Cristoferi
- 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
| | - Vincenzo Ronca
- 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
- National Institute of Health Research Liver Biomedical Research Centre Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Clara Mancuso
- 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
| | - Chiara Milani
- 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
| | - Daphne D'Amato
- 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
| | - Sarah Elizabeth O'Donnell
- 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
| | - 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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34
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Inflammation: Cause or consequence of chronic cholestatic liver injury. Food Chem Toxicol 2020; 137:111133. [PMID: 31972189 DOI: 10.1016/j.fct.2020.111133] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/04/2019] [Accepted: 01/14/2020] [Indexed: 12/12/2022]
Abstract
Cholestasis is a result of obstruction of the biliary tracts. It is a common cause of liver pathology after exposure to toxic xenobiotics and during numerous other liver diseases. Accumulation of bile acids in the liver is thought to be a major driver of liver injury during cholestasis and can lead to eventual liver fibrosis and cirrhosis. As such, current therapy in the field of chronic liver diseases with prominent cholestasis relies heavily on increasing choleresis to limit accumulation of bile acids. Many of these same diseases also present with autoimmunity before the onset of cholestasis though, indicating the inflammation may be an initiating component of the pathology. Moreover, cytotoxic inflammatory mediators accumulate during cholestasis and can propagate liver injury. Anti-inflammatory biologics and small molecules have largely failed clinical trials in these diseases though and as such, targeting inflammation as a means to address cholestatic liver injury remains debatable. The purpose of this review is to understand the different roles that inflammation can play during cholestatic liver injury and attempt to define how new therapeutic targets that limit or control inflammation may be beneficial for patients with chronic cholestatic liver disease.
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Abstract
Though ursodeoxycholic acid (UDCA) remains the baseline treatment for most cholestatic liver diseases, UDCA treatment leaves approximately one-third of patients with primary biliary cholangitis (PBC) and all patients with primary sclerosing cholangitis (PSC) at risk for disease progression. New anticholestatic agents, including nuclear receptor agonists, choleretics, and bile acid synthesis suppressors, will likely increase response rates to therapy in PBC and PSC. Strategies that target early immune-mediated injury have so far been disappointing, hampered by the lack of biomarkers to detect early disease states, which then could profit from immunomodulatory therapy. Future concepts need to personalize treatments according to disease stage, progression, and phase, and to combine multiple drugs to target different pathogenic pathways.
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Affiliation(s)
- Martin Wagner
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of Graz, 8036 Graz, Austria
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36
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Abstract
Primary biliary cholangitis is an uncommon cholestatic liver disease predominantly affecting middle-aged women. Left untreated, there is a high risk of progression to end-stage liver disease. Few treatment options exist. To date, ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only medical therapies approved for use, other than symptomatic treatments and liver transplantation, the latter of which is reserved for those developing complications of cirrhosis or with intractable pruritus. UDCA improves outcomes, but many patients do not adequately respond. OCA therapy may improve response, but long-term data are limited. New therapies are desperately needed, but evaluation has been limited by the fact that the disease is heterogeneous, hard end points take years to develop, and there are different criteria in use for determining therapeutic response based on surrogate biomarkers. Fibrates appear to be the most promising new therapy and have beneficially affected surrogate end points and are beginning to show improvement in clinical end points.
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37
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Gerussi A, D'Amato D, Cristoferi L, O'Donnell SE, Carbone M, Invernizzi P. Multiple therapeutic targets in rare cholestatic liver diseases: Time to redefine treatment strategies. Ann Hepatol 2020; 19:5-16. [PMID: 31771820 DOI: 10.1016/j.aohep.2019.09.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 09/27/2019] [Accepted: 09/27/2019] [Indexed: 02/04/2023]
Abstract
Primary biliary cholangitis and primary sclerosing cholangitis are rare diseases affecting the bile ducts and the liver. The limited knowledge of their pathogenesis leads to limited therapeutic options. Nevertheless, the landscape of novel therapies for these cholangiopathies is now rapidly changing, providing new treatment opportunities for patients and clinicians involved in their care. The aim of this review is to summarize the evidence of novel molecules under investigation for primary biliary cholangitis and primary sclerosing cholangitis and to discuss how they can potentially change current treatment paradigms.
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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
| | - Daphne D'Amato
- 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
| | - Laura Cristoferi
- 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
| | - Sarah Elizabeth O'Donnell
- 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
| | - 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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38
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Gottlieb A, Canbay A. Why Bile Acids Are So Important in Non-Alcoholic Fatty Liver Disease (NAFLD) Progression. Cells 2019; 8:cells8111358. [PMID: 31671697 PMCID: PMC6912605 DOI: 10.3390/cells8111358] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 10/27/2019] [Accepted: 10/28/2019] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a complex disease, affecting not just the liver, but also all other organs in the body. Despite an increasing amount of people worldwide developing NAFLD and having it progress to non-alcoholic steatohepatitis (NASH) and potentially cirrhosis, there is still no approved therapy. Therefore, huge efforts are being made to find and develop a successful treatment. One of the special interests is understanding the liver-gut axis and especially the role of bile acids in the progression of NAFLD. Farnesoid X receptor (FXR)-agonists have been approved und used in other liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), and have shown signs of being able to decrease inflammation and potentially steatosis. This review will mainly focus on targets/ligands that play an important role in bile acid metabolism and give an overview of ongoing clinical as well as pre-clinical trials. With the complexity of the issue, we did not aim at giving a complete review, rather highlighting important targets and potential treatments that could be approved for NAFLD/NASH treatment within the next few years.
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Affiliation(s)
- Aline Gottlieb
- Department of Physiology, Johns Hopkins University, Baltimore, MD 21224, USA.
| | - Ali Canbay
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany.
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D, Vierling JM, Adams D, Alpini G, Banales JM, Beuers U, Björnsson E, Bowlus C, Carbone M, Chazouillères O, Dalekos G, De Gottardi A, Harada K, Hirschfield G, Invernizzi P, Jones D, Krawitt E, Lanzavecchia A, Lian ZX, Ma X, Manns M, Mavilio D, Quigley EM, Sallusto F, Shimoda S, Strazzabosco M, Swain M, Tanaka A, Trauner M, Tsuneyama K, Zigmond E, Gershwin ME. The challenges of primary biliary cholangitis: What is new and what needs to be done. J Autoimmun 2019; 105:102328. [PMID: 31548157 DOI: 10.1016/j.jaut.2019.102328] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 08/18/2019] [Accepted: 08/20/2019] [Indexed: 02/06/2023]
Abstract
Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Epatocentro Ticino, Lugano, Switzerland; Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; European Reference Network ERN RARE-LIVER.
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK
| | - John M Vierling
- Division of Abdominal Transplantation and Section of Gastroenterology and Hepatology, Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - David Adams
- Birmingham NIHR Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesMedical School, University of Birmingham, Birmingham, UK
| | - Gianfranco Alpini
- Indiana Center for Liver Research, Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN, USA
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastián, Spain
| | - Ulrich Beuers
- European Reference Network ERN RARE-LIVER; Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Einar Björnsson
- Division of Gastroenterology and Hepatology, Landspitali the National University Hospital of Iceland, Reykjavík, Iceland
| | - Christopher Bowlus
- Division of Gastroenterology and Hepatology, University of California at Davis School of Medicine, Davis, CA, USA
| | - Marco Carbone
- Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan-Bicocca School of Medicine, Monza, Italy
| | - Olivier Chazouillères
- European Reference Network ERN RARE-LIVER; Service d'Hépatologie, Hôpital Saint-Antoine, Paris, France
| | - George Dalekos
- Institute of Internal Medicine and Hepatology, Department of Medicine and Research, Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece
| | - Andrea De Gottardi
- European Reference Network ERN RARE-LIVER; Epatocentro Ticino & Division of Gastroenterology and Hepatology Ente Ospedaliero Cantonale and Università della Svizzera Italiana, Lugano, Switzerland
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Gideon Hirschfield
- Toronto Centre for Liver Disease, University Health Network and University of Toronto, Toronto, Canada
| | - Pietro Invernizzi
- European Reference Network ERN RARE-LIVER; Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan-Bicocca School of Medicine, Monza, Italy
| | - David Jones
- Institute of Cellular Medicine and NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK
| | - Edward Krawitt
- Department of Medicine, University of Vermont, Burlington, VT, USA
| | | | - Zhe-Xiong Lian
- Institutes for Life Sciences, South China University of Technology, Higher Education Mega Center, Guangzhou, China
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, Jiao Tong University School of Medicine, Shanghai, China
| | - Michael Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Domenico Mavilio
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Italy
| | - Eamon Mm Quigley
- Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA
| | - Federica Sallusto
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
| | - Shinji Shimoda
- Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Mario Strazzabosco
- Liver Center, Department of Medicine, Yale University, New Haven, CT, USA
| | - Mark Swain
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Ehud Zigmond
- Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, California, USA.
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Corpechot C, Poupon R, Chazouillères O. New treatments/targets for primary biliary cholangitis. JHEP Rep 2019; 1:203-213. [PMID: 32039371 PMCID: PMC7001536 DOI: 10.1016/j.jhepr.2019.05.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 05/11/2019] [Accepted: 05/14/2019] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC) is an autoimmune, cholestatic, chronic liver disease that ultimately progresses towards cirrhosis and liver failure if untreated. While ursodeoxycholic acid has been established as standard of care for PBC in the last few decades, significant advances in second-line treatment options have recently been made and new therapeutic developments are currently under evaluation. The purpose of this article is to provide the clinician with an overview of the current treatment options and future opportunities for patients with PBC.
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Affiliation(s)
- Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology Department, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP); INSERM UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France
- Corresponding author. Address: Hepatology Department, Saint Antoine Hospital, 184 rue du Faubourg Saint Antoine, 75571 Paris Cedex 12, France.
| | - Raoul Poupon
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology Department, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP); INSERM UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France
| | - Olivier Chazouillères
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology Department, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP); INSERM UMR_S938, Saint-Antoine Research Center, Sorbonne University, Paris, France
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Abstract
New treatments for primary biliary cholangitis (PBC) are progressively emerging, including first and second generations of farnesoid X receptor and peroxisome proliferator-activated receptors agonists. Even though ursodeoxycholic acid monotherapy remains the standard of care treatment for PBC, these additional therapeutic options, already or soon to be available, lead us to revise our priorities and strategies with respect to future clinical trials. The present article is a personal view of where we currently stand in this field and where and how we should be going to achieve new progress.
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Affiliation(s)
- Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis (MIVB-H), French Network for Pediatric and Adult Rare Liver Diseases (FILFOIE), Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
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42
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Bowlus CL, Yang GX, Liu CH, Johnson CR, Dhaliwal SS, Frank D, Levy C, Peters MG, Vierling JM, Gershwin ME. Therapeutic trials of biologics in primary biliary cholangitis: An open label study of abatacept and review of the literature. J Autoimmun 2019; 101:26-34. [DOI: 10.1016/j.jaut.2019.04.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 04/01/2019] [Accepted: 04/06/2019] [Indexed: 12/12/2022]
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Tang S, Pan Y, Lou D, Ji S, Zhu L, Tan J, Qi N, Yang Q, Zhang Z, Yang B, Zhao W, Wang B. Structural and functional characterization of a novel acidophilic 7α-hydroxysteroid dehydrogenase. Protein Sci 2019; 28:910-919. [PMID: 30839141 PMCID: PMC6460000 DOI: 10.1002/pro.3599] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 02/21/2019] [Accepted: 02/22/2019] [Indexed: 11/09/2022]
Abstract
7α-Hydroxysteroid dehydrogenase (7α-HSDH) is an NAD(P)H-dependent oxidoreductase belonging to the short-chain dehydrogenases/reductases. In vitro, 7α-HSDH is involved in the efficient biotransformation of taurochenodeoxycholic acid (TCDCA) to tauroursodeoxycholic acid (TUDCA). In this study, a gene encoding novel 7α-HSDH (named as St-2-1) from fecal samples of black bear was cloned and heterologously expressed in Escherichia coli. The protein has subunits of 28.3 kDa and a native size of 56.6 kDa, which suggested a homodimer. We studied the relevant properties of the enzyme, including the optimum pH, optimum temperature, thermal stability, activators, and inhibitors. Interestingly, the data showed that St-2-1 differs from the 7α-HSDHs reported in the literature, as it functions under acidic conditions. The enzyme displayed its optimal activity at pH 5.5 (TCDCA). The acidophilic nature of 7α-HSDH expands its application environment and the natural enzyme bank of HSDHs, providing a promising candidate enzyme for the biosynthesis of TUDCA or other related chemical entities.
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Affiliation(s)
- Shijin Tang
- Key Laboratory of Biorheological Science and TechnologyMinistry of Education, College of Bioengineering, Chongqing UniversityChongqing 400030China
| | - Yinping Pan
- Key Laboratory of Biorheological Science and TechnologyMinistry of Education, College of Bioengineering, Chongqing UniversityChongqing 400030China
| | - Deshuai Lou
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir RegionSchool of Biological & Chemical Engineering, Chongqing University of EducationChongqing 400067China
| | - Shunlin Ji
- Key Laboratory of Biorheological Science and TechnologyMinistry of Education, College of Bioengineering, Chongqing UniversityChongqing 400030China
| | - Liancai Zhu
- Key Laboratory of Biorheological Science and TechnologyMinistry of Education, College of Bioengineering, Chongqing UniversityChongqing 400030China
- Modern Life Science Experiment Teaching CenterCollege of Bioengineering, Chongqing UniversityChongqing 400030China
| | - Jun Tan
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir RegionSchool of Biological & Chemical Engineering, Chongqing University of EducationChongqing 400067China
| | - Na Qi
- Key Laboratory of Biorheological Science and TechnologyMinistry of Education, College of Bioengineering, Chongqing UniversityChongqing 400030China
| | - Qiong Yang
- Key Laboratory of Biorheological Science and TechnologyMinistry of Education, College of Bioengineering, Chongqing UniversityChongqing 400030China
- Chongqing Key Laboratory of Inorganic Special Functional MaterialsCollaborative Innovation Center for Green Development in Wuling Mountain Areas, Yangtze Normal UniversityChongqing 408100China
| | - Zhi Zhang
- Key Laboratory of Biorheological Science and TechnologyMinistry of Education, College of Bioengineering, Chongqing UniversityChongqing 400030China
| | - Biling Yang
- Key Laboratory of Biorheological Science and TechnologyMinistry of Education, College of Bioengineering, Chongqing UniversityChongqing 400030China
| | - Wenyan Zhao
- Key Laboratory of Biorheological Science and TechnologyMinistry of Education, College of Bioengineering, Chongqing UniversityChongqing 400030China
| | - Bochu Wang
- Key Laboratory of Biorheological Science and TechnologyMinistry of Education, College of Bioengineering, Chongqing UniversityChongqing 400030China
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Durazzo M, Bonetto S, Fagoonee S, Morgando A, Pellicano R. Management of primary biliary cholangitis prior to obeticholic acid availability. Minerva Med 2018; 109:410-417. [PMID: 30022645 DOI: 10.23736/s0026-4806.18.05774-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease with unknown etiology. The prognosis of patients affected by PBC is heterogeneous, with a relevant improvement achieved after the introduction of ursodeoxycolic acid (UDCA). Since in the last years obeticholic acid (OCA) has been approved for the combined treatment of PBC, in patient non-responders to UDCA or as monotherapy in those intolerant to UDCA, we evaluated the response to UDCA in a cohort of patients with PBC managed in a specialistic setting. METHODS We included 38 UCDA-treated non-cirrhotic, early-PBC patients. Data were retrieved from documents compiled during the annual follow-up. The response to therapy was assessed comparing the parameters of our cohort with the inclusion criteria of the POISE Trial and the Paris I and Paris II criteria. RESULTS The cohort included 34/38 female patients and the average age was 65.34±10.69 years. Over 50% of the patients were affected by at least one disease associated to PBC. Using the POISE criteria and the Paris I and Paris II criteria, we identified 5, 2 and 5 non-responders, respectively. All patients with severe fibrosis had a biochemical response to UDCA according to the three different criteria applied. No side effect was reported. CONCLUSIONS We confirm that UDCA is a safe and effective treatment in patients with PBC. Non-responder patients represent 13% of our population, with high risk of disease progression and complications. In this context, further therapy using OCA should be considered.
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Affiliation(s)
- Marilena Durazzo
- Department of Medical Sciences, University of Turin, Turin, Italy -
| | - Silvia Bonetto
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Sharmila Fagoonee
- Institute for Biostructures and Bioimages (CNR) c/o Molecular Biotechnology Center, Turin, Italy
| | - Anna Morgando
- Unit of Gastroenterology, Molinette-SGAS Hospital, Turin, Italy
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Rodrigues PM, Perugorria MJ, Santos-Laso A, Bujanda L, Beuers U, Banales JM. Primary biliary cholangitis: A tale of epigenetically-induced secretory failure? J Hepatol 2018; 69:1371-1383. [PMID: 30193962 DOI: 10.1016/j.jhep.2018.08.020] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 08/14/2018] [Accepted: 08/24/2018] [Indexed: 12/16/2022]
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune-related destruction of small to medium size intrahepatic bile ducts. The aetiology of PBC is unknown and its pathogenesis remains obscure. Both genetic variants and environmental factors have been linked to increased PBC susceptibility, with other alterations known to cooperate in disease pathobiology. Increasing evidence indicates the presence of epigenetic abnormalities in PBC, particularly alterations of cholangiocellular microRNAs (miRNAs or miRs). This review highlights and discusses the most relevant epigenetic alterations found in patients with PBC, focusing on the role of miR-506 in the promotion of cholestasis and immune activation.
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Affiliation(s)
- Pedro M Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Maria J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Alvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), Spain
| | - Ulrich Beuers
- Tytgat Institute for Liver and Intestinal Research and Department of Gastroenterology & Hepatology, Amsterdam Gastroenterology and Metabolism, AMC, Amsterdam, The Netherlands
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
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46
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Goldstein J, Levy C. Novel and emerging therapies for cholestatic liver diseases. Liver Int 2018; 38:1520-1535. [PMID: 29758112 DOI: 10.1111/liv.13880] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 05/01/2018] [Indexed: 02/06/2023]
Abstract
While bile acids are important for both digestion and signalling, hydrophobic bile acids can be harmful, especially when in high concentrations. Mechanisms for the protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signalling, among others. By altering or overwhelming these defence mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation. While PBC is currently treated with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), many fail treatment, and we have yet to find an effective therapy for PSC. Novel therapies under evaluation target nuclear and surface receptors including FXR, transmembrane G-protein-coupled receptor 5 (TGR5), peroxisome proliferator-activated receptor (PPAR) and pregnane X receptor (PXR). Modulation of these receptors leads to altered bile composition, decreased cytotoxicity, decreased inflammation and improved metabolism. This review summarizes our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, presents the rationale for already approved medical therapies and discusses novel pharmacologic therapies under investigation.
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Affiliation(s)
- Jordan Goldstein
- Division of Internal Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Cynthia Levy
- Division of Hepatology, University of Miami Miller School of Medicine, Miami, FL, USA
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Hirschfield GM, Dyson JK, Alexander GJM, Chapman MH, Collier J, Hübscher S, Patanwala I, Pereira SP, Thain C, Thorburn D, Tiniakos D, Walmsley M, Webster G, Jones DEJ. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut 2018; 67:1568-1594. [PMID: 29593060 PMCID: PMC6109281 DOI: 10.1136/gutjnl-2017-315259] [Citation(s) in RCA: 213] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 01/22/2018] [Accepted: 01/23/2018] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.
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Affiliation(s)
- Gideon M Hirschfield
- NIHR Birmingham Biomedical Research Centre, Birmingham, UK
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Jessica K Dyson
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom
| | - Graeme J M Alexander
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
| | - Michael H Chapman
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Jane Collier
- Translational Gastroenterology Unit, Oxford University Hospitals, University of Oxford, Oxford, UK
| | - Stefan Hübscher
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Imran Patanwala
- Department of Gastroenterology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
- University of Liverpool, Liverpool, UK
| | - Stephen P Pereira
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | | | - Douglas Thorburn
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
| | - Dina Tiniakos
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | | | - George Webster
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | - David E J Jones
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom
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Abstract
Primary biliary cholangitis is a progressive, autoimmune disease of the interlobular bile ducts, leading to secondary damage of hepatocytes that may progress to cirrhosis and liver failure. Until recently, the only approved treatment was ursodeoxycholic acid. However, 40% of patients do not have an adequate response. Obeticholic acid was approved for treatment as add-on therapy in this group of patients. Off-label use of fibrates has also been reported to be effective. Several new therapies are in development and may further add to the treatment options available to patients with primary biliary cholangitis.
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Affiliation(s)
- Kimberly A Wong
- Department of Internal Medicine, UC Davis School of Medicine, 4150 V Street, PSSB 3000, Sacramento, CA 95817, USA
| | - Runalia Bahar
- Department of Internal Medicine, UC Davis School of Medicine, 4150 V Street, PSSB 3000, Sacramento, CA 95817, USA
| | - Chung H Liu
- Division of Gastroenterology and Hepatology, UC Davis School of Medicine, 4150 V Street, PSSB 3500, Sacramento, CA 95817, USA
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, UC Davis School of Medicine, 4150 V Street, PSSB 3500, Sacramento, CA 95817, USA.
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49
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van Niekerk J, Kersten R, Beuers U. Role of Bile Acids and the Biliary HCO 3- Umbrella in the Pathogenesis of Primary Biliary Cholangitis. Clin Liver Dis 2018; 22:457-479. [PMID: 30259847 DOI: 10.1016/j.cld.2018.03.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The biliary HCO3- umbrella hypothesis states that human cholangiocytes and hepatocytes create a protective apical alkaline barrier against millimolar concentrations of potentially toxic glycine-conjugated bile salts in bile by secreting HCO3- into the bile duct lumen. This alkaline barrier may retain biliary bile salts in their polar, deprotonated, and membrane-impermeant state to avoid uncontrolled invasion of apolar toxic bile acids, which initiate apoptosis, autophagy and senescence. In primary biliary cholangitis, defects of the biliary HCO3- umbrella, leading to impaired biliary HCO3- secretion have been identified. Current medical therapies stabilize the putatively defective biliary HCO3- umbrella and improve long-term prognosis.
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Affiliation(s)
- Jorrit van Niekerk
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands
| | - Remco Kersten
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
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50
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Harms MH, van Buuren HR, van der Meer AJ. Improving prognosis in primary biliary cholangitis - Therapeutic options and strategy. Best Pract Res Clin Gastroenterol 2018; 34-35:85-94. [PMID: 30343714 DOI: 10.1016/j.bpg.2018.06.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 06/08/2018] [Indexed: 01/31/2023]
Abstract
Overall survival in primary biliary cholangitis is diminished. As patients are often asymptomatic, the disease may silently progress towards cirrhosis and liver failure. Timely diagnosis and effective treatment options are of vital importance to improve the prognosis of affected patients. Ursodeoxycholic acid is the standard of care first-line therapy and is associated with a reduced risk of liver transplantation and death. Treatment with UDCA is relevant for all patients, irrespective of disease stage or biochemical response. In case of incomplete biochemical response according to internationally accepted criteria, second-line treatment should be considered to improve long-term prognosis. Ursodeoxycholic acid has been the only accepted treatment for PBC during the last decades. Recent research, however, has identified a number of new therapeutic targets and agents, including obeticholic acid, fibrates and budesonide. While these agents all qualify as potentially beneficial second-line treatment, obeticholic acid is currently the only drug specifically approved for the treatment of PBC. Although long-term follow-up studies for these agents are mostly lacking, improvement of biochemical surrogate markers of clinical outcome induced by these drugs suggests a therapeutic benefit. The authors of this review aim to provide a summary of the results of previous and current studies evaluating medical treatments, and propose a treatment strategy based on the evidence available today.
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Affiliation(s)
- Maren H Harms
- Erasmus University Medical Center, Rotterdam, The Netherlands.
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