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Reshetnyak VI, Maev IV. Bile acid therapy for primary biliary cholangitis: Pathogenetic validation. World J Exp Med 2025; 15:101771. [PMID: 40115760 PMCID: PMC11718588 DOI: 10.5493/wjem.v15.i1.101771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/25/2024] [Accepted: 11/07/2024] [Indexed: 12/26/2024] Open
Abstract
Knowledge of the etiological and pathogenetic mechanisms of the development of any disease is essential for its treatment. Because the cause of primary biliary cholangitis (PBC), a chronic, slowly progressive cholestatic liver disease, is still unknown, treatment remains symptomatic. Knowledge of the physicochemical properties of various bile acids and the adaptive responses of cholangiocytes and hepatocytes to them has provided an important basis for the development of relatively effective drugs based on hydrophilic bile acids that can potentially slow the progression of the disease. Advances in the use of hydrophilic bile acids for the treatment of PBC are also associated with the discovery of pathogenetic mechanisms of the development of cholangiocyte damage and the appearance of the first signs of this disease. For 35 years, ursodeoxycholic acid (UDCA) has been the unique drug of choice for the treatment of patients with PBC. In recent years, the list of hydrophilic bile acids used to treat cholestatic liver diseases, including PBC, has expanded. In addition to UDCA, the use of obeticholic acid, tauroursodeoxycholic acid and norursodeoxycholic acid as drugs is discussed. The pathogenetic rationale for treatment of PBC with various bile acid drugs is discussed in this review. Emphasis is made on the mechanisms explaining the beneficial therapeutic effects and potential of each of the bile acid as a drug, based on the understanding of the pathogenesis of the initial stages of PBC.
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Affiliation(s)
- Vasiliy I Reshetnyak
- Department of Propaedeutics of Internal Diseases and Gastroenterology, Russian University of Medicine, Moscow 127473, Russia
| | - Igor V Maev
- Department of Propaedeutics of Internal Diseases and Gastroenterology, Russian University of Medicine, Moscow 127473, Russia
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2
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Xie F, Niu Y, Chen X, Kong X, Yan G, Zhuang A, Li X, Lian L, Qin D, Zhang Q, Zhang R, Yang K, Xia X, Chen K, Xiao M, Yang C, Wu T, Shen Y, Yu C, Luo C, Lin SH, Li W. Ursodeoxycholic acid inhibits the uptake of cystine through SLC7A11 and impairs de novo synthesis of glutathione. J Pharm Anal 2025; 15:101068. [PMID: 39902457 PMCID: PMC11788867 DOI: 10.1016/j.jpha.2024.101068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 07/18/2024] [Accepted: 08/03/2024] [Indexed: 02/03/2025] Open
Abstract
Ursodeoxycholic acid (UDCA) is a naturally occurring, low-toxicity, and hydrophilic bile acid (BA) in the human body that is converted by intestinal flora using primary BA. Solute carrier family 7 member 11 (SLC7A11) functions to uptake extracellular cystine in exchange for glutamate, and is highly expressed in a variety of human cancers. Retroperitoneal liposarcoma (RLPS) refers to liposarcoma originating from the retroperitoneal area. Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects. The augmentation of UDCA concentration (≥25 μg/mL) demonstrated a suppressive effect on the proliferation of liposarcoma cells. [15N2]-cystine and [13C5]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione (GSH) synthesis. Mechanistically, UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis, leading to reactive oxygen species (ROS) accumulation and mitochondrial oxidative damage. Furthermore, UDCA can promote the anti-cancer effects of ferroptosis inducers (Erastin, RSL3), the murine double minute 2 (MDM2) inhibitors (Nutlin 3a, RG7112), cyclin dependent kinase 4 (CDK4) inhibitor (Abemaciclib), and glutaminase inhibitor (CB839). Together, UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity, and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA. More importantly, in combination with other antitumor chemotherapy or physiotherapy treatments, UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.
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Affiliation(s)
- Fu'an Xie
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Yujia Niu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Xiaobing Chen
- Department of Retroperitoneal Tumor Surgery, Peking University International Hospital, Beijing, 102206, China
| | - Xu Kong
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Guangting Yan
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Aobo Zhuang
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Xi Li
- School of Public Health, Harvard University, Boston, MA, 02115, USA
| | - Lanlan Lian
- Department of Laboratory Medicine, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, 361102, China
| | - Dongmei Qin
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Quan Zhang
- National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Ruyi Zhang
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Kunrong Yang
- Laboratory of Biochemistry and Molecular Biology Research, Department of Clinical Laboratory, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Xiaogang Xia
- Department of Hepatobiliary Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Kun Chen
- Department of Hepatobiliary Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
| | - Mengmeng Xiao
- Department of General Surgery, Peking University People's Hospital, Beijing, 100032, China
| | - Chunkang Yang
- Department of Gastrointestinal Surgical Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Ting Wu
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
- Department of Retroperitoneal Tumor Surgery, Peking University International Hospital, Beijing, 102206, China
| | - Ye Shen
- Department of Management, Jiang Xia Blood Technology Co., Ltd., Shanghai, 200000, China
| | - Chundong Yu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Chenghua Luo
- Department of General Surgery, Peking University People's Hospital, Beijing, 100032, China
| | - Shu-Hai Lin
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
| | - Wengang Li
- Cancer Research Center, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
- Department of Hepatobiliary Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China
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Bhushan S, Sohal A, Kowdley KV. Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Therapy Landscape. Am J Gastroenterol 2025; 120:151-158. [PMID: 39480026 DOI: 10.14309/ajg.0000000000003174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 10/25/2024] [Indexed: 11/02/2024]
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are rare, and chronic cholestatic diseases that can progress to liver failure. The goals of treatment are to halt the progression of liver disease to cirrhosis and/or liver failure, and alleviate symptoms associated with these diseases. Ursodeoxycholic acid has historically been the first-line treatment of PBC, with obeticholic acid and fibrates used as second-line or adjunctive therapies. However, the treatment landscape is rapidly expanding. Recently, 2 new second-line agents gained US Food and Drug Administration approval for the treatment of PBC, and several other therapies remain under investigation with promising results. Although significant progress has been made in the development of therapies for PBC, there are no current approved treatments of PSC other than liver transplantation although several emerging therapies have shown encouraging results. This review outlines the current and upcoming treatments of PBC and PSC.
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Affiliation(s)
| | - Aalam Sohal
- Liver Institute Northwest, Seattle, Washington, USA
| | - Kris V Kowdley
- Liver Institute Northwest, Seattle, Washington, USA
- Elson S. Floyd College of Medicine, Washington State University, Spokane, Washington, USA
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Sun Z, He W, Meng H, Li P, Qu J. Endoplasmic reticulum stress in acute lung injury and pulmonary fibrosis. FASEB J 2024; 38:e70232. [PMID: 39651914 DOI: 10.1096/fj.202401849rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 11/21/2024] [Accepted: 11/25/2024] [Indexed: 12/19/2024]
Abstract
Pulmonary fibrosis (PF) is a progressive and irreversible lung disease that leads to diminished lung function, respiratory failure, and ultimately death and typically has a poor prognosis, with an average survival time of 2 to 5 years. Related articles suggested that endoplasmic reticulum (ER) stress played a critical role in the occurrence and progression of PF. The ER is responsible for maintaining protein homeostasis. However, factors such as aging, hypoxia, oxidative stress, or inflammation can disrupt this balance, promoting the accumulation of misfolded proteins in the ER and triggering ER stress. To cope with this situation, cells activate the unfolded protein response (UPR). Since acute lung injury (ALI) is one of the key onset events of PF, in this review, we will discuss the role of ER stress in ALI and PF by activating multiple signaling pathways and molecular mechanisms that affect the function and behavior of different cell types, with a focus on epithelial cells, fibroblasts, and macrophages. Linking ER stress to these cell types may broaden our understanding of the mechanisms underlying lung fibrosis and help us target these cells through these mechanisms. The relationship between ER stress and PF is still evolving, and future research will explore new strategies to regulate UPR pathways, providing novel therapeutic targets.
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Affiliation(s)
- Zhiheng Sun
- College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
- State Key Laboratory of Cell Differentiation and Regulation, Xinxiang, Henan, China
| | - Wanyu He
- College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
- State Key Laboratory of Cell Differentiation and Regulation, Xinxiang, Henan, China
| | - Huiwen Meng
- College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
- State Key Laboratory of Cell Differentiation and Regulation, Xinxiang, Henan, China
| | - Peizhi Li
- Department of Anesthesiology, Xinxiang First People's Hospital, The Affiliated People's Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Junxing Qu
- Institutes of Health Central Plains, Xinxiang Medical University, Xinxiang, Henan, China
- Xinxiang Key Laboratory for Tumor Drug Screening and Targeted Therapy, Xinxiang, Henan, 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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Muzahim Y, Wakil A, Bassi M, Pyrsopoulos N. Treatment of Primary Biliary Cholangitis including Transplantation. Clin Liver Dis 2024; 28:103-114. [PMID: 37945152 DOI: 10.1016/j.cld.2023.07.003] [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] [Indexed: 11/12/2023]
Abstract
Ursodeoxycholic acid (UDCA) is the first-line treatment of primary biliary cholangitis (PBC). Long-term UDCA use significantly reduces progression to cirrhosis. UDCA improves liver enzymes and transplant-free survival rates. Despite the association between PBC and hyperlipidemia, treatment is indicated under specific circumstances with statins and fibrates being safe options. Osteoporosis, which is frequently seen, is usually managed based on data from postmenopausal women. Sicca syndrome is treated similarly to its standalone condition with the use of hydroxypropyl methylcellulose eye drops and anticholinergic drugs.
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Affiliation(s)
- Yasameen Muzahim
- Division of Gastroenterology and Hepatlogy, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB H Rm - 536, Newark, NJ 07101, USA
| | - Ali Wakil
- Division of Gastroenterology and Hepatlogy, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB H Rm - 536, Newark, NJ 07101, USA
| | - Mehak Bassi
- Division of Gastroenterology and Hepatoloy, Saint Peter's University Hospital, 254 Easton Avenue, New Brunswick, NJ 08901, USA
| | - Nikolaos Pyrsopoulos
- Division of Gastroenterology and Hepatlogy, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB H Rm - 536, Newark, NJ 07101, USA.
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Patel VS, Mahmood SF, Bhatt KH, Khemkar RM, Jariwala DR, Harris B, George MM, Kurudamannil RA, Anyagwa OE, Tak RS, Kassem M. Ursodeoxycholic Acid's Effectiveness in the Management of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Euroasian J Hepatogastroenterol 2024; 14:92-98. [PMID: 39022193 PMCID: PMC11249908 DOI: 10.5005/jp-journals-10018-1434] [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: 04/08/2024] [Accepted: 05/10/2024] [Indexed: 07/20/2024] Open
Abstract
Aim This meta-analysis's objective was to assess the effectiveness of ursodeoxycholic acid (UDCA) in the management of nonalcoholic fatty liver disease (NAFLD). Methods Electronic databases like PubMed, Embase, Scopus, and Cochrane Library were thoroughly looked for randomized controlled trials determining ursodeoxycholic acid's (UDCAs) effectiveness on the serum liver function tests in NAFLD patients. After screening, seven randomized controlled trials were incorporated overall. Utilizing a fixed effects model, quantitative data synthesis was performed in R version 4.3.1. Results The meta-analysis showed significant reductions in alanine transaminase (ALT) (p ≤ 0.0001), aspartate transaminase (p = 0.0009), and gamma-glutamyl transferase (GGT) (p ≤ 0.0001) after UDCA therapy. However, significant reductions in bilirubin (p = 0.6989) and alkaline phosphatase (ALP) (p = 0.1172) levels were not noted. Sensitivity analysis by removing the studies with some concerns of bias was successful in demonstrating a remarkable reduction in heterogeneity for aspartate transaminase and ALP, which was also observed while performing the subgroup analyses via dosage. Conclusion Ursodeoxycholic acid was beneficial in patients diagnosed with NAFLD as it significantly reduced aspartate transaminase, ALT and GGT levels. However, more randomized controlled trials are required to be conducted in the future to increase the certainty of the evident findings. Clinical significance This meta-analysis strengthens the evidence about the reductions in AST, ALT, and GGT levels observed with ursodeoxycholic acid therapy in NAFLD patients by pooling the data together from the latest RCTs thus proving its hepatoprotective effects which can be beneficial in preventing the associated complications. How to cite this article Patel VS, Mahmood SF, Bhatt KH, et al. Ursodeoxycholic Acid's Effectiveness in the Management of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Euroasian J Hepato-Gastroenterol 2024;14(1):92-98.
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Affiliation(s)
- Vaibhavi S Patel
- Faculty of Medicine, David Tvildiani Medical University, Tbilisi, Georgia
| | - Safa F Mahmood
- School of Medicine, David Tvildiani Medical University, Tbilisi, Georgia
| | - Kunal H Bhatt
- Faculty of Medicine, David Tvildiani Medical University, Tbilisi, Georgia
| | - Richisha M Khemkar
- School of Medicine, David Tvildiani Medical University, Tbilisi, Georgia
| | | | - Bilal Harris
- School of Medicine, David Tvildiani Medical University, Tbilisi, Georgia
| | - Mirna M George
- School of Medicine, David Tvildiani Medical University, Tbilisi, Georgia
| | - Reuel A Kurudamannil
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
| | | | - Rajeeka S Tak
- School of Medicine, New Vision University, Tbilisi, Georgia
| | - Maha Kassem
- School of Medicine, New Vision University, Tbilisi, Georgia
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Cifuentes-Silva E, Cabello-Verrugio C. Bile Acids as Signaling Molecules: Role of Ursodeoxycholic Acid in Cholestatic Liver Disease. Curr Protein Pept Sci 2024; 25:206-214. [PMID: 37594109 DOI: 10.2174/1389203724666230818092800] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/05/2023] [Accepted: 07/18/2023] [Indexed: 08/19/2023]
Abstract
Ursodeoxycholic acid (UDCA) is a natural substance physiologically produced in the liver. Initially used to dissolve gallstones, it is now successfully used in treating primary biliary cirrhosis and as adjuvant therapy for various hepatobiliary cholestatic diseases. However, the mechanisms underlying its beneficial effects still need to be clarified. Evidence suggests three mechanisms of action for UDCA that could benefit humans with cholestatic liver disease (CLD): protection of cholangiocytes against hydrophobic bile acid (BA) cytotoxicity, stimulation of hepatobiliary excretion, and protection of hepatocytes against BA-induced apoptosis. These mechanisms may act individually or together to potentiate them. At the molecular level, it has been observed that UDCA can generate modifications in the transcription and translation of proteins essential in the transport of BA, correcting the deficit in BA secretion in CLD, in addition to activating signaling pathways to translocate these transporters to the sites where they should fulfill their function. Inhibition of BA-induced hepatocyte apoptosis may play a role in CLD, characterized by BA retention in the hepatocyte. Thus, different mechanisms of action contribute to the improvement after UDCA administration in CLD. On the other hand, the effects of UDCA on tissues that possess receptors that may interact with BAs in pathological contexts, such as skeletal muscle, are still unclear. This work aims to describe the main molecular mechanisms by which UDCA acts in the human body, emphasizing the interaction in tissues other than the liver.
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Affiliation(s)
- Eduardo Cifuentes-Silva
- Laboratory of Muscle Pathology, Fragility, and Aging, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
| | - Claudio Cabello-Verrugio
- Laboratory of Muscle Pathology, Fragility, and Aging, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
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Sim KK, Fernando T, Tarquinio L, Navadgi S. Hepatic reactive lymphoid hyperplasia-associated primary biliary cholangitis masquerading as a neoplastic liver lesion. BMJ Case Rep 2023; 16:e254963. [PMID: 37967929 PMCID: PMC10660965 DOI: 10.1136/bcr-2023-254963] [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] [Accepted: 10/30/2023] [Indexed: 11/17/2023] Open
Abstract
Hepatic reactive lymphoid hyperplasia is an uncommon benign condition, often found incidentally as a solitary liver lesion. The chronic inflammatory reaction associated with autoimmune conditions and malignancies has been postulated as a possible aetiology. The diagnosis is challenging as it often mimics various malignancies radiologically and histologically, hence the diagnosis being made only after surgical resection. Lymphadenopathy is common with primary biliary cholangitis, though rarely reported with reactive lymphoid hyperplasia. We report a case of hepatic reactive lymphoid hyperplasia associated with portacaval lymphadenopathy in a patient with primary biliary cholangitis, diagnosed after surgical resection. We propose lesional biopsy be considered in patients with primary biliary cholangitis found to have a solitary lesion with supporting low-risk clinical and radiological features.
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Affiliation(s)
- Kwang Kiat Sim
- General Surgery, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
| | - Tarini Fernando
- Anatomical Pathology, Australian Clinical Labs, Clayton, Victoria, Australia
| | - Lorenzo Tarquinio
- School of Medicine, The University of Notre Dame Australia, Fremantle, Western Australia, Australia
| | - Suresh Navadgi
- Upper GI-HPB Surgery, Royal Perth Hospital, Perth, Western Australia, Australia
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Schönau J, Wester A, Schattenberg JM, Hagström H. Risk of fractures and postfracture mortality in 3980 people with primary biliary cholangitis: A population-based cohort study. J Intern Med 2023; 294:164-177. [PMID: 36823685 DOI: 10.1111/joim.13624] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
BACKGROUND Morbidity in primary biliary cholangitis (PBC) is multifactorial. Osteoporosis related to cholestasis is an extrahepatic complication of PBC. It is not fully established to what extent people with PBC have an increased risk for fractures, and if mortality after a fracture is increased, compared to the general population. METHODS All Swedish people with PBC diagnosed between 2001 and 2016 were identified from the National Swedish Patient Register using ICD-10 codes. Incident fractures were ascertained in the same register and compared to matched controls from the Swedish general population (1:10 for age, sex, and municipality). Cox regression was used to investigate the rates of fractures and postfracture mortality. The cumulative incidence of fractures was calculated while accounting for competing risks (death or liver transplantation). RESULTS People with PBC (n = 3980) showed a higher risk of fractures at all-time points during follow-up compared to matched controls (n = 37,196), which was seen both in men and women. At 5 years of follow-up, the cumulative incidence of any fracture in people with PBC was 16.8% (95% confidence interval [CI] = 15.6-18.1), compared to 11.6% (95%CI = 11.3-12.0) in controls. The rate of osteoporotic fractures was particularly high (adjusted Hazard ratio [aHR] = 1.9; 95% = CI 1.7-2.0). The 30-day as well as the 1-year mortality after a fracture was significantly higher in people with PBC compared to controls that also experienced a fracture (aHR = 2.2; 95%CI = 1.5-3.2; aHR = 2.0; 95%CI 1.7-2.4). CONCLUSION People with PBC have a significantly higher risk of fractures and postfracture mortality compared to matched controls from the general population.
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Affiliation(s)
- Johanna Schönau
- Department of Internal Medicine I, University Medical Center Mainz, Langenbeckstrasse, 1, Mainz, Rhineland-Palatinate, 55131, Germany
| | - Axel Wester
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Jörn M Schattenberg
- Department of Internal Medicine I, University Medical Center Mainz, Langenbeckstrasse, 1, Mainz, Rhineland-Palatinate, 55131, Germany
| | - Hannes Hagström
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
- Unit of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
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Ebhohon E, Chung RT. Systematic review: efficacy of therapies for cholestatic pruritus. Therap Adv Gastroenterol 2023; 16:17562848231172829. [PMID: 37255856 PMCID: PMC10226044 DOI: 10.1177/17562848231172829] [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: 10/17/2022] [Accepted: 04/13/2023] [Indexed: 06/01/2023] Open
Abstract
Background Pruritus is a symptom of several cholestatic liver diseases (CLDs) that can impair health-related quality of life (HRQoL). Despite evidence-based guideline therapy, managing cholestatic pruritus (CP) remains challenging, thus making the need for newer, more effective therapeutic agents more evident. Objective Our study evaluated the efficacy of existing CP therapies. Design Systematic review. Data sources From inception until March 2023, we conducted a comprehensive search of MEDLINE, Cochrane, EMBASE, Scopus, ClinicalTrial.gov, and other sources, including pharmaceutical webpages and conference proceedings published in English that reported on CP interventions. Methods Two reviewers independently conducted screening and full-text review of articles with extraction conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The methodological quality of studies included in our qualitative synthesis was assessed by using the Cochrane ROBINS-I and ROBINS-II tools for interventional studies and the National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The primary outcome assessed in our systematic review was the severity of CP after therapy. Results Of 3293 screened articles, 92 studies were eligible for inclusion in the qualitative synthesis. Some patients' HRQoL improved with evidence-based standard therapy. Others, particularly those with severe and refractory CP, often required conversion to or addition of experimental noninvasive (e.g., ondansetron) or extracorporeal liver support to alleviate CP. In addition, studies investigating a newer class drug, the ileal bile acid transporter inhibitor (IBATi), demonstrate its effectiveness in reducing serum bile acid and alleviating CP with sustained improvement noted in patients with the inherited childhood cholestatic disorders - progressive familial intrahepatic cholestasis and Alagille syndrome. Conclusion Our findings consolidate data on the efficacy of guideline-based approaches and newer therapies for CP. While the initial findings are promising, additional clinical trials will be needed to determine the full extent of IBATi's efficacy and potential use in treating other common CLDs. These results provide a foundation for future research and highlight the need for continued investigation into the management and treatment of CLDs.
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Affiliation(s)
| | - Raymond T. Chung
- Gastrointestinal Division, Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Pharmacological Therapy of Pruritus in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. J Clin Gastroenterol 2023; 57:143-152. [PMID: 36598806 DOI: 10.1097/mcg.0000000000001797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
GOALS We aim to summarize the current management of pruritus in primary biliary cholangitis (PBC) by evaluating the efficacy and safety of pharmacological therapies. BACKGROUND Pruritus is a common symptom of PBC, and evidence regarding the most effective antipruritic agents available is lacking. New pharmacotherapy for PBC has shown promising antipruritic effects. STUDY We performed a systematic literature review and meta-analysis including all available double-blind, randomized, placebo-controlled clinical trials that evaluated the efficacy of pharmacotherapy for the symptomatic management of pruritus in PBC. Pruritus was assessed as either a change from baseline or a postintervention score. RESULTS We included 33 studies and 20 medications. Using the visual analog scale, cholestyramine did not significantly improve pruritus compared with placebo [standardized mean differences (SMD): -0.94, 95% CI: -2.05 to 0.17], whereas rifampin and nalfurafine hydrochloride both significantly improved pruritus (SMD: -3.29, 95% CI: -5.78 to -0.80; n=23 and SMD: -0.58, 95% CI: -1.04 to -0.12). In addition, Bezafibrate and linerixibat significantly improved pruritus (SMD: -1.05, 95% CI: -1.41 to -0.68; n=110 and SMD: -0.31, 95% CI: -0.62 to -0.04, respectively). This effect was also present within the subgroup analysis by pruritus scale, where both bezafibrate and linerixibat significantly improved pruritus compared with placebo (SMD: -1.09, 95% CI: -1.54 to -0.65; P <0.001; visual analog scale; as postintervention score and SMD: -0.31, 95% CI: -0.62 to -0.01; P =0.04; numeric rating scale; as a change from baseline score, respectively). CONCLUSIONS Bezafibrate and Linerixibat are potential second-line antipruritic medications for PBC, particularly those with moderate to severe pruritus.
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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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14
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Xu C, Yue R, Lv X, Wang S, Du M. Efficacy and safety of pharmacological interventions for pruritus in primary biliary cholangitis: A systematic review and meta-analysis. Front Pharmacol 2022; 13:835991. [PMCID: PMC9631940 DOI: 10.3389/fphar.2022.835991] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 09/27/2022] [Indexed: 11/13/2022] Open
Abstract
Background and objective: Pruritus is a common complication in patients with primary biliary cholangitis (PBC). The pathogenesis is not clear, and also the precise therapeutic measures remain alluring. In order to systematically evaluate the efficacy and safety of drug interventions in the treatment of pruritus associated with PBC, this systemic review and meta-analysis was conducted. Methods: The randomized controlled trials (RCTs) on drug interventions in the treatment of pruritus associated with primary cholangitis were searched in the electronic databases of PubMed, EMBASE, Cochrane Library, Web of Science, and ClinicalTrials.gov. Two researchers independently screened the literature, extracted and integrated the data, and assessed the bias risk of the selected literature, according to the Cochrane handbook. Finally, the STATA 15.0 software was used for the meta-analysis. Results: A total of 23 RCTs involving 2,194 patients were studied, that included 12 pharmacological interventions. In terms of itching relief, compared with placebo, UDCA, methotrexate and GSK2330672 had a definite effect in improving pruritus (pruritus remission rate before and after treatment, p < 0.05). In terms of serum indexes, compared with placebo group, UDCA, OCA, rifampicin, cyclosporine, NGM282, seladelpar and colchicine may improve blood alkaline phosphatase (ALP) (p < 0.05), but only rifampicin showed low heterogeneity. UDCA, bezafibrate, OCA, rifampicin, NGM282 and others may improve blood γ-glutamyl transpeptidase (γ-GGT) (p < 0.05), but due to the high heterogeneity and the limitation of research samples, a clear conclusion cannot be drawn. In terms of adverse events, except high (>15 mg/kg/day) and low doses (<13 mg/kg/day) of UDCA increased the incidence of adverse events, there were no risk of increasing the incidence of adverse events compared with placebo (p > 0.05), and a moderate dose of UDCA (13–15 mg/kg/day) and malotilate (1,500 mg/day) may also help in reducing the incidence of adverse events (p < 0.05). Conclusion: UDCA, methotrexate and GSK2330672 may relieve itching in patients with PBC, but there is a lack of robust evidence to support their effect on ALP or γ-GGT. Due to the heterogeneity in the published studies, based on the present review, we cannot explicitly recommend any specific drug for the treatment of PBC-related pruritus. Systematic Review Registration:link-https://osf.io/2g8ya, identifier 10.17605/OSF.IO/2G8YA
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Affiliation(s)
- Chenyi Xu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Rensong Yue
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Rensong Yue,
| | - Xuelian Lv
- Xinjin Hospital of Traditional Chinese Medicine, Chengdu, China
| | - Shengnan Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mengmeng Du
- Qing Dao NO.6 People’s Hospital, Qing Dao, China
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15
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Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases. Transl Neurodegener 2022; 11:33. [PMID: 35659112 PMCID: PMC9166453 DOI: 10.1186/s40035-022-00307-z] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 05/08/2022] [Indexed: 01/08/2023] Open
Abstract
Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The neurodegenerative process is mediated by numerous metabolic pathways, most of which lead to apoptosis. In recent years, hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, with numerous experimental and clinical evidence suggesting their possible therapeutic use as disease-modifiers in neurodegenerative diseases. Experimental evidence on the mechanisms underlying TUDCA's neuroprotective action derives from animal models of Alzheimer's disease, Parkinson's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS) and cerebral ischemia. Preclinical studies indicate that TUDCA exerts its effects not only by regulating and inhibiting the apoptotic cascade, but also by reducing oxidative stress, protecting the mitochondria, producing an anti-neuroinflammatory action, and acting as a chemical chaperone to maintain the stability and correct folding of proteins. Furthermore, data from phase II clinical trials have shown TUDCA to be safe and a potential disease-modifier in ALS. ALS is the first neurodegenerative disease being treated with hydrophilic bile acids. While further clinical evidence is being accumulated for the other diseases, TUDCA stands as a promising treatment for neurodegenerative diseases.
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16
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Dervout C, Boulais N, Barnetche T, Nousbaum JB, Brenaut E, Misery L. Efficacy of Treatments for Cholestatic Pruritus: A Systemic Review and Meta-analysis. Acta Derm Venereol 2022; 102:adv00653. [PMID: 35088869 PMCID: PMC9609979 DOI: 10.2340/actadv.v102.310] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cholestatic itch is a disabling symptom that may be secondary to liver or biliary diseases. Management of cholestatic pruritus is complex. A systematic review and meta-analysis on the efficacy of treatments for cholestatic pruritus were performed. PubMed and Cochrane Library were searched using the algorithm “(hepatitis OR cholestatic OR liver) AND (pruritus OR itch) AND (management OR treatment OR treatments)” for 1975–2019. Of the 2,264 articles identified, 93 were included in a systematic review and 15 in a meta-analysis (studies evaluating pruritus with a visual analogue scale). Some treatments act by reducing levels of pruritogens in the enterohepatic cycle, others modify the metabolism or secretion of these pruritogens, or act on pruritus pathways. A further possible treatment is albumin dialysis. However, due to many heterogeneities in the reviewed studies it is difficult to identify and recommend an optimum treatment. Only 15 studies were included in the meta-analysis, due to the small number of randomized studies using a visual analogue scale.
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Affiliation(s)
| | | | | | | | - Emilie Brenaut
- Department of Dermatology, University Hospital, FR-29609 Brest, France.
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17
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Tustumi F, Pinheiro Filho JEL, Stolzemburg LCP, Serigiolle LC, Costa TN, Pajecki D, Santo MA, Nahas SC. Management of biliary stones in bariatric surgery. Ther Adv Gastrointest Endosc 2022; 15:26317745221105087. [PMID: 36388729 PMCID: PMC9664186 DOI: 10.1177/26317745221105087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 05/16/2022] [Indexed: 11/25/2022] Open
Abstract
Morbidly obese and post-bariatric surgery patients are at increased risk for
biliary stones formation. The complications related to biliary stones may impose
complexity on their management. This study aimed to review the management of
biliary conditions in obese and bariatric patients. In this study, a narrative
review was performed of the medical, surgical, and endoscopic procedures for the
management of biliary stones and their related complications. Knowing the main
prophylactic and therapeutic interventions options is essential for clinicians
to properly manage the biliary stones in patients candidates or submitted to
bariatric surgery.
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Affiliation(s)
- Francisco Tustumi
- Department of Gastroenterology, Universidade de São Paulo, Av. Dr Eneas de Carvalho Aguiar, 255, Cerqueira Cesar, São Paulo 05403-000, SP, Brazil
- Department of Surgery, Faculdade de Medicina do ABC, Santo André, Brazil
| | | | | | | | | | - Denis Pajecki
- Department of Gastroenterology, Universidade de São Paulo, São Paulo, Brazil
| | - Marco Aurélio Santo
- Department of Gastroenterology, Universidade de São Paulo, São Paulo, Brazil
| | - Sérgio Carlos Nahas
- Department of Gastroenterology, Universidade de São Paulo, São Paulo, Brazil
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18
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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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19
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Sorda JA, González Ballerga E, Barreyro FJ, Avagnina A, Carballo P, Paes de Lima A, Daruich J. Bezafibrate therapy in primary biliary cholangitis refractory to ursodeoxycholic acid: a longitudinal study of paired liver biopsies at 5 years of follow up. Aliment Pharmacol Ther 2021; 54:1202-1212. [PMID: 34587309 DOI: 10.1111/apt.16618] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/16/2020] [Accepted: 09/10/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Ursodeoxycholic acid (UDCA) is the first-line therapy for primary biliary cholangitis (PBC). However, nearly 40% of patients have an incomplete response to UDCA. The addition of bezafibrate has shown biochemical benefit in this group of patients. AIM To evaluate the long-term effects of UDCA in combination with bezafibrate on histological outcomes in patients with UDCA-refractory PBC. METHODS Fifty-nine patients refractory to UDCA were included. Clinical parameters were monitored and paired liver biopsy (PLB) was performed after 5 years of follow-up. RESULTS Of the total cohort, 49 subjects were analysed and 31 had PLB at 5 years. Values for serum ALP, AST, ALT and GGT significantly improved with UDCA-bezafibrate. This beneficial effect was observed at 12 months where 86% achieved ALP at normal levels. Analyses of PLB showed a significant decrease in liver damage as reflected by Ludwig (baseline 2.29 ± 1.2, to 1.84 ± 1 at year 5, P = 0.0242) and Ishak (baseline 6.19 ± 2.2 to 4.77 ± 2.2 at year 5, P = 0.0008) scores. Overall, regression of fibrosis was attained in 48% of patients. Furthermore, we observed a significant reduction in the proportion with cirrhosis from 19% at baseline to 3% at 5 years (P < 0.001). These beneficial effects were associated with better predictive risk scores using the GLOBE and UK-PBC prognosis models. CONCLUSIONS Adding bezafibrate to UDCA in patients with UDCA-refractory PBC showed a significant decrease in fibrosis and inflammatory histological scores at 5 years. These beneficial effects warrant further evaluation in long-term cohort studies and controlled trials.
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Affiliation(s)
- Juan Antonio Sorda
- Department of Gastroenterology and Hepatology, University Hospital "José de San Martín", Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Esteban González Ballerga
- Department of Gastroenterology and Hepatology, University Hospital "José de San Martín", Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Fernando Javier Barreyro
- Biotechnology Institute of Misiones (INBIOMIS), National University of Misiones, National Scientific and Technical Research Council (CONICET), Posadas, Argentina
| | - Alejandra Avagnina
- Department of Pathology, University Hospital "José de San Martín", Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Pilar Carballo
- Department of Pathology, University Hospital "José de San Martín", Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Andrea Paes de Lima
- Department of Pathology, University Hospital "José de San Martín", Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Jorge Daruich
- Department of Gastroenterology and Hepatology, University Hospital "José de San Martín", Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
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20
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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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21
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Shu Y, Song Y, Bai T, Pan X, Shang H, Yang L, Ye J, Du F. Predictive Model of Ursodeoxycholic Acid Treatment Response in Primary Biliary Cholangitis. J Clin Transl Hepatol 2021; 9:187-193. [PMID: 34007800 PMCID: PMC8111104 DOI: 10.14218/jcth.2020.00127] [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: 11/24/2020] [Revised: 01/21/2021] [Accepted: 02/13/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND AIMS Although ursodeoxycholic acid (UDCA) treatment in primary biliary cholangitis is effective in many patients, there are still many people who respond poorly to it. Identifying and intervening these patients early is important. Therefore, exploring the risk factors and proposing a predictor index to predict the UDCA treatment nonresponse earlier among primary biliary cholangitis patients were the aims of this research. METHODS A total of 135 primary biliary cholangitis patients treated with UDCA (13-15 mg/kg/d) were enrolled in this retrospective study. The response to treatment was evaluated based on Paris I criteria. The univariate and logistic multivariate regression analyses were adopted to determine the independent risk factors and propose a predictor index. Receiver operating characteristic curve was used to evaluate the predictive ability of the predictor index. RESULTS Total bilirubin, albumin, globulin, immunoglobin M, and aspartate aminotransferase-to-platelet ratio index were the five independent risk factors associating with early biochemical nonresponse to UDCA treatment. Based on these factors, we established a predictor index with the predictive value being 0.886 (sensitivity: 82.80%, specificity: 84.40%). CONCLUSIONS We developed a predictor index that had an accurate prediction of the early biochemical nonresponse to UDCA treatment, which is expected to provide valuable information for the high-risk group before treatment begins.
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Affiliation(s)
- Yanyun Shu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuhu Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tao Bai
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoli Pan
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Haitao Shang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jin Ye
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fan Du
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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22
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Langedijk JAGM, Beuers UH, Oude Elferink RPJ. Cholestasis-Associated Pruritus and Its Pruritogens. Front Med (Lausanne) 2021; 8:639674. [PMID: 33791327 PMCID: PMC8006388 DOI: 10.3389/fmed.2021.639674] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/12/2021] [Indexed: 12/17/2022] Open
Abstract
Pruritus is a debilitating symptom of various cholestatic disorders, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and inherited progressive familial intrahepatic cholestasis (PFIC). The molecular mechanisms leading to cholestasis-associated pruritus are still unresolved and the involved pruritogens are indecisive. As a consequence of pruritus, patients suffer from sleep deprivation, loss of daytime concentration, auto-mutilation and sometimes even suicidal ideations. Current guideline-approved therapy of cholestasis-associated pruritus includes stepwise administration of several medications, which may alleviate complaints in some, but not all affected patients. Therefore, also experimental therapeutic approaches are required to improve patients' quality of life. This article reviews the current state of research on pruritogens and their receptors, and shortly discusses the most recent experimental therapies.
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Affiliation(s)
| | | | - Ronald P. J. Oude Elferink
- Amsterdam University Medical Centers, Tytgat Institute for Liver and Intestinal Research, Research Institute Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), University of Amsterdam, Amsterdam, Netherlands
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23
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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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Xiang X, Yang X, Shen M, Huang C, Liu Y, Fan X, Yang L. Ursodeoxycholic Acid at 18-22 mg/kg/d Showed a Promising Capacity for Treating Refractory Primary Biliary Cholangitis. Can J Gastroenterol Hepatol 2021; 2021:6691425. [PMID: 33542908 PMCID: PMC7843178 DOI: 10.1155/2021/6691425] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/13/2021] [Accepted: 01/15/2021] [Indexed: 02/05/2023] Open
Abstract
Aim To compare the response between the current recommended dosage 13-15 mg/kg/d and 20 mg/kg/d dose of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) patients who do not respond completely to a standard dose of UDCA. Methods We included 73 patients with poor response and randomized them into two groups to investigate whether increasing the dosage of UDCA was beneficial to nonresponders. Patients assigned to the 13-15 mg/kg/d group continued with standard therapy, and participants in the 18-22 mg/kg/d group switched to the higher dosage (18-22 mg/kg/d), with a follow-up of 12 months for both groups. The primary endpoints were the rate of response at 6 months and drug side effects. Results According to the Paris 2 criteria, patients receiving 18-22 mg/kg/d UDCA achieved a response rate of 59.4% compared with 36.1% in the standard dosage group (P=0.046) at 6 months, respectively. At 12 months, the high-UDCA-dosage group achieved a response rate of 59.4% compared with 47.2% in the standard dosage group (P=0.295), respectively. Additionally, the risk score predicted by the UK-PBC model was lower in high-dosage UDCA-treated patients than in the standard dosage group (all P < 0.05). Side effects include diarrhea, nausea and vomiting, rash, and newly developed high blood pressure, which were mild and tolerated. Conclusions Patients treated with the high UDCA dosage showed some advantages over those who continued the standard dosage in terms of biochemical remission and disease progression, indicating that standard therapy with UDCA for 6 months and then another 1 year with high UDCA dosage for nonresponders could be a treatment option before second-line therapy is recommended.
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Affiliation(s)
- Xinyu Xiang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoli Yang
- Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Mengyi Shen
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Chen Huang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Yifeng Liu
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoli Fan
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Li Yang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
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25
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Namisaki T, Fujinaga Y, Moriya K, Yoshiji H. The association of histological progression with biochemical response to ursodeoxycholic acid in primary biliary cholangitis. Hepatol Res 2021; 51:31-38. [PMID: 33210415 DOI: 10.1111/hepr.13593] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 11/01/2020] [Accepted: 11/03/2020] [Indexed: 02/08/2023]
Abstract
Primary biliary cholangitis (PBC) is currently diagnosed at an early stage; therefore, the number of patients with PBC without symptoms at the time of diagnosis is increasing. However, up to 30% of patients with PBC exhibit the suboptimal response to ursodeoxycholic acid (UDCA) and are at high risk of end-stage liver disease. Obeticholic acid is an approved second-line therapy for patients with PBC that are refractory to UDCA. Novel surrogate endpoints are required to identify individuals eligible for second-line therapies. An inadequate biochemical response to UDCA is a useful predictor of poor outcomes in patients with PBC. In addition to UDCA effects on biochemical parameters, histological outcomes could be considered as candidate surrogate endpoints. Alterations in liver histology are used as surrogate endpoints in clinical studies. However, current staging systems are insufficient to determine PBC disease severity and progression because of the pathological heterogeneity of the disease. Histological features at baseline and biochemical response to UDCA treatment can affect the disease course of PBC. Therefore, novel surrogate endpoints must be represented by parameters characterized by histological outcomes and treatment responses in PBC. In this review, we discuss the existing histological parameters and newly created factors to identify patients with PBC who are at a high risk of developing end-stage liver disease and, consequently, the potential need for additional treatments.
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Affiliation(s)
- Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Yukihisa Fujinaga
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
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26
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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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Abstract
Neonatal cholestasis is characterized by conjugated hyperbilirubinemia in the newborn and young infant and is a sign common to over 100 hepatobiliary and/or metabolic disorders. A timely evaluation for its etiology is critical in order to quickly identify treatable causes such as biliary atresia, many of which benefit from early therapy. An expanding group of molecularly defined disorders involving bile formation, canalicular transporters, tight junction proteins and inborn errors of metabolism are being continuously discovered because of advances in genetic testing and bioinformatics. The advent of next generation sequencing has transformed our ability to test for multiple genes and whole exome or whole genome sequencing within days to weeks, enabling rapid and affordable molecular diagnosis for disorders that cannot be directly diagnosed from standard blood tests or liver biopsy. Thus, our diagnostic algorithms for neonatal cholestasis are undergoing transformation, moving genetic sequencing to earlier in the evaluation pathway once biliary atresia, "red flag" disorders and treatable disorders are excluded. Current therapies focus on promoting bile flow, reducing pruritus, ensuring optimal nutrition, and monitoring for complications, without addressing the underlying cause of cholestasis in most instances. Our improved understanding of bile formation and the enterohepatic circulation of bile acids has led to emerging therapies for cholestasis which require appropriate pediatric clinical trials. Despite these advances, the cause and optimal therapy for biliary atresia remain elusive. The goals of this review are to outline the etiologies, diagnostic pathways and current and emerging management strategies for neonatal cholestasis.
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Affiliation(s)
- Amy G. Feldman
- Pediatric Liver Center, Digestive Health Institute, Children’s Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Ronald J. Sokol
- Pediatric Liver Center, Digestive Health Institute, Children’s Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA,Colorado Clinical and Translational Sciences Institute, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA,Corresponding Author: Ronald J. Sokol, Digestive Health Institute, Children’s Hospital Colorado, Box B290, 13123 E. 16th Ave., Aurora, Colorado, 80045, USA Phone: 720-777-6669, Fax: 720-777-7277,
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28
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Simental-Mendía M, Sánchez-García A, Simental-Mendía LE. Effect of ursodeoxycholic acid on liver markers: A systematic review and meta-analysis of randomized placebo-controlled clinical trials. Br J Clin Pharmacol 2020; 86:1476-1488. [PMID: 32285958 DOI: 10.1111/bcp.14311] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 03/05/2020] [Accepted: 03/23/2020] [Indexed: 12/25/2022] Open
Abstract
AIM The objective of this meta-analysis was to evaluate the effect of ursodeoxycholic acid (UDCA) therapy on serum liver function tests. METHODS PubMed, Web of Science, Scopus and Google Scholar databases were searched to identify randomized placebo-controlled trials assessing the impact of UDCA on hepatic parameters. Meta-analysis was conducted using a random-effects model and sensitivity analysis through the leave-one-out method in the Review Manager statistical software version 5.3. RESULTS After UDCA treatment, meta-analysis revealed a significant reduction of alanine aminotransferase (weighted mean difference [WMD]: -15.28 U/L, 95% confidence interval [CI]: -23.42, -7.15, P = 0.0002, I2 = 97%), aspartate aminotransferase (WMD: -16.13 U/L, 95% CI: -23.84, -8.42, P < 0.0001, I2 = 97%), gamma-glutamyl transferase (WMD: -23.29 U/L, 95% CI: -33.97, -12.61, P < 0.0001, I2 = 97%), alkaline phosphatase (WMD: -93.80 U/L, 95% CI: -126.36, -61.25, P < 0.0001, I2 = 95%) and bilirubin (WMD: -0.18 U/L, 95% CI: -0.35, -0.01, P = 0.04, I2 = 93%), but not significant changes in albumin levels (WMD: 0.10 U/L, 95% CI: -0.05, 0.24, P = 0.18, I2 = 80%). CONCLUSION The results of the present meta-analysis suggest a hepatoprotective effect of UDCA by reducing serum liver parameters.
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Affiliation(s)
- Mario Simental-Mendía
- Department of Orthopedics and Traumatology, Hospital Universitario "Dr. José E. González", Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, NL, Mexico
| | - Adriana Sánchez-García
- Endocrinology Division, Hospital Universitario "Dr. José E. González", Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, NL, Mexico
| | - Luis E Simental-Mendía
- Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Mexico
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29
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Trivedi HD, Danford CJ, Goyes D, Bonder A. Osteoporosis in Primary Biliary Cholangitis: Prevalence, Impact and Management Challenges. Clin Exp Gastroenterol 2020; 13:17-24. [PMID: 32021374 PMCID: PMC6970242 DOI: 10.2147/ceg.s204638] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 12/31/2019] [Indexed: 12/11/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic, cholestatic condition associated with symptoms that directly impact the quality of life in those afflicted with the disease. In addition to pruritus and fatigue, patients with PBC may develop metabolic bone disease from reduced bone density, such as osteopenia and osteoporosis. Osteoporosis increases the risk of fractures, as well as morbidity and mortality. The prevalence of osteoporosis in PBC is expected to increase in conjunction with the rising prevalence of PBC as a whole. Timely diagnosis, prevention and management of osteoporosis are crucial in order to optimize the quality of life. There is a paucity of data evaluating the management of osteoporosis in PBC. The optimal timing for diagnosis and monitoring is not yet established and is guided by expert opinion. National guidelines recommend screening for osteoporosis at the time of diagnosis of PBC. Monitoring strategies are based on results of initial screening and individual risk factors for bone disease. Identifying reduced bone density is imperative to institute timely preventive and treatment strategies. However, treatment remains challenging as efficacious therapies are currently lacking. The data on treatment of osteoporosis in PBC are mostly extrapolated from postmenopausal osteoporosis literature. However, this data has not directly translated to useful treatment strategies for PBC-related osteoporosis, partly because of the different pathophysiological mechanisms of the two diseases. The lack of useful preventive measures and efficacious treatment strategies remains the largest pitfall that challenges the management of patients with PBC. In this review, we comprehensively outline the epidemiology, clinical implications and challenges, as well as management strategies of PBC-related osteoporosis.
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Affiliation(s)
- Hirsh D Trivedi
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Christopher J Danford
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Daniela Goyes
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Alan Bonder
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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de Vries E, Beuers U. Ursodeoxycholic acid in pregnancy? J Hepatol 2019; 71:1237-1245. [PMID: 31479696 DOI: 10.1016/j.jhep.2019.08.020] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Revised: 08/19/2019] [Accepted: 08/26/2019] [Indexed: 02/08/2023]
Abstract
The case of a 34-year-old woman with primary biliary cholangitis (PBC) before, during and after pregnancy is described. The use of ursodeoxycholic acid (UDCA) during and after pregnancy is discussed. UDCA has not been approved by the drug regulatory authorities as a pregnancy-safe drug; therefore, the reluctance of clinicians to prescribe UDCA during pregnancy is understandable. This Grand Round aims to provide a detailed analysis of the current evidence, safety data and clinical experience with UDCA (and alternative drugs) during pregnancy and lactation. Based on this analysis, advice for clinicians regarding the use of UDCA during pregnancy and lactation is given.
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Affiliation(s)
- Elsemieke de Vries
- Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Location AMC, Amsterdam, The Netherlands.
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31
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Baldo DC, Dellavance A, Ferraz MLG, Andrade LEC. Evolving liver inflammation in biochemically normal individuals with anti-mitochondria antibodies. AUTOIMMUNITY HIGHLIGHTS 2019; 10:10. [PMID: 32257066 PMCID: PMC7065335 DOI: 10.1186/s13317-019-0120-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 09/24/2019] [Indexed: 01/20/2023]
Abstract
Background Anti-mitochondria autoantibodies (AMA) occur in > 95% primary biliary cholangitis (PBC) patients. Biochemically normal AMA-positive (BN/AMA+) individuals, occasionally noticed by indirect immunofluorescence (IIF) on HEp-2 cells and confirmed in AMA-specific assays, may represent early stages of PBC. The Enhanced Liver Fibrosis (ELF) score is a surrogate marker for liver fibrosis. This prospective study investigated the ELF score in BN/AMA+ individuals and PBC patients, considering autoantibody avidity and serum levels along the years. Methods 327 samples from 35 PBC and 59 BN/AMA+ were prospectively obtained in average 3.83 (range 0.50-7.40) years apart. Samples were tested by IIF on rat-kidney (IIF-AMA), western-blot for AMA (WB-AMA), and ELISA for antibodies against pyruvate-dehydrogenase (PDC-E2), gp210, sp100 and CENP-A/B. Anti-PDC-E2 avidity was determined by 6 M urea-elution ELISA. Alkaline phosphatase (ALP), gamma glutamyl transferase (ɣGT) and ELF score were measured by automated methods. Results Along the follow-up period BN/AMA+ subjects and PBC patients presented significant increase in serum anti-PDC-E2 (mean 10.45% and 8.86% per year; respectively), anti-PDC-E2 avidity (3.02% and 4.94%/year) and ELF score (3.24% and 2.71%/year). IIF-AMA and ɣGT increased in BN/AMA+ (6.59% and 2.36%) and decreased in PBC (- 4.89%/year and - 3.88%/year). In BN/AMA+ individuals there was positive correlation of ELF with IIF-AMA titer (r = 0.465; p < 0.001) and with anti-PDC-E2 levels (r = 0.239; p < 0.001). Expansion of autoantibody targets along time occurred in 39% BN/AMA+ and 49% PBC patients. The frequency of BN/AMA+ with high probability of having established PBC increased from 7 to 14%. Conclusions BN/AMA+ individuals present an orchestrated increase in ELF score and humoral autoimmune response over time, indicating an opportunity for early therapeutic intervention and prevention in autoimmunity.
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Affiliation(s)
- Danielle Cristiane Baldo
- 1Rheumatology Division, Universidade Federal de São Paulo, UNIFESP, Rua Botucatu 740, São Paulo, SP 04023-900 Brazil.,Research and Development Division, Fleury Medicine and Health Laboratories, São Paulo, Brazil
| | - Alessandra Dellavance
- Research and Development Division, Fleury Medicine and Health Laboratories, São Paulo, Brazil
| | | | - Luis Eduardo C Andrade
- 1Rheumatology Division, Universidade Federal de São Paulo, UNIFESP, Rua Botucatu 740, São Paulo, SP 04023-900 Brazil
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Fujinaga Y, Namisaki T, Moriya K, Kitade M, Kawaratani H, Shimozato N, Kaji K, Takaya H, Sawada Y, Seki K, Akahane T, Okura Y, Sato S, Saikawa S, Nakanishi K, Kubo T, Furukawa M, Kitagawa K, Ozutsumi T, Tsuji Y, Kaya D, Mashitani T, Ishida K, Ogawa H, Takagi H, Noguchi R, Mitoro A, Yamao J, Yoshiji H. Identification of clinical risk factors for histological progression of primary biliary cholangitis. Hepatol Res 2019; 49:1015-1025. [PMID: 31021038 DOI: 10.1111/hepr.13355] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 04/11/2019] [Accepted: 04/12/2019] [Indexed: 02/08/2023]
Abstract
AIM To identify laboratory predictors of histological progression (HP) of primary biliary cholangitis (PBC). METHODS Sequential biopsies were carried out on 35 (11.4%) of 308 patients with PBC treated with ursodeoxycholic acid (UDCA). Patients were divided into high γ-glutamyl transpeptidase (GGT) (n = 18) and low GGT (n = 17) groups, based on the median value of GGT at baseline. Patients were then categorized as showing HP (progressive group, PG) or lacking HP (non-progressive group, NPG) according to the Scheuer and Nakanuma classifications, with the latter grading liver fibrosis (fibrosis score) and bile duct loss (BDL score). RESULTS According to the Scheuer definition, 12 patients had HP and 23 did not. According to the Nakanuma definition, 8 and 27 patients were in the PG and NPG groups, respectively. The fibrosis and BDL scores progressed in 13 and 8 patients, respectively, whereas 22 and 25 patients did not show HP, respectively. Fisher's exact probability test analysis revealed that the rate of HP using the Nakanuma fibrosis score was significantly higher in the high GGT group compared to the low GGT group (P < 0.05). However, no significant correlation was found between the HP of PBC and the biochemical response to UDCA therapy. Both univariate and multivariate logistic regression analyses indicated that the serum GGT level at baseline is an independent risk factor for an increased Nakanuma fibrosis score. CONCLUSIONS The level of serum GGT at baseline is significantly associated with liver fibrosis progression in PBC, and therefore could help to predict the HP of PBC.
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Affiliation(s)
- Yukihisa Fujinaga
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Naotaka Shimozato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Yasuhiko Sawada
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Kenichiro Seki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Takemi Akahane
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Yasushi Okura
- Department of Endoscopy, Nara Medical University, Kashihara, Japan
| | - Shinya Sato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Soichiro Saikawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Keisuke Nakanishi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Takuya Kubo
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Masanori Furukawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Koh Kitagawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Takahiro Ozutsumi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Yuki Tsuji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Daisuke Kaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Tsuyoshi Mashitani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Koji Ishida
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Hiroyuki Ogawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Hirotetsu Takagi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Ryuichi Noguchi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Akira Mitoro
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Junichi Yamao
- Department of Endoscopy, Nara Medical University, Kashihara, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
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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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Harms MH, van Buuren HR, Corpechot C, Thorburn D, Janssen HLA, Lindor KD, Hirschfield GM, Parés A, Floreani A, Mayo MJ, Invernizzi P, Battezzati PM, Nevens F, Ponsioen CY, Mason AL, Kowdley KV, Lammers WJ, Hansen BE, van der Meer AJ. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis. J Hepatol 2019; 71:357-365. [PMID: 30980847 DOI: 10.1016/j.jhep.2019.04.001] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 03/12/2019] [Accepted: 04/01/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The clinical efficacy of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) remains subject to debate as definitive randomized controlled trials are lacking. We aimed to determine whether UDCA prolongs liver transplant (LT)-free survival in patients with PBC. METHODS This international cohort study included patients from the Global PBC Study Group database, originating from 8 countries in Europe and North America. Both UDCA-treated and untreated patients were included. LT and death were assessed as a combined endpoint through Cox regression analyses, with inverse probability treatment weighting (IPTW). RESULTS In the 3,902 patients included, the mean (SD) age was 54.3 (11.9) years, 3,552 patients (94.0%) were female, 3,529 patients (90.4%) were treated with UDCA and 373 patients (9.6%) were not treated. The median (interquartile range) follow-up was 7.8 (4.1-12.1) years. In total, 721 UDCA-treated patients and 145 untreated patients died or underwent LT. After IPTW, the 10-year cumulative LT-free survival was 79.7% (95% CI 78.1-81.2) among UDCA-treated patients and 60.7% (95% CI 58.2-63.4) among untreated patients (p <0.001). UDCA was associated with a statistically significant reduced risk of LT or death (hazard ratio 0.46, 95% CI 0.40-0.52; p <0.001). The hazard ratio remained statistically significant in all stages of disease. Patients classified as inadequate biochemical responders after 1 year of UDCA had a lower risk of LT or death than patients who were not treated (adjusted hazard ratio 0.56; 95% CI 0.45-0.69; p <0.001). CONCLUSION The use of UDCA improves LT-free survival among patients with PBC, regardless of the disease stage and the observed biochemical response. These findings support UDCA as the current universal standard of care in PBC. LAY SUMMARY In this international multicenter study of 3,902 patients with primary biliary cholangitis, we found that treatment with ursodeoxycholic acid is associated with prolonged liver transplant-free survival. This association was significant, irrespective of sex, age, or disease stage. The survival benefit remained statistically significant in patients with an incomplete biochemical response to ursodeoxycholic acid therapy.
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Affiliation(s)
- Maren H Harms
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Henk R van Buuren
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Christophe Corpechot
- Centre de Référence des Maladies Inflammatoires des Voies Biliaires, Hôpital Saint-Antoine, APHP, Paris, France
| | - Douglas Thorburn
- The Sheila Sherlock Liver Centre, and UCL Institute of Liver and Digestive Health, The Royal Free Hospital, London, United Kingdom
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Francis Family Liver Clinic, Toronto General Hospital, Toronto, ON, Canada
| | - Keith D Lindor
- Arizona State University, College of Health Solutions, Phoenix, AZ, USA; Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, Francis Family Liver Clinic, Toronto General Hospital, Toronto, ON, Canada; Birmingham NIHR Biomedical Research Centre, and Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - Albert Parés
- Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Marlyn J Mayo
- Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Pietro Invernizzi
- Division of Gastroenterology and Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | | | - Frederik Nevens
- Department of Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Andrew L Mason
- Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, AB, Canada
| | - Kris V Kowdley
- Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, WA, USA
| | - Willem J Lammers
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Bettina E Hansen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands; Toronto Centre for Liver Disease, Francis Family Liver Clinic, Toronto General Hospital, Toronto, ON, Canada
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
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Lee JY, Danford CJ, Trivedi HD, Tapper EB, Patwardhan VR, Bonder A. Treatment of Fatigue in Primary Biliary Cholangitis: A Systematic Review and Meta-Analysis. Dig Dis Sci 2019; 64:2338-2350. [PMID: 30632051 DOI: 10.1007/s10620-019-5457-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 01/03/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Fatigue is the most common complication of primary biliary cholangitis (PBC) and can be debilitating. Numerous interventions have been trialed targeting several proposed mechanisms of PBC-associated fatigue. We sought to summarize and perform a meta-analysis to determine the efficacy of these interventions. METHODS A comprehensive database search was conducted from inception through March 27, 2018. The primary outcome was proportion of fatigued patients or reduction in degree of fatigue. Adverse events were a secondary outcome. We assessed studies for risk of bias, graded quality of evidence, and used meta-analysis to obtain overall effect by pooling studies of the same class. RESULTS We identified 16 studies evaluating ursodeoxycholic acid (UDCA) (7), liver transplantation (2), serotonin reuptake inhibitors (2), colchicine (1), methotrexate (1), cyclosporine (1), modafinil (1), and obeticholic acid (1). On meta-analysis, UDCA was not associated with a reduction in risk of fatigue (RR = 0.86, 95% CI 0.69-1.08, p = 0.19, I2 = 56.2%). While liver transplantation did reduce degree of fatigue (SMD - 0.57, 95% CI - 0.89 to - 0.24, p = 0.001, I2 = 67.3%), fatigue did not return to baseline indicating the underlying cause may not be addressed. CONCLUSIONS While there is some improvement in fatigue with liver transplantation, there is a lack of high-quality evidence supporting the efficacy of any other intervention in the treatment of PBC-related fatigue. Further research into the underlying pathophysiology may help guide future trials.
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Affiliation(s)
- Jennifer Y Lee
- Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA, 02215, USA
| | - Christopher J Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Dana 603, Boston, MA, 02215, USA
| | - Hirsh D Trivedi
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Dana 603, Boston, MA, 02215, USA
| | - Elliot B Tapper
- Division of Gastroenterology and Hepatology, University Hospital, University of Michigan, Floor 2, Room 2B353, 1500 E. Medical Center Dr SPC 5051, Ann Arbor, MI, 48109-5051, USA
| | - Vilas R Patwardhan
- Liver Center, Autoimmune and Cholestatic Liver Disease Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Alan Bonder
- Liver Center, Autoimmune and Cholestatic Liver Disease Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
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Samant H, Manatsathit W, Dies D, Shokouh-Amiri H, Zibari G, Boktor M, Alexander JS. Cholestatic liver diseases: An era of emerging therapies. World J Clin Cases 2019; 7:1571-1581. [PMID: 31367616 PMCID: PMC6658370 DOI: 10.12998/wjcc.v7.i13.1571] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 06/05/2019] [Accepted: 06/10/2019] [Indexed: 02/05/2023] Open
Abstract
Recently the field of cholestasis has expanded enormously reflecting an improved understanding of the molecular mechanisms underlying bile secretion and its perturbation in chronic cholestatic disease. Novel anti-cholestatic therapeutic options have been developed for patients not favorably responding to ursodeoxycholic acid (UDCA), the current standard treatment for cholestatic liver disease. Important novel treatment targets now also include nuclear receptors involved in bile acid (BA) homoeostasis like farnesoid X receptor and G protein-coupled receptors e.g., the G-protein-coupled BA receptor "transmembrane G coupled receptor 5". Fibroblast growth factor-19 and enterohepatic BA transporters also deserve attention as additional drug targets as does the potential treatment agent norUDCA. In this review, we discuss recent and future promising therapeutic agents and their potential molecular mechanisms in cholestatic liver disorders.
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Affiliation(s)
- Hrishikesh Samant
- Division of Gastroenterology and Hepatology, Department of medicine, LSU health, Shreveport, LA 71103, United States
- John C McDonald Transplant Center, Willis Knighton Medical Center, Shreveport, LA 71103, United States
| | - Wuttiporn Manatsathit
- Division of Gastroenterology and Hepatology, University of Nebraska, Omaha, NE 68194, United States
| | - David Dies
- John C McDonald Transplant Center, Willis Knighton Medical Center, Shreveport, LA 71103, United States
| | - Hosein Shokouh-Amiri
- John C McDonald Transplant Center, Willis Knighton Medical Center, Shreveport, LA 71103, United States
| | - Gazi Zibari
- John C McDonald Transplant Center, Willis Knighton Medical Center, Shreveport, LA 71103, United States
| | - Moheb Boktor
- Division of Gastroenterology and Hepatology, Department of medicine, LSU health, Shreveport, LA 71103, United States
| | - Jonathan Steve Alexander
- Department of Molecular and Cellular Physiology, Louisiana State University, School of Medicine, Shreveport, LA 71103, United States
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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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Feldman AG, Sokol RJ. Neonatal cholestasis: emerging molecular diagnostics and potential novel therapeutics. Nat Rev Gastroenterol Hepatol 2019; 16:346-360. [PMID: 30903105 DOI: 10.1038/s41575-019-0132-z] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Neonatal cholestasis is a group of rare disorders of impaired bile flow characterized by conjugated hyperbilirubinaemia in the newborn and young infant. Neonatal cholestasis is never physiological but rather is a sign of hepatobiliary and/or metabolic disorders, some of which might be fatal if not identified and treated rapidly. A step-wise timely evaluation is essential to quickly identify those causes amenable to treatment and to offer accurate prognosis. The aetiology of neonatal cholestasis now includes an expanding group of molecularly defined entities with overlapping clinical presentations. In the past two decades, our understanding of the molecular basis of many of these cholestatic diseases has improved markedly. Simultaneous next-generation sequencing for multiple genes and whole-exome or whole-genome sequencing now enable rapid and affordable molecular diagnosis for many of these disorders that cannot be directly diagnosed from standard blood tests or liver biopsy. Unfortunately, despite these advances, the aetiology and optimal therapeutic approach of the most common of these disorders, biliary atresia, remain unclear. The goals of this Review are to discuss the aetiologies, algorithms for evaluation and current and emerging therapeutic options for neonatal cholestasis.
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Affiliation(s)
- Amy G Feldman
- Pediatric Liver Center, Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, USA
| | - Ronald J Sokol
- Pediatric Liver Center, Digestive Health Institute, Children's Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, USA. .,Colorado Clinical and Translational Sciences Institute, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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Simental-Mendía LE, Simental-Mendía M, Sánchez-García A, Banach M, Serban MC, Cicero AFG, Sahebkar A. Impact of ursodeoxycholic acid on circulating lipid concentrations: a systematic review and meta-analysis of randomized placebo-controlled trials. Lipids Health Dis 2019; 18:88. [PMID: 30954082 PMCID: PMC6451779 DOI: 10.1186/s12944-019-1041-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 04/01/2019] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE The aim of this meta-analysis of randomized placebo-controlled trials was to examine whether ursodeoxycholic acid treatment is an effective lipid-lowering agent. METHODS PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched in order to find randomized controlled trials evaluating the effect of ursodeoxycholic acid on lipid profile. A random-effect model and the generic inverse variance weighting method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A random-effects meta-regression model was performed to explore the association between potential confounders and the estimated effect size on plasma lipid concentrations. RESULTS Meta-analysis of 20 treatment arms revealed a significant reduction of total cholesterol following ursodeoxycholic acid treatment (WMD: - 13.85 mg/dL, 95% CI: -21.45, - 6.25, p < 0.001). Nonetheless, LDL-C (WMD: -6.66 mg/dL, 95% CI: -13.99, 0.67, p = 0.075), triglycerides (WMD: - 1.42 mg/dL, 95% CI: -7.51, 4.67, p = 0.648) and HDL-C (WMD: -0.18 mg/dL, 95% CI: -5.23, 4.87, p = 0.944) were not found to be significantly altered by ursodeoxycholic acid administration. In the subgroup of patients with primary biliary cirrhosis, ursodeoxycholic acid reduced total cholesterol (WMD: - 29.86 mg/dL, 95% CI: -47.39, - 12.33, p = 0.001) and LDL-C (WMD: -37.27 mg/dL, 95% CI: -54.16, - 20.38, p < 0.001) concentrations without affecting TG and HDL-C. CONCLUSION This meta-analysis suggests that ursodeoxycholic acid therapy might be associated with significant total cholesterol lowering particularly in patients with primary biliary cirrhosis.
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Affiliation(s)
- Luis E Simental-Mendía
- Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Mexico, Mexico
| | - Mario Simental-Mendía
- Department of Orthopedics and Traumatology, Hospital Universitario "Dr. José E. González", Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, NL, Mexico
| | - Adriana Sánchez-García
- Endocrinology Division, Hospital Universitario "Dr. José E. González", Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, NL, Mexico
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland
- Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| | - Maria-Corina Serban
- Department of Functional Sciences, Discipline of Pathophysiology, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Arrigo F G Cicero
- Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, P.O. Box: 91779-48564, Mashhad, Iran.
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Cabrera D, Arab JP, Arrese M. UDCA, NorUDCA, and TUDCA in Liver Diseases: A Review of Their Mechanisms of Action and Clinical Applications. Handb Exp Pharmacol 2019; 256:237-264. [PMID: 31236688 DOI: 10.1007/164_2019_241] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Bile acids (BAs) are key molecules in generating bile flow, which is an essential function of the liver. In the last decades, there have been great advances in the understanding of BA physiology, and new insights have emerged regarding the role of BAs in determining cell damage and death in several liver diseases. This new knowledge has helped to better delineate the pathophysiology of cholestasis and the adaptive responses of hepatocytes to cholestatic liver injury as well as of the mechanisms of injury of biliary epithelia. In this context, therapeutic approaches for liver diseases using hydrophilic BA (i.e., ursodeoxycholic acid, tauroursodeoxycholic, and, more recently, norursodeoxycholic acid), have been revamped. In the present review, we summarize current experimental and clinical data regarding these BAs and its role in the treatment of certain liver diseases.
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Affiliation(s)
- Daniel Cabrera
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Ciencias Químicas y Biológicas, Facultad de Salud, Universidad Bernardo O'Higgins, Santiago, Chile
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
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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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Martínez J, Aguilera L, Albillos A. Risk stratification and treatment of primary biliary cholangitis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2018; 111:63-70. [PMID: 30338693 DOI: 10.17235/reed.2018.5662/2018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Primary biliary cholangitis is a chronic liver disorder characterized by progressive cholestasis that may evolve to liver cirrhosis. While ursodeoxycholic acid is the treatment of choice, around 30% of patients do not respond to this therapy. These patients have a poorer prognosis, hence should be identified early in order to be offered therapy options. Along these lines, improved understanding of the condition's pathophysiology has allowed the development of newer drugs, including obeticholic acid and fibrates. This review offers a perspective on risk stratification and treatment for these patients, from ursodeoxycholic acid to second-line treatments.
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Affiliation(s)
- Javier Martínez
- Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, España
| | | | - Agustín Albillos
- Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, España
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Abstract
Primary cholangitis (cirrhosis) is a chronic cholestatic disease with an unquestionable female predominance. It is characterised by inflammation of the small and medium size bile ducts, and can eventually progress to cirrhosis. Most patients remain asymptomatic and are diagnosed by the casual finding of an anicteric biochemical cholestasis with increased alkaline phosphatase. The pathogenesis is unknown and of presumed autoimmune origin in genetic susceptible subjects. M2-type antimitochondrial antibodies, and specific antinuclear antibodies (gp210 and Sp100) are typical and specific of the disease. The positivity of these antibodies and a biochemical cholestasis are sufficient for diagnosis, without the need for liver biopsy. Ursodeoxycholic acid is the specific treatment with an excellent response in more than 60% of patients. When this optimal response is not observed, it can be combined with new agents, but those that have shown to be effective are those that improve cholestasis such as fibrates and obeticholic acid.
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Affiliation(s)
- Albert Parés
- Unidad de Hepatología, Hospital Clinic, Universidad de Barcelona, IDIBAPS, CIBERehd, Barcelona, España.
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Santiago P, Scheinberg AR, Levy C. Cholestatic liver diseases: new targets, new therapies. Therap Adv Gastroenterol 2018; 11:1756284818787400. [PMID: 30159035 PMCID: PMC6109852 DOI: 10.1177/1756284818787400] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 06/14/2018] [Indexed: 02/04/2023] Open
Abstract
Cholestatic liver diseases result from gradual destruction of bile ducts, accumulation of bile acids and self-perpetuation of the inflammatory process leading to damage to cholangiocytes and hepatocytes. If left untreated, cholestasis will lead to fibrosis, biliary cirrhosis, and ultimately end-stage liver disease. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the two most common chronic cholestatic liver diseases affecting adults, and their etiologies remain puzzling. While treatment with ursodeoxycholic acid (UDCA) has significantly improved outcomes and prolonged transplant-free survival for patients with PBC, treatment options for UDCA nonresponders remain limited. Furthermore, there is no available medical therapy for PSC. With recent advances in molecular biochemistry specifically related to bile acid regulation and understanding of immunologic pathways, novel pharmacologic treatments have emerged. In this review, we discuss the standard of care and emphasize the various emerging treatments for PBC and PSC.
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Affiliation(s)
- Priscila Santiago
- Department of Medicine, University of Miami/Jackson Memorial Hospital
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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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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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Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C, Vincent C, Rust C, Parés A, Mason A, Marschall H, Shapiro D, Adorini L, Sciacca C, Beecher‐Jones T, Böhm O, Pencek R, Jones D. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology 2018; 67:1890-1902. [PMID: 29023915 PMCID: PMC5947631 DOI: 10.1002/hep.29569] [Citation(s) in RCA: 219] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 08/24/2017] [Accepted: 09/27/2017] [Indexed: 12/11/2022]
Abstract
UNLABELLED Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double-blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg -53.9% [-62.5, -29.3], OCA 50 mg -37.2% [-54.8, -24.6]) compared to placebo (-0.8% [-6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open-label extension treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus. CONCLUSION OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of open-label extension treatment. (Hepatology 2018;67:1890-1902).
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Affiliation(s)
| | - Velimir Luketic
- Virginia Commonwealth University and McGuire Research InstituteMcGuire DVAMCRichmondVA
| | - Roger Chapman
- Department of Gastroenterology, John Radcliffe HospitalHeadingtonOxfordUK
| | - Gideon M. Hirschfield
- Centre for Liver Research and NIHR Biomedical Research CentreUniversity of BirminghamBirminghamUK
| | | | - Christoph Schramm
- 1st Department of MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | | | - Christian Rust
- Department of Medicine 2, GrosshadernUniversity of MunichMunichGermany
| | - Albert Parés
- Liver Unit, Hospital Clinic, IDIBAPS, CIBERehdUniversity of BarcelonaBarcelonaSpain
| | - Andrew Mason
- Division of GastroenterologyUniversity of AlbertaEdmontonAlbertaCanada
| | - Hanns‐Ulrich Marschall
- Sahlgrenska AcademyDepartment of Molecular and Clinical Medicine, University of GothenburgGothenburgSweden
| | | | | | | | | | | | | | - David Jones
- Institute of Cellular MedicineNewcastle UniversityNewcastle‐upon‐TyneUK
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Floreani A, Mangini C. Primary biliary cholangitis: Old and novel therapy. Eur J Intern Med 2018; 47:1-5. [PMID: 28669591 DOI: 10.1016/j.ejim.2017.06.020] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 06/16/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023]
Abstract
Primary biliary cholangitis (PBC), formerly called primary biliary cirrhosis, is a chronic cholestatic liver disease that progresses slowly to end-stage liver disease. The first Food and Drug Administration (FDA)-approved treatment for PBC was ursodeoxycholic acid (UDCA). This treatment slows the progress of the disease, but approximatively 30-40% of patients fail to respond to UDCA. A number of options are under investigation as second line treatment. Obeticholic acid (OCA), a Farnesoid X Receptor agonist, has been approved in May 2017 by FDA for patients non responders or intolerant to UDCA. The results of a randomized, double blind, phase 3 study of OCA (mg or 10mg) compared to placebo, showed that approximatively 50% of patients reached a significant reduction in serum alkaline phosphatase, a marker predictive of disease progression, liver transplantation or death. Other emerging therapies include: agents targeting fibrosis, inflammation, or immunological response. Indeed, after 30years of UDCA therapy as unique choice for PBC patients, a number of targets, derived from a deeper knowledge of the pathophysiology of the disease, has been discovered and they offer different and new therapeutic approaches that are now under evaluation.
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Affiliation(s)
- Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy.
| | - Chiara Mangini
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy
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Parés A. Advances in treatment options for patients with primary biliary cholangitis. Expert Opin Orphan Drugs 2017. [DOI: 10.1080/21678707.2017.1394840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Albert Parés
- Liver Unit, University of Barcelona, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
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Beneficial effects of ursodeoxycholic acid via inhibition of airway remodelling, apoptosis of airway epithelial cells, and Th2 immune response in murine model of chronic asthma. Allergol Immunopathol (Madr) 2017; 45:339-349. [PMID: 28256288 DOI: 10.1016/j.aller.2016.12.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 11/19/2016] [Accepted: 12/03/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS In previous studies, anti-inflammatory, anti-apoptotic and immunomodulatory effects of ursodeoxycholic acid (UDCA) on liver diseases have been shown. In this study, we aimed to investigate the effects of UDCA on airway remodelling, epithelial apoptosis, and T Helper (Th)-2 derived cytokine levels in a murine model of chronic asthma. METHODS Twenty-seven BALB/c mice were divided into five groups; PBS-Control, OVA-Placebo, OVA-50mg/kg UDCA, OVA-150mg/kg UDCA, OVA-Dexamethasone. Mice in groups OVA-50mg/kg UDCA, OVA-150mg/kg UDCA, OVA-Dexamethasone received the UDCA (50mg/kg), UDCA (150mg/kg), and dexamethasone, respectively. Epithelium thickness, sub-epithelial smooth muscle thickness, number of mast and goblet cells of samples isolated from the lung were measured. Immunohistochemical scorings of the lung tissue for matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEG-F), transforming growth factor-beta (TGF-β), terminal deoxynucleotidyl transferase-mediated dUTP nick endlabeling (TUNEL) and cysteine-dependent aspartate-specific proteases (caspase)-3 were determined. IL-4, IL-5, IL-13, Nitric oxide, ovalbumin-specific immunoglobulin (Ig) E levels were quantified. RESULTS The dose of 150mg/kg UDCA treatment led to lower epithelial thickness, sub-epithelial smooth muscle thickness, goblet and mast cell numbers compared to placebo. Except for MMP-9 and TUNEL all immunohistochemical scores were similar in both UDCA treated groups and the placebo. All cytokine levels were significantly lower in group IV compared to the placebo. CONCLUSIONS These findings suggested that the dose of 150mg/kg UDCA improved all histopathological changes of airway remodelling and its beneficial effects might be related to modulating Th-2 derived cytokines and the inhibition of apoptosis of airway epithelial cells.
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