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Calvaruso V, Celsa C, Cristoferi L, Scaravaglio M, Smith R, Kaur S, Di Maria G, Capodicasa L, Pennisi G, Gerussi A, Nofit E, Malinverno F, Lampertico P, Cazzagon N, Marzioni M, Vespasiani-Gentilucci U, Colapietro F, Andreone P, Lleo A, Rigamonti C, Viganò M, Giannini EG, Russello M, Vanni E, Cerini F, Orlandini A, Brunetto M, Niro GA, Vettori G, Castellaneta A, Cardinale V, Alvaro D, Mega A, Palitti VP, Cossiga V, Morisco F, Bellanti F, Baiocchi L, Fabris L, Persico M, Degasperi E, Labanca S, Bonaiuto E, Pezzato F, Federico A, Petta S, Di Marco V, Mells GF, Culver E, Invernizzi P, Cammà C, Carbone M. Noninvasive Assessment of portal Hypertension in Patients With Primary Biliary Cholangitis is Affected by Severity of Cholestasis. Clin Gastroenterol Hepatol 2024:S1542-3565(24)01070-X. [PMID: 39674236 DOI: 10.1016/j.cgh.2024.10.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 10/19/2024] [Accepted: 10/22/2024] [Indexed: 12/16/2024]
Abstract
BACKGROUND & AIMS Noninvasive tests (NITs) for ruling-out clinical significant portal hypertension (CSPH) and high-risk varices (HRVs) in patients with primary biliary cholangitis (PBC) and compensated advanced chronic liver disease (cACLD) are lacking. We evaluated NITs in these patients and the influence of cholestasis on their performance. METHODS Consecutive patients from the "Italian PBC registry" and 2 United Kingdom large-volume PBC referral centers with upper endoscopy within 6 months from biochemical evaluation and transient elastography were included. Rete Sicilia Selezione Terapia (RESIST), Baveno VI (BVI), and Expanded Baveno VI (EBVI) criteria for ruling out HRV were assessed according to alkaline phosphatase (ALP) levels (< or ≥1.5 × upper limit of normal). Decision curve analysis was performed. Prevalence of any sized esophageal varices among patients fitting Baveno VII (BVII) criteria was also calculated. RESULTS The final cohort consisted of 293 patients with cACLD. RESIST criteria were associated with the lowest rate of missed HRV (2.5% vs 9.8% for BVI and 8.9% for EBVI). In patients with ALP levels ≥1.5 × upper limit of normal, BVI and EBVI missed a higher rate of HRV (15.5% and 14.5%, respectively) than RESIST (3.1%). Decision curve analysis demonstrated the highest net benefit of RESIST criteria for ruling out HRV, regardless of ALP levels. Among 75 patients classified as low risk of CSPH according to BVII, 14 (18.7%) showed esophageal varices. CONCLUSIONS Biochemical-based RESIST criteria demonstrate the highest net benefit compared with elastography-based criteria for ruling out HRV. The severity of cholestasis affects NITs performance to rule out HRV and CSPH in patients with PBC and cACLD.
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Affiliation(s)
- Vincenza Calvaruso
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy
| | - Ciro Celsa
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy
| | - Laura Cristoferi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Miki Scaravaglio
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Rachel Smith
- Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Senamjit Kaur
- Translational Gastroenterology and Liver Unit, Oxford University Hospitals NHS Foundation Trust, and NIHR Oxford Biomedical Research Centre (BRC), Oxford, United Kingdom
| | - Gabriele Di Maria
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy
| | - Luigi Capodicasa
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy
| | - Grazia Pennisi
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy
| | - Alessio Gerussi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Eugenia Nofit
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Federica Malinverno
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Nora Cazzagon
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Marco Marzioni
- Clinic of Gastroenterology, Hepatology, and Emergency Digestive Endoscopy, Università Politecnica delle Marche, Ancona, Italy
| | | | - Francesca Colapietro
- Internal Medicine and Hepatology, Humanitas Clinical and Research Center IRCCS, Humanitas University, Milan, Italy
| | - Pietro Andreone
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, Modena, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Cristina Rigamonti
- Department of Translational Medicine, Università del Piemonte Orientale, Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Mauro Viganò
- Gastroenterology Hepatology and Transplantation Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Edoardo Giovanni Giannini
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | | | - Ester Vanni
- Gastroenterology Unit, Città della Salute e della Scienza, University Hospital, Turin, Italy
| | | | - Alessia Orlandini
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Maurizia Brunetto
- Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Grazia Anna Niro
- Gastroenterology Unit, Fondazione Casa Sollievo Della Sofferenza IRCCS, San Giovanni Rotondo, Foggia, Italy
| | - Giovanni Vettori
- Gastroenterology and Endoscopy Unit, Santa Chiara Hospital, Azienda Provinciale Per I Servizi Sanitari (APSS), Trento, Italy
| | - Antonino Castellaneta
- Gastroenterology Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Bari, Italy
| | - Vincenzo Cardinale
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Andrea Mega
- Gastroenterology Unit, Bolzano Regional Hospital, Bolzano, Italy
| | | | - Valentina Cossiga
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples "Federico II", Naples, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples "Federico II", Naples, Italy
| | - Federico Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | | | - Luca Fabris
- Department of Molecular Medicine, University of Padua, and Division of General Medicine, Padua University-Hospital, Padua, Italy
| | - Marcello Persico
- Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana," University of Salerno, Baronissi, Italy
| | - Elisabetta Degasperi
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Sara Labanca
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Emanuela Bonaiuto
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Francesco Pezzato
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Alessandro Federico
- Division of Hepatogastroenterology, Department of Precision Medicine, Università della Campania "Luigi Vanvitelli", Naples, Italy
| | - Salvatore Petta
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy
| | - Vito Di Marco
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy
| | - George F Mells
- Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Emma Culver
- Translational Gastroenterology and Liver Unit, Oxford University Hospitals NHS Foundation Trust, and NIHR Oxford Biomedical Research Centre (BRC), Oxford, United Kingdom
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital and Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Calogero Cammà
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Italy.
| | - Marco Carbone
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
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Hu YF, Li SX, Liu HL, Du ZX, Wang SS, Chen MY, Wang L, Xiong QF, Zhong YD, Liu DX, Yang YF. Precirrhotic Primary Biliary Cholangitis with Portal Hypertension: Bile Duct Injury Correlate. Gut Liver 2024; 18:867-876. [PMID: 38623061 PMCID: PMC11391138 DOI: 10.5009/gnl230468] [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: 11/13/2023] [Revised: 12/20/2023] [Accepted: 01/05/2024] [Indexed: 04/17/2024] Open
Abstract
Background/Aims The histological characteristics and natural history of precirrhotic primary biliary cholangitis (PBC) with portal hypertension (PH) are unclear. Our aim was to clarify the prevalence, risk factors, and histological characteristics of precirrhotic PBC patients with PH. Methods This retrospective study compared the clinical features, histological characteristics, and response to ursodeoxycholic acid (UDCA) between the PH and non-PH groups of precirrhotic PBC patients. Results Out of 165 precirrhotic PBC patients, 40 (24.2%) also had PH. According to histological stage 1, 2 and 3 disease, 5.3% (1/19), 17.3% (17/98), and 45.8% (22/48) of patients also had PH, respectively. Precirrhotic PBC with PH was significantly positively correlated with bile duct loss, degree of cytokeratin 7 positivity, and degree of fibrosis in the portal area, but significantly negatively correlated with lymphoid follicular aggregation. Compared to the non-PH group, patients in the PH group showed a higher prevalence of obliterative portal venopathy, incomplete septal fibrosis, portal tract abnormalities and non-zonal sinusoidal dilatation (p<0.05). In addition, patients with PH were more likely to present with symptoms of jaundice, ascites, epigastric discomfort, a poorer response to UDCA, and more decompensation events (p<0.05). High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values were risk factors for precirrhotic PBC with PH. Conclusions Approximately 24.2% of precirrhotic PBC patients have PH, which is histologically related to the injury of bile ducts. High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values are associated with increased risk of precirrhotic PBC with PH.
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Affiliation(s)
- Yi-Fan Hu
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shun-Xin Li
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hong-Li Liu
- Department of Second Clinical Medical College, Southeast University School of Medicine, Nanjing, China
| | - Zhi-Xiang Du
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shuang-Shuang Wang
- Department of School of Public Health, Nanjing Medical University, Nanjing, China
| | - Miao-Yang Chen
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Li Wang
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qing-Fang Xiong
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yan-Dan Zhong
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Du-Xian Liu
- Department of Pathology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yong-Feng Yang
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, China
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Zhang Y, Lai H, Chen J, Lai R, Lin X, Lin S, Liu B, Lin Q, Wang B, Zheng Q. Clinically significant portal hypertension in patients with primary biliary cholangitis: Clinicopathological features and prognostic value. Ann Hepatol 2024; 30:101577. [PMID: 39276989 DOI: 10.1016/j.aohep.2024.101577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 07/26/2024] [Accepted: 08/21/2024] [Indexed: 09/17/2024]
Abstract
INTRODUCTION AND OBJECTIVES Primary biliary cholangitis (PBC) may progress to clinically significant portal hypertension (CSPH) before the development of cirrhosis. This study aimed to investigate CSPH incidence as well as the clinicopathological characteristics and predictive value of these features for the prognosis of patients with PBC, especially at early histologic stage. PATIENTS AND METHODS Patients diagnosed with PBC between January 2013 and April 2022 were retrospectively enrolled. The prognostic value of baseline clinicopathological characteristics for long-term outcomes in PBC patients with CSPH was assessed using Kaplan-Meier survival analysis and COX regression analysis. RESULTS Among 280 patients with PBC, 104 underwent liver biopsy and 68 were at early histologic stage. CSPH was present in 47.2 % of participants with 20.6 % at early histologic stage. CSPH was a risk factor for predicting the liver transplant-free survival in PBC patients (hazard ratio [HR], 6.78; 95 % CI, 2.94-15.63), especially those at early stage. Perisinusoidal fibrosis and nodular regenerative hyperplasia (NRH) were common histopathological features in PBC patients with CSPH at the early stages. Fibrous septa formation in the hepatic lobules (HR, 4.85; 95 % CI, 1.51-15.52) and cholestasis (HR, 7.70; 95 % CI, 2.56-23.18) were independent predictors of adverse outcomes. CONCLUSIONS CSPH indicates an increased risk of adverse outcomes in PBC patients, especially those in early histologic stage. Perisinusoidal fibrosis and NRH are valuable histological features of CSPH in patients with early-stage PBC. Identification of clinicopathological features and assessment of portal hypertension (especially at early stage), contribute to the development of personalized strategies.
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Affiliation(s)
- Ying Zhang
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, PR China; Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian Province, PR China
| | - Huaying Lai
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, PR China; Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian Province, PR China
| | - Jing Chen
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, PR China; Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian Province, PR China
| | - Ruimin Lai
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, PR China; Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian Province, PR China
| | - Xiaoyu Lin
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, PR China; Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian Province, PR China
| | - Shan Lin
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, PR China; Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian Province, PR China
| | - Bingping Liu
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, PR China; Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian Province, PR China
| | - Qiuxiang Lin
- DepartmentofHepatology, Mengchao Hepatobiliary hospital of Fujian Medical University, Fuzhou 350025, Fujian Province, PR China
| | - Bin Wang
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, PR China; Diagnostic Pathology Centre, Fujian Medical University, Fuzhou, Fujian Province, PR China; Department of Pathology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, Fujian Province, PR China.
| | - Qi Zheng
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, Fujian Province, PR China; Department of Hepatology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, Fujian Province, PR China.
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Carbone M, Gerussi A, Cardinale V, Cazzagon N, Cossiga V, Lleo A, Marrone G, Marzioni M, Moschetta A, Muratori L, Rigamonti C, Vespasiani-Gentilucci U, Fraquelli M, Calvaruso V. Position paper of the Italian Association for the Study of the Liver (AISF): Management and treatment of primary biliary cholangitis. Dig Liver Dis 2024; 56:1461-1474. [PMID: 38902184 DOI: 10.1016/j.dld.2024.05.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/26/2024] [Accepted: 05/02/2024] [Indexed: 06/22/2024]
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Rigamonti C, Cittone MG, Manfredi GF, De Benedittis C, Paggi N, Baorda F, Di Benedetto D, Minisini R, Pirisi M. Spleen stiffness measurement predicts decompensation and rules out high-risk oesophageal varices in primary biliary cholangitis. JHEP Rep 2024; 6:100952. [PMID: 38192539 PMCID: PMC10772386 DOI: 10.1016/j.jhepr.2023.100952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 10/17/2023] [Accepted: 10/17/2023] [Indexed: 01/10/2024] Open
Abstract
Background & Aims Primary biliary cholangitis (PBC) may lead to portal hypertension (PH). Spleen stiffness measurement (SSM) by vibration-controlled transient elastography accurately predicts PH. We aimed to assess SSM role in stratifying the risk of liver decompensation in PBC. Methods In this monocentric, prospective, cross-sectional study, we included 114 patients with PBC who underwent liver stiffness measurement (LSM) and SSM. In total, 78 and 33 patients underwent two and three sequential vibration-controlled transient elastography examinations, respectively (longitudinal study). Screening for high-risk oesophageal varices by oesophagogastroduodenoscopy was performed according to guidelines and proposed to all patients with SSM >40 kPa. Results Among the 114 patients, 20 (17%) had LSM ≥10 kPa, whereas 17 (15%) had SSM >40 kPa. None of the patients with SSM ≤40 kPa had high-risk oesophageal varices, compared with three of 14 patients with SSM >40 kPa (21%; three refused endoscopy); any-size oesophageal varices were found in nine of 14 patients (64%). During a median follow-up of 15 months (IQR 10-31 months), five (4%) patients developed liver decompensation. The probability of liver decompensation was significantly higher among patients with both LSM ≥10 kPa and SSM >40 kPa: 41% at 24 months vs. 0% in other patient groups (i.e. LSM <10 kPa and SSM ≤40 kPa, or LSM ≥10 kPa and SSM ≤40 kPa, or LSM <10 kPa and SSM >40 kPa) (p <0.0001). Among the 78 patients undergoing longitudinal evaluation, four of nine patients (44%) with SSM increase during follow-up experienced liver decompensation, whereas none of those with stable LSM and SSM had liver decompensation. Conclusions Both LSM and SSM predict liver decompensation in patients with PBC. SSM ≤40 kPa rules out high-risk oesophageal varices and might be used in combination with LSM to improve the prediction of PH-related complications. Impact and implications Spleen stiffness measurement by vibration-controlled transient elastography accurately predicts portal hypertension in patients with chronic viral hepatitis. The present study is the first to demonstrate that in primary biliary cholangitis the combination of liver stiffness and spleen stiffness measurement can significantly improve risk stratification by predicting liver decompensation. Moreover, when spleen stiffness is combined with liver stiffness measurement and platelet count, it aids in identifying individuals with a low probability of having high-risk oesophageal varices, thereby allowing the avoidance of unnecessary endoscopy examinations. Further validation of our results in larger cohorts of patients with primary biliary cholangitis is needed to implement spleen stiffness measurement in clinical practice.
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Affiliation(s)
- Cristina Rigamonti
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Micol Giulia Cittone
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Giulia Francesca Manfredi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Carla De Benedittis
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Noemi Paggi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Francesca Baorda
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Davide Di Benedetto
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
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Martini F, Balducci D, Mancinelli M, Buzzanca V, Fracchia E, Tarantino G, Benedetti A, Marzioni M, Maroni L. Risk Stratification in Primary Biliary Cholangitis. J Clin Med 2023; 12:5713. [PMID: 37685780 PMCID: PMC10488776 DOI: 10.3390/jcm12175713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/25/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Primary Biliary Cholangitis (PBC) is a chronic cholestatic liver disease with a heterogeneous presentation, symptomatology, disease progression, and response to therapy. The current risk stratification assessment, aimed at identifying patients with a higher risk of disease progression, encompasses an in-depth analysis of demographic data, clinical and laboratory findings, antibody profiles, and the evaluation of liver fibrosis using both invasive and noninvasive techniques. Treatment response scores after one year of therapy remain to date a major factor influencing the prognosis of PBC patients. While the initial therapeutic approach with ursodeoxycholic acid (UDCA) is universally applied, new second-line treatment options have recently emerged, with many others under investigation. Consequently, the prevailing one-size-fits-all approach is poised to be supplanted by tailored strategies, ensuring high-risk patients receive the most appropriate treatment regimen from diagnosis. This will require the development of a risk prediction model to assess, at the time of diagnosis, the course, outcome, and response to first and additional treatments of PBC patients. This manuscript provides a comprehensive overview of the current and emerging tools used for risk stratification in PBC and speculates on how these developments might shape the disease landscape in the near future.
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Affiliation(s)
- Francesco Martini
- Clinic of Gastroenterology, Hepatology, and Emergency Digestive Endoscopy, Università Politecnica delle Marche, 60126 Ancona, Italy; (D.B.); (M.M.); (V.B.); (E.F.); (G.T.); (A.B.); (M.M.); (L.M.)
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Bhan I, Schaefer EA, Bradley WR, Rodriguez-Lopez JM, Crowley JC, Hutchison B. Case 4-2023: A 56-Year-Old Man with Abnormal Results on Liver Testing. N Engl J Med 2023; 388:544-554. [PMID: 36780679 DOI: 10.1056/nejmcpc2201249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Affiliation(s)
- Irun Bhan
- From the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Harvard Medical School - both in Boston
| | - Esperance A Schaefer
- From the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Harvard Medical School - both in Boston
| | - William R Bradley
- From the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Harvard Medical School - both in Boston
| | - Josanna M Rodriguez-Lopez
- From the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Harvard Medical School - both in Boston
| | - Jerome C Crowley
- From the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Harvard Medical School - both in Boston
| | - Bailey Hutchison
- From the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Massachusetts General Hospital, and the Departments of Medicine (I.B., E.A.S., J.M.R.-L.), Radiology (W.R.B.), Anesthesia (J.C.C.), and Pathology (B.H.), Harvard Medical School - both in Boston
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8
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Gender and Autoimmune Liver Diseases: Relevant Aspects in Clinical Practice. J Pers Med 2022; 12:jpm12060925. [PMID: 35743710 PMCID: PMC9225254 DOI: 10.3390/jpm12060925] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 05/25/2022] [Accepted: 05/28/2022] [Indexed: 12/12/2022] Open
Abstract
Autoimmune liver diseases (AILDs) include autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis. The etiologies of AILD are not well understood but appear to involve a combination of genetic and environmental factors. AILDs commonly affect young individuals and are characterized by a highly variable clinical course. These diseases significantly influence quality of life and can progress toward liver decompensation or the onset of hepatocellular or cholangiocarcinoma; a significant number of patients eventually progress to end-stage liver disease, requiring liver transplantation. In this review, we focus on the sex characteristics and peculiarities of AILD patients and highlight the relevance of a sex-specific analysis in future studies. Understanding the sex differences underlying AILD immune dysregulation may be critical for developing more effective treatments.
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9
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Yan Y, Xing X, Wang X, Yang L. Liver stiffness by two-dimensional shear wave elastography for screening high-risk varices in patients with compensated advanced chronic liver disease. Eur Radiol 2022; 32:2078-2088. [PMID: 34713329 DOI: 10.1007/s00330-021-08280-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/03/2021] [Accepted: 08/17/2021] [Indexed: 02/05/2023]
Abstract
OBJECTIVES To investigate the usefulness of the criteria with liver stiffness (LS) measured by two-dimensional shear wave elastography (2D-SWE) and platelet count (PLT) for ruling out high-risk varices in patients with compensated advanced chronic liver disease (cACLD). METHODS A total of 661 patients with cACLD had successfully undergone 2D-SWE and endoscopy screening. We analyzed risk factors for the presence of high-risk varices and compared proportions of patients who were spared endoscopy when used the predicting criteria with LS (ranged from 16 to 25 kPa) and PLT (ranged from 80 × 109/L to 150 × 109/L). RESULTS PLT, albumin, LS were found to be independent predictors of high-risk varices. The LS values for ruling out and ruling in high-risk varices were 14.0 kPa and 24.8 kPa, respectively. When the Baveno VI criteria LS < 20 kPa and PLT > 150 × 109/L were used, the high-risk varices miss rate was 2.1%, while the saved endoscopy rate only was 19.2%. The new criteria that LS < 16 kPa and PLT > 100 × 109/L saved 30.4-34.6% endoscopy with 0-3.2% high-risk varices miss rate in the subgroup analysis stratified according to the types of underlying liver disease. CONCLUSIONS The Baveno VI criteria can be applied to LS measurement by 2D-SWE. The new criteria that LS < 16 kPa and PLT > 100 × 109/L could be a potential model to spare more endoscopy screening with < 5% high-risk varices miss rate. KEY POINTS • LS measured by 2D-SWE is reliable predictive factor for predicting all-size varices and high-risk varices in patients with compensated advanced chronic liver disease. • LS measured by 2D-SWE < 16 kPa and PLT > 100 × 109 /L, which can spare more endoscopy than Baveno VI criteria with < 5% high-risk varices miss rate. • The Baveno VI criteria can be applied to LS measurement by 2D-SWE.
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Affiliation(s)
- Yuling Yan
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, 37 Guoxue Lane, Chengdu, 610041, People's Republic of China
- Sichuan University-University of Oxford Huaxi Joint for Gastrointestinal Cancer Centre, Chengdu, People's Republic of China
| | - Xian Xing
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, 37 Guoxue Lane, Chengdu, 610041, People's Republic of China
- Sichuan University-University of Oxford Huaxi Joint for Gastrointestinal Cancer Centre, Chengdu, People's Republic of China
| | - Xiaoze Wang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, 37 Guoxue Lane, Chengdu, 610041, People's Republic of China
- Sichuan University-University of Oxford Huaxi Joint for Gastrointestinal Cancer Centre, Chengdu, People's Republic of China
| | - Li Yang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, 37 Guoxue Lane, Chengdu, 610041, People's Republic of China.
- Sichuan University-University of Oxford Huaxi Joint for Gastrointestinal Cancer Centre, Chengdu, People's Republic of China.
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10
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Moharm AEA, El-Kalla FSED, Kobtan AA, Elkhalawany WA. Combination of Albumin-Bilirubin Grade and Platelet Count as a Predictor of Esophageal Varices’ Presence and Grading in Egyptian Patients with HCV Related Cirrhosis. THE OPEN BIOMARKERS JOURNAL 2022; 12. [DOI: 10.2174/18753183-v12-2112230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 11/09/2021] [Accepted: 11/25/2021] [Indexed: 01/04/2025]
Abstract
Background:
Screening guidelines recommend that all patients who are newly diagnosed with cirrhosis should be screened for esophageal varices (EV). This study aimed at predicting the presence of esophageal varices among Egyptian hepatitis C cirrhotic patients by a combination of albumin-bilirubin grade and platelet count score (ALBI-Platelet score).
Methods:
This study was performed on 150 cirrhotic patients. Eighty- seven patients with hepatitis C virus (HCV) related cirrhosis and esophageal varices formed Group (A), while Group (B) consisted of sixty-three patients with HCV related cirrhosis and no esophageal varices. Full metabolic profile, Complete blood count (CBC), ultrasonography, and endoscopy were done.
Results:
There was a significant difference between studied groups regarding serum bilirubin, serum albumin and platelet count. The cutoff point of platelets count as a predictor for esophageal varices among studied groups was <154.5. The cutoff value for albumin-bilirubin (ALBI) score as a predictor for esophageal varices of any size was -1.67 with 52.9% sensitivity, 59.6% specificity, 47% negative predictive value (NPV) and 64% positive predictive value (PPV). The ALBI-Plt score >3 had 42.5%, specificity 63.5%, negative predictive value 40% and positive predictive value 65%. The cutoff value for the ALBI score representing large-sized esophageal varices was -1.27. The ALBI-Plt score >4 for large-sized varices had sensitivity 61.9%, specificity 55%, negative predictive value 59%, positive predictive value 50%.
Conclusion:
ALBI-Platelet score is a non-costly, readily available and reliable new non-invasive predictor of the presence of EV that could easily be used in screening for the presence of esophageal varices and risky large-sized esophageal varices in cases of hepatitis C Virus related hepatic cirrhosis, lessening the need for endoscopic screening.
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11
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Warnes TW, Roberts SA, Smith A, Cope VM, Vales P, Haboubi NY, McMahon RF. Portal hypertension in primary biliary cholangitis: prevalence, natural history and histological correlates. Eur J Gastroenterol Hepatol 2021; 33:1595-1602. [PMID: 33323761 DOI: 10.1097/meg.0000000000002033] [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] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The histopathological mechanisms underlying portal hypertension in primary biliary cholangitis (PBC) are poorly understood, as is its natural history. We have therefore determined the prevalence, severity and progression of portal hypertension in PBC and investigated whether its presence is related to specific histological lesions. METHODS Hepatic venous pressure gradient (HVPG) was measured in 86 patients, with 186 assessments over up to 7 years of follow-up and the results correlated with a semiquantitative grading of 8 histological features and nodular regenerative hyperplasia (NRH). RESULTS Portal hypertension (HVPG >5 mmHg) was present in 88% of all assessments (86% at baseline), and in 45% of patients at baseline was >12 mmHg (high-risk portal hypertension). The rise in portal pressure occurs early in the disease, since 45% of patients with normal serum bilirubin had a raised HVPG, as did 72% of patients with early (Ludwig stages 1 and 2) disease. After baseline, there was a small increase in HVPG over the next 5 years in most patients. In patients with precirrhotic PBC, 82% had portal hypertension and in 34% this was >12 mmHg. Portal pressure correlated significantly with a semiquantitative grading of cholestasis, interface hepatitis and portal tract and sinusoidal fibrosis. NRH was present in only 20% of wedge biopsies. CONCLUSIONS Portal hypertension commences in the early stages of PBC, long preceding both rises in serum bilirubin and the development of cirrhosis. Around 34% of precirrhotic PBC patients have 'high-risk' portal hypertension, which is associated with lesions in the portal tracts and sinusoids rather than with NRH.
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Affiliation(s)
- Thomas W Warnes
- Liver Unit, Department of Gastroenterology, Manchester Royal Infirmary
| | - Stephen A Roberts
- Centre of Biostatistics, School of Health Sciences, Manchester Academic Health Science Centre, University of Manchester
| | - Alexander Smith
- Liver Unit, Department of Gastroenterology, Manchester Royal Infirmary
| | | | - Patricia Vales
- Department of Medical Physics, Manchester Royal Infirmary
| | | | - Raymond F McMahon
- Department of Histopathology, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK
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12
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Yan Y, Xing X, Lu Q, Wang X, Men R, Luo X, Yang L. Two-dimensional shear wave elastography for screening varices in Asian patients with primary biliary cholangitis. Expert Rev Gastroenterol Hepatol 2021; 15:965-973. [PMID: 33513034 DOI: 10.1080/17474124.2021.1884071] [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: 07/07/2020] [Accepted: 01/28/2021] [Indexed: 02/08/2023]
Abstract
Objectives: The presence of varices affects the survival of patients with primary biliary cholangitis (PBC). The aim of this study is to assess the criteria based on liver stiffness (LS) measured by two-dimensional shear wave elastography (2D-SWE) and platelet count (PLT), and recently published noninvasive models for triaging PBC patients.Methods: 231 patients with PBC who underwent EGD and 2D-SWE examination were enrolled. Areas under the receiver-operating characteristic curve (AUROC) were used to assess the performance of 2D-SWE for predicting all-size varices and high-risk varices. All-size varices and high-risk varices miss rate < 10% and <5%, respectively, were acceptable for screening varices.Results: The AUROCs of LS for predicting all-size varices and high-risk varices were 0.87 (95%CI: 0.82-0.91) and 0.84 (95%CI: 0.74-0.86), respectively. LS <25 kPa and PLT >110 × 109/L spared 46.3% EGD screening, with 3.7% high-risk varices miss rate and 8.4% all-size varices miss rate. One hundred and sixteen (50.2%) patients met the Newcastle varices in PBC score (cutoff, 0.5), with 4.3% high-risk varices miss rate and 11.2% all-size varices miss rate.Conclusion: The criteria based on LS and PLT are useful for triaging PBC patients. LS <25 kPa and PLT >110 × 109/L could be the optimal criteria for screening varices.
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Affiliation(s)
- Yuling Yan
- Sichuan University-University of Oxford Huaxi Joint for Gastrointestinal Cancer Centre, Sichuan University, Chengdu, Sichuan, China
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xian Xing
- Sichuan University-University of Oxford Huaxi Joint for Gastrointestinal Cancer Centre, Sichuan University, Chengdu, Sichuan, China
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qiang Lu
- Department of Ultrasound, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoze Wang
- Sichuan University-University of Oxford Huaxi Joint for Gastrointestinal Cancer Centre, Sichuan University, Chengdu, Sichuan, China
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ruoting Men
- Sichuan University-University of Oxford Huaxi Joint for Gastrointestinal Cancer Centre, Sichuan University, Chengdu, Sichuan, China
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xuefeng Luo
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Li Yang
- Sichuan University-University of Oxford Huaxi Joint for Gastrointestinal Cancer Centre, Sichuan University, Chengdu, Sichuan, China
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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13
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Chang PE, Tan CK, Cheah CC, Li W, Chow WC, Wong YJ. Validation of the Expanded Baveno-VI Criteria for Screening Gastroscopy in Asian Patients with Compensated Advanced Chronic Liver Disease. Dig Dis Sci 2021; 66:1343-1348. [PMID: 32440746 DOI: 10.1007/s10620-020-06334-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 05/08/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND The expanded Baveno-VI criteria may further reduce the need for screening gastroscopy compared to Baveno-VI criteria. AIM We sought to validate the performance of these criteria in a cohort of compensated advanced chronic liver disease (cACLD) patients with predominantly hepatitis B infection. METHODS Consecutive cACLD patients from 2006 to 2012 with paired liver stiffness measurements and screening gastroscopy within 1 year were included. The expanded Baveno-VI criteria were applied to evaluate the sensitivity (SS), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) for the presence of high-risk varices (HRV). RESULTS Among 165 cACLD patients included, 17 (10.3%) had HRV. The commonest etiology of cACLD was chronic hepatitis B (36.4%) followed by NAFLD (20.0%). Application of expanded Baveno-VI criteria avoided more screening gastroscopy (43.6%) as compared to the original Baveno-VI criteria (18.8%) without missing more HRV (1 with both criteria). The overall SS, SP, PPV and NPV of the expanded Baveno-VI criteria in predicting HRV were 94.1%, 48.0%, 17.2% and 98.6%, respectively. CONCLUSION Application of the expanded Baveno-VI criteria can safely avoid screening gastroscopy in 43.6% of cACLD patients with an excellent ability to exclude HRV.
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Affiliation(s)
- Pik-Eu Chang
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
| | - Chee-Kiat Tan
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
| | - Chang-Chuen Cheah
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
| | - Weiquan Li
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore
| | - Wan Cheng Chow
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
| | - Yu-Jun Wong
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore.
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14
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Leung KK, Deeb M, Hirschfield GM. Review article: pathophysiology and management of primary biliary cholangitis. Aliment Pharmacol Ther 2020; 52:1150-1164. [PMID: 32813299 DOI: 10.1111/apt.16023] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/13/2020] [Accepted: 07/18/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC), an immune-mediated disease characterised by destruction of intrahepatic bile ducts, results in progressive damage to the biliary tree, cholestasis and ultimately advanced liver disease. In the last decade, advances in practice have improved clinical care, driven novel therapeutic options and improved risk stratification tools. AIMS To provide an overview of the disease characteristics of PBC and review a patient-centred management approach for the clinical team caring for those with PBC. METHODS We reviewed the current literature and guidelines on PBC with a focus on management and therapies. RESULTS A confident diagnosis of PBC is usually made based on serum liver tests and immune serology. Management of PBC should focus on three main 'process' pillars: (a) treat and risk-stratify through use of biochemical and prognostic criteria; (b) manage concurrent symptoms and other associated diseases; and (c) stage disease, monitor progression and prevent complications. With ongoing complexities in management, including a newly licensed therapy (obeticholic acid) and alternative non-licensed treatments and ongoing clinical trials, discussion with PBC expert centres is encouraged. CONCLUSIONS PBC is a dynamic disease wherein current treatment goals have become appropriately ambitious. Goals of care should prioritise prevention of end-stage liver disease and amelioration of patient symptom burden for all.
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Affiliation(s)
- Kristel K Leung
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada.,Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Maya Deeb
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada.,Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Gideon M Hirschfield
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON, Canada.,Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
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15
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Dalekos GN, Gatselis NK. Variant and Specific Forms of Autoimmune Cholestatic Liver Diseases. Arch Immunol Ther Exp (Warsz) 2019; 67:197-211. [PMID: 31165900 DOI: 10.1007/s00005-019-00550-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Accepted: 05/31/2019] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the main autoimmune cholestatic liver diseases. IgG4-associated sclerosing cholangitis is another distinct immune-mediated cholestatic disorder of unknown aetiology that is frequently associated with autoimmune pancreatitis or other IgG4-related diseases. Although the majority of PBC and PSC patients have a typical presentation, there are common and uncommon important variants or specific subgroups that observed in everyday routine clinical practice. In this updated review, we summarize the published data giving also our own experience on the variants and specific groups of autoimmune cholestatic liver diseases. Actually, we give in detail the underlining difficulties and the rising dilemmas concerning the diagnosis and management of these special conditions in the clinical spectrum of autoimmune cholestatic liver diseases including the IgG4-associated sclerosing cholangitis highlighting also the uncertainties and the potential new eras of the research agenda.
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Affiliation(s)
- George N Dalekos
- Institute of Internal Medicine and Hepatology, Larissa, Greece.
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, 41110, Larissa, Greece.
| | - Nikolaos K Gatselis
- Institute of Internal Medicine and Hepatology, Larissa, Greece
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, 41110, Larissa, Greece
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16
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Non-Invasive Prediction of High-Risk Varices in Patients with Primary Biliary Cholangitis and Primary Sclerosing Cholangitis. Am J Gastroenterol 2019; 114:446-452. [PMID: 30315285 DOI: 10.1038/s41395-018-0265-7] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Baveno-VI guidelines recommend that patients with compensated cirrhosis with liver stiffness by transient elastography (LSM-TE) <20 kPa and platelets >150,000/mm(3) do not need an esophagogastroduodenoscopy (EGD) to screen for varices, since the risk of having varices needing treatment (VNT) is <5%. It remains uncertain if this tool can be used in patients with cholestatic liver diseases (ChLDs): primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). These patients may have a pre-sinusoidal component of portal hypertension that could affect the performance of this rule. In this study we evaluated the performance of Baveno-VI, expanded Baveno-VI (LSM-TE <25 kPa and platelets >110,000/mm(3)), and other criteria in predicting the absence of VNT. METHODS This was a multicenter cross-sectional study in four referral hospitals. We retrospectively analyzed data from 227 patients with compensated advanced chronic liver disease (cACLD) due to PBC (n = 147) and PSC (n = 80) that had paired EGD and LSM-TE. We calculated false negative rate (FNR) and number of saved endoscopies for each prediction rule. RESULTS Prevalence of VNT was 13%. Baveno-VI criteria had a 0% FNR in PBC and PSC, saving 39 and 30% of EGDs, respectively. In PBC the other LSM-TE-based criteria resulted in FNRs >5%. In PSC the expanded Baveno criteria had an adequate performance. In both conditions LSM-TE-independent criteria resulted in an acceptable FNR but saved less EGDs. CONCLUSIONS Baveno-VI criteria can be applied in patients with cACLD due to ChLDs, which would result in saving 30-40% of EGDs. Expanded criteria in PBC would lead to FNRs >5%.
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18
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Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology 2019; 69:394-419. [PMID: 30070375 DOI: 10.1002/hep.30145] [Citation(s) in RCA: 402] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 05/30/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Keith D Lindor
- Arizona State University, Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ
| | | | | | | | - Marlyn Mayo
- University of Texas Southwestern Medical Center, Dallas, TX
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19
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Hirschfield GM, Dyson JK, Alexander GJM, Chapman MH, Collier J, Hübscher S, Patanwala I, Pereira SP, Thain C, Thorburn D, Tiniakos D, Walmsley M, Webster G, Jones DEJ. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut 2018; 67:1568-1594. [PMID: 29593060 PMCID: PMC6109281 DOI: 10.1136/gutjnl-2017-315259] [Citation(s) in RCA: 218] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 01/22/2018] [Accepted: 01/23/2018] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.
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Affiliation(s)
- Gideon M Hirschfield
- NIHR Birmingham Biomedical Research Centre, Birmingham, UK
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Jessica K Dyson
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom
| | - Graeme J M Alexander
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
| | - Michael H Chapman
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Jane Collier
- Translational Gastroenterology Unit, Oxford University Hospitals, University of Oxford, Oxford, UK
| | - Stefan Hübscher
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Imran Patanwala
- Department of Gastroenterology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
- University of Liverpool, Liverpool, UK
| | - Stephen P Pereira
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | | | - Douglas Thorburn
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
| | - Dina Tiniakos
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | | | - George Webster
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | - David E J Jones
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom
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Abstract
Patients with primary biliary cholangitis (PBC) are at risk for various harmful consequences of chronic cholestasis. These include fat-soluble vitamin deficiency, even in the setting of macronutrient sufficiency, as well as metabolic bone disease, including osteoporosis with fractures. Hyperlipidemia is often present and less commonly associated with risk of cardiovascular event; however, the long-term effect of new emerging therapies for PBC remains to be determined. Patients with PBC also have infrequent but notable risk of portal hypertension despite early-stage disease. This review discusses the background, evaluation, and practical management of these complications of chronic cholestasis.
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Affiliation(s)
- David N Assis
- Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street, 1080 LMP, New Haven, CT 06510, USA.
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21
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Abstract
Primary biliary cholangitis (PBC) is a chronic progressive cholestatic disease characterized by destruction of small- and medium-sized intrahepatic bile ducts. It is no longer a rare disease, since many new asymptomatic cases are incidentally identified. Liver biopsy is diagnostically critical but not always feasible or practical to be performed. Many potential, noninvasive, markers have been proposed to replace liver biopsy and further provide the assessment of disease severity and ultimate prognosis. In this review, we evaluated serum biomarkers proposed for diagnosis, extent of fibrosis, disease prognosis and attempts for early prediction of treatment response. Older biochemical and immunological markers are presented along with recent reports including the role of microRNAs and promising results based on proteomics and metabolomics.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, University Hospital and Medical School, University of Crete, Heraklion, Crete, Greece
| | - Demetrius Samonakis
- Department of Gastroenterology, University Hospital of Heraklion, Crete, Greece
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Khanna A, Leighton J, Lee Wong L, Jones DE. Symptoms of PBC - Pathophysiology and management. Best Pract Res Clin Gastroenterol 2018; 34-35:41-47. [PMID: 30343709 DOI: 10.1016/j.bpg.2018.06.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 06/08/2018] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis is a chronic cholestatic liver disease characterised by progressive bile duct damage and, ultimately, biliary cirrhosis. Though up to fifty percent of the patients can be asymptomatic at presentation, symptoms when present are frequently debilitating with significant impact on quality of life and functional status. Characteristic symptoms include pruritus, fatigue and an increasingly recognised mild cognitive impairment. With the exception of pruritus, the "classic" cholestatic symptom, therapeutic options to treat PBC related symptoms are currently limited leaving patients with often significant residual problems. Symptoms can frequently contribute to depression and social isolation further compounding the quality of life impairment. There is need to better understand the current therapeutic options available in order to optimise their use, and to explore newer avenues to understand the pathophysiology of the symptom-generating processed in PBC in order to develop new therapies.
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Affiliation(s)
- Amardeep Khanna
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; NIHR Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK.
| | - Jess Leighton
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
| | - Lin Lee Wong
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; NIHR Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK.
| | - David E Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; NIHR Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK.
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Patterns of disease progression and incidence of complications in primary biliary cholangitis (PBC). Best Pract Res Clin Gastroenterol 2018; 34-35:71-83. [PMID: 30343713 DOI: 10.1016/j.bpg.2018.06.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 06/08/2018] [Indexed: 02/07/2023]
Abstract
Clinical outcome for patients with primary biliary cholangitis (PBC) is dictated by development of cirrhosis, portal hypertension and its associated complications; including for some, a predisposition toward hepatocellular carcinoma. However rates of clinical progression vary, and accurately identifying disease course is of critical importance to patients, clinicians, as well as industry, who are committed to developing new effective and life-prolonging therapy as well as treating symptoms that appear disproportionate to underlying disease severity. Patients seek reassurance and guidance as to their own prognosis, and clinicians wish to confidently recognise those at highest risk of poor outcomes as equally as they strive to reassure individuals with a more favourable disease trajectory. International registries have facilitated a much greater knowledge of disease incidence and heterogeneity of presenting phenotypes. In so doing they highlight the opportunity to provide a more individualized estimate of the clinical course that patients experience, and have led to a renewed approach to risk stratification; both in terms of 'hard outcomes' and also disease-associated complications in PBC specifically.
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Khanna A, Jones DE. Novel strategies and therapeutic options for the management of primary biliary cholangitis. Therap Adv Gastroenterol 2017; 10:791-803. [PMID: 29051789 PMCID: PMC5638183 DOI: 10.1177/1756283x17728669] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 07/25/2017] [Indexed: 02/04/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease. It has a varied course of progression ranging from being completely asymptomatic to aggressive disease leading to cirrhosis and resulting in liver transplantation. In addition, symptoms can be debilitating and can have a major impact on quality of life. For decades, there was only one anti-cholestatic agent available to target this disease and that was only effective in around half of patients, with little or no effect on symptoms. With increasing understanding of the pathogenic mechanisms of PBC and potential targets for drug treatment, pharmaceutical companies have shown a greater interest in this rare disease. A large number of novel therapeutic molecules have been developed and are currently being evaluated. In this review article all the novel molecules in use and in trials targeting cholestasis and symptoms in PBC are discussed.
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Affiliation(s)
| | - David E. Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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25
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Hirschfield GM, Beuers U, Corpechot C, Invernizzi P, Jones D, Marzioni M, Schramm C. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017; 67:145-172. [PMID: 28427765 DOI: 10.1016/j.jhep.2017.03.022] [Citation(s) in RCA: 883] [Impact Index Per Article: 110.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 03/23/2017] [Indexed: 02/07/2023]
Abstract
Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune cholestatic liver disease, which when untreated will culminate in end-stage biliary cirrhosis. Diagnosis is usually based on the presence of serum liver tests indicative of a cholestatic hepatitis in association with circulating antimitochondrial antibodies. Patient presentation and course can be diverse and risk stratification is important to ensure all patients receive a personalised approach to their care. The goals of treatment and management are the prevention of end-stage liver disease, and the amelioration of associated symptoms. Pharmacologic approaches in practice, to reduce the impact of the progressive nature of disease, currently include licensed therapies (ursodeoxycholic acid and obeticholic acid) and off-label therapies (fibric acid derivatives, budesonide). These clinical practice guidelines summarise the evidence for the importance of a structured, life-long and individualised, approach to the care of patients with PBC, providing a framework to help clinicians diagnose and effectively manage patients.
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Gao L, Meng F, Cheng J, Li H, Han J, Zhang W. Prediction of oesophageal varices in patients with primary biliary cirrhosis by non-invasive markers. Arch Med Sci 2017; 13:370-376. [PMID: 28261290 PMCID: PMC5332465 DOI: 10.5114/aoms.2017.65450] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 02/25/2015] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Preliminary data suggested that non-invasive methods could be useful to assess presence of oesophageal varices (OV) in liver cirrhosis. The primary objectives were to investigate non-invasive markers for diagnosing and grading OV in patients with primary biliary cirrhosis. MATERIAL AND METHODS This study included a total of 106 consecutive treatment-naive patients with primary biliary cirrhosis (PBC). Results of physical examination, blood tests, and abdominal ultrasound scan (USS) were measured. Performance of non-invasive markers for OV was expressed as sensitivity, specificity, positive, and negative predictive values (PPV, NPV), accuracy, and area under the curve (AUC). RESULTS Oesophageal varices were found in 54 (50.9%) and large OV in 28 of the 106 patients. Variables found to differ significantly between patients with any grade or large and without OV included increased spleen length, increased portal vein diameter, low platelet count, and low levels of albumin or low γ-glutamyltranspeptidase (γ-GTP) values. Area under the receiver operating characteristic curve showed that spleen length (cutoff = 156.0) had AUC 0.753 (95% CI: 0.657-0.849), and high NPV (82.1%) to exclude any grade OV. Large OV could be excluded with NPV 70.6% by spleen length. CONCLUSIONS Predictive risk factors that use readily available laboratory results and ultrasound scan results may reliably identify esophageal varices in patients with PBC.
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Affiliation(s)
- Lili Gao
- Department of General Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Fanping Meng
- Center for Liver Cirrhosis, Beijing 302 Hospital, Beijing, China
| | - Jun Cheng
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Hanwei Li
- Center for Liver Cirrhosis, Beijing 302 Hospital, Beijing, China
| | - Jun Han
- Center for Liver Cirrhosis, Beijing 302 Hospital, Beijing, China
| | - Weihui Zhang
- Center for Liver Cirrhosis, Beijing 302 Hospital, Beijing, China
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Stasi C, Milani S. Evolving strategies for liver fibrosis staging: Non-invasive assessment. World J Gastroenterol 2017; 23:191-196. [PMID: 28127192 PMCID: PMC5236498 DOI: 10.3748/wjg.v23.i2.191] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 10/22/2016] [Accepted: 12/08/2016] [Indexed: 02/06/2023] Open
Abstract
Transient elastography and the acoustic radiation force impulse techniques may play a pivotal role in the study of liver fibrosis. Some studies have shown that elastography can detect both the progression and regression of fibrosis. Similarly, research results have been analysed and direct and indirect serum markers of hepatic fibrosis have shown high diagnostic accuracy for advanced fibrosis/cirrhosis. The prognosis of different stages of cirrhosis is well established and various staging systems have been proposed, largely based on clinical data. However, it is still unknown if either non-invasive markers of liver fibrosis or elastography may contribute to a more accurate staging of liver cirrhosis, in terms of prognosis and fibrosis regression after effective therapy. In fact, not enough studies have shown both the fibrosis regression in different cirrhosis stages and the point beyond which the prognosis does not change - even in the event of fibrosis regression. Therefore, future studies are needed to validate non-invasive methods in predicting the different phases of liver cirrhosis.
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28
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Patel A, Seetharam A. Primary Biliary Cholangitis: Disease Pathogenesis and Implications for Established and Novel Therapeutics. J Clin Exp Hepatol 2016; 6:311-318. [PMID: 28003721 PMCID: PMC5157913 DOI: 10.1016/j.jceh.2016.10.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 10/10/2016] [Indexed: 02/07/2023] Open
Abstract
Primary Biliary Cholangitis is a progressive, autoimmune cholestatic liver disorder. Cholestasis with disease progression may lead to dyslipidemia, osteodystrophy and fat-soluble vitamin deficiency. Portal hypertension may develop prior to advanced stages of fibrosis. Untreated disease may lead to cirrhosis, hepatocellular cancer and need for orthotopic liver transplantation. Classically, diagnosis is made with elevation of alkaline phosphatase, demonstration of circulating antimitochondrial antibody, and if performed: asymmetric destruction/nonsupperative cholangitis of intralobular bile ducts on biopsy. Disease pathogenesis is complex and results from innate and adaptive (cell-mediated and humoral) responses that lead to inflammation of biliary duct epithelium. Ongoing damage is amplified and sustained through bile acid toxicity. Use of weight based (13-15mg/kg) ursodeoxycholic acid is well established in retarding disease progression and improving survival; however, is ineffective in achieving complete biochemical remission in many. Recently, a Farnesoid X Receptor agonist, obeticholic acid, has been approved for use. A number of ongoing clinical studies are underway to evaluate utility of fibric acid derivatives, biologics, antifibrotics, and stem cells as monotherapy or in combination with ursodeoxycholic acid for primary biliary cholangitis. The aim of this review is to discuss disease pathogenesis and highlight rationale/implications for both established and novel therapeutics.
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Key Words
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AMAbs, anti-mitochondrial antibodies
- ASBT, apical sodium BA transporter
- BA, bile acids
- CDCA, chenodeoxycholic acid
- FGF-19, fibroblast growth factor
- FXR, farnesoid X receptor
- GGT, gamma-glutamyltranspeptidase
- IL, interleukin
- MHC, major histocompatibility complex
- OCA, obeticholic acid
- PBC
- PBC, primary biliary cholangitis
- PPARα, peroxisome proliferator-activated α-receptor
- UC-MSC, umbilical cord mesenchymal stem cells
- ULN, upper limit of normal
- biologic
- fibric acid
- liver transplantation
- obeticholic acid
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Affiliation(s)
- Amitkumar Patel
- University of Arizona College of Medicine-Phoenix, Department of Gastroenterology, 1111 E. McDowell Road, Phoenix, AZ 85006, United States
| | - Anil Seetharam
- University of Arizona College of Medicine-Phoenix, Banner Transplant and Advanced Liver Disease Center, 1300 N. 12th Street Suite 404, Phoenix, AZ 85006, United States,Address for correspondence: University of Arizona College of Medicine-Phoenix, Banner Transplant and Advanced Liver Disease Center, 1300 N. 12th Street Suite 404, Phoenix, AZ 85006, United States. Fax: +1 602 839 2606.University of Arizona College of Medicine-Phoenix, Banner Transplant and Advanced Liver Disease Center1300 N. 12th Street Suite 404PhoenixAZ85006United States
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29
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Huang YQ. Recent advances in the diagnosis and treatment of primary biliary cholangitis. World J Hepatol 2016; 8:1419-1441. [PMID: 27957241 PMCID: PMC5124714 DOI: 10.4254/wjh.v8.i33.1419] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 07/26/2016] [Accepted: 08/29/2016] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cholangitis (PBC), formerly referred to as primary biliary cirrhosis, is an infrequent progressive intrahepatic cholestatic autoimmune illness that can evolve into hepatic fibrosis, hepatic cirrhosis, hepatic failure, and, in some cases, hepatocellular carcinoma. The disease itself is characterized by T-lymphocyte-mediated chronic non-suppurative destructive cholangitis and elevated serum levels of extremely specific anti-mitochondrial autoantibodies (AMAs). In this article, we will not only review epidemiology, risk factors, natural history, predictive scores, radiologic approaches (e.g., acoustic radiation force impulse imaging, vibration controlled transient elastography, and magnetic resonance elastography), clinical features, serological characteristics covering biochemical markers, immunoglobulins, infections markers, biomarkers, predictive fibrosis marker, specific antibodies (including AMAs such as AMA-M2), anti-nuclear autoantibodies [such as anti-multiple nuclear dot autoantibodies (anti-sp100, PML, NDP52, anti-sp140), anti-rim-like/membranous anti-nuclear autoantibodies (anti-gp210, anti-p62), anti-centromere autoantibodies, and some of the novel autoantibodies], histopathological characteristics of PBC, diagnostic advances, and anti-diastole of PBC. Furthermore, this review emphasizes the recent advances in research of PBC in terms of therapies, including ursodeoxycholic acid, budesonide, methotrexate, obeticholic acid, cyclosporine A, fibrates such as bezafibrate and fenofibrate, rituximab, mesenchymal stem cells transplant, and hepatic transplant. Currently, hepatic transplant remains the only optimal choice with acknowledged treatment efficiency for end-stage PBC patients.
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30
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Juliusson G, Imam M, Björnsson ES, Talwalkar JA, Lindor KD. Long-term outcomes in antimitochondrial antibody negative primary biliary cirrhosis. Scand J Gastroenterol 2016; 51:745-52. [PMID: 26776319 DOI: 10.3109/00365521.2015.1132337] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Antimitochondrial antibodies (AMA) are a sensitive and specific marker for primary biliary cirrhosis (PBC). AMAs are present in 95% of patients with PBC. However, 5% do not have AMAs and data on these patients is scarce. We aim to evaluate the long-term outcomes of patients with AMA negative PBC. METHODS A retrospective chart review of 71 AMA negative PBC patients. Disease presentation, laboratory results, and clinical endpoints were recorded. AMA negative patients were matched on year of diagnosis to a control group of 71 AMA positive patients. RESULTS Ninety-six percent of the AMA negative patients were of female gender with a median age at diagnosis of 55 years and a length of follow-up of 7.5 years vs. 86% females, a median age of 56 and a follow-up of 8.3 years in the control group. Mean total bilirubin and alkaline phosphatase levels were 0.7 mg/dL vs. 0.6 and 570 U/L vs 341, in AMA negative vs. AMA positive patients at presentation, respectively (p = NS). AMA negative patients did not differ in terms of age, serum IgM levels, ANA status, or length of follow-up. Notably, AMA negative patients had a significantly reduced survival free of liver-related complications including transplantation and death compared to AMA positive patients (p = 0.0182). CONCLUSION In this large experience, AMA negative PBC patients had a significantly worse prognosis compared to AMA positive PBC patients. The reason for the difference in prognosis is unclear, as it may be true difference or reflect delays in case detection among AMA negative patients.
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Affiliation(s)
- Gunnar Juliusson
- a Faculty of Medicine , University of Iceland , Reykjavík , Iceland
| | - Mohamad Imam
- b Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA
| | - Einar S Björnsson
- a Faculty of Medicine , University of Iceland , Reykjavík , Iceland ;,c Department of Gastroenterology and Hepatology , Landspitali University Hospital , Reykjavík , Iceland
| | - Jayant A Talwalkar
- b Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA
| | - Keith D Lindor
- d Arizona State University , College of Health Solutions , Phoenix , AZ , USA
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31
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Stasi C, Leoncini L, Biagini MR, Arena U, Madiai S, Laffi G, Marra F, Milani S. Assessment of liver fibrosis in primary biliary cholangitis: Comparison between indirect serum markers and fibrosis morphometry. Dig Liver Dis 2016; 48:298-301. [PMID: 26632448 DOI: 10.1016/j.dld.2015.10.024] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 10/19/2015] [Accepted: 10/28/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND The accuracy of non-invasive methods for the quantification of liver fibrosis in primary biliary cholangitis (PBC) is still debated. AIMS To determine the histo-morphometric measurement of fibrotic tissue and to explore the possible association between indirect markers (APRI, FORNS, FIB-4, and Lok) and morphometry. METHODS Retrospective analysis of medical data from patients with PBC, on whom needle liver biopsy was performed as part of the diagnostic assessment. One section of each biopsy stained with Sirius red was used for calculating the percentage of collagen. Quantitative measure of fibrotic tissue (fibrosis morphometry) was calculated as a percentage of collagen content by digital image analysis. Morphometry results were divided into four groups reflecting Ludwig's staging and compared with values for indirect serum markers. RESULTS 50 PBC patients were enrolled (86% females, mean age 57 ± 12.30 years), 19 were Ludwig's stage I (38%), 14 stage II (28%), 12 stage III (24%), and five stage IV (10%). Morphometry results were significantly different among Ludwig stages (p<0.05). No significant differences were found for indirect serum markers. A significant correlation was found between morphometry results and indirect serum markers tested (p<0.05). CONCLUSION In our cohort, the histo-morphometric values of fibrotic tissue increased progressively with Ludwig's stages of PBC, while non-invasive markers did not.
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Affiliation(s)
- Cristina Stasi
- Department of Experimental and Clinical Medicine, University of Florence, Italy.
| | - Luisa Leoncini
- Department of Clinical and Experimental Biomedical Sciences, University of Florence, Italy
| | - Maria Rosa Biagini
- Department of Clinical and Experimental Biomedical Sciences, University of Florence, Italy
| | - Umberto Arena
- Department of Experimental and Clinical Medicine, University of Florence, Italy
| | - Stefania Madiai
- Department of Experimental and Clinical Medicine, University of Florence, Italy
| | - Giacomo Laffi
- Department of Experimental and Clinical Medicine, University of Florence, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Italy
| | - Stefano Milani
- Department of Clinical and Experimental Biomedical Sciences, University of Florence, Italy
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32
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Abstract
Primary biliary cirrhosis is a chronic cholestatic liver disease characterised by destruction of small intrahepatic bile ducts, leading to fibrosis and potential cirrhosis through resulting complications. The serological hallmark of primary biliary cirrhosis is the antimitochondrial antibody, a highly disease-specific antibody identified in about 95% of patients with primary biliary cirrhosis. These patients usually have fatigue and pruritus, both of which occur independently of disease severity. The typical course of primary biliary cirrhosis has changed substantially with the introduöction of ursodeoxycholic acid (UDCA). Several randomised placebo-controlled studies have shown that UDCA improves transplant-free survival in primary biliary cirrhosis. However, about 40% of patients do not have a biochemical response to UDCA and would benefit from new therapies. Liver transplantation is a life-saving surgery with excellent outcomes for those with decompensated cirrhosis. Meanwhile, research on nuclear receptor hormones has led to the development of exciting new potential treatments. This Seminar will review the current understanding of the epidemiology, pathogenesis, and natural history of primary biliary cirrhosis, discuss management of the disease and its sequelae, and introduce research on new therapeutic options.
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Affiliation(s)
- Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Ahmad H Ali
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA; Arizona State University, College of Health Solutions, Phoenix, AZ, USA.
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33
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Ali AH, Carey EJ, Lindor KD. Diagnosis and management of primary biliary cirrhosis. Expert Rev Clin Immunol 2014; 10:1667-78. [DOI: 10.1586/1744666x.2014.979792] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Biochemical response to ursodeoxycholic acid predicts survival in a North American cohort of primary biliary cirrhosis patients. J Gastroenterol 2014; 49:1414-20. [PMID: 24317935 PMCID: PMC4048793 DOI: 10.1007/s00535-013-0903-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2013] [Accepted: 10/20/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND Biochemical response to ursodeoxycholic acid among patients with primary biliary cirrhosis remains variable, and there is no agreement of an ideal model. Novel assessment of response coupled to histologic progression was recently defined by the Toronto criteria. We retrospectively assessed transplant-free survival and clinical outcomes associated with ursodeoxycholic acid response to evaluate the Toronto criteria using a large North American cohort of PBC patients. METHODS Three hundred and ninety-eight PBC patients from the Mayo Clinic PBC Genetic Epidemiology Registry were assessed for ursodeoxycholic acid treatment and biochemical response per the Toronto criteria. Responders were defined by reduction in alkaline phosphatase to less than or equal to 1.67 times the upper normal limit by 2 years of treatment, whereas non-responders had alkaline phosphatase values greater than 1.67 times the upper normal limit. Probability of survival was estimated using the Kaplan-Meier method. RESULTS Three hundred and two (76 %) patients were responders and 96 (24 %) were non-responders. Significantly more non-responders developed adverse events related to chronic liver disease compared to responders (hazard ratio (HR) 2.77, P = 0.001). Biochemical responders and early-stage disease at treatment start was associated with improved overall transplant-free survival compared to non-responders (HR 1.9) and patients with late-stage disease (HR 2.7) after age and sex adjustment. CONCLUSIONS The Toronto criteria are capable of identifying ursodeoxycholic acid-treated primary biliary cirrhosis patients at risk of poor transplant-free survival and adverse clinical outcomes. Our data reveal that despite advanced disease at diagnosis, biochemical response per the Toronto criteria associates with improved overall transplant-free survival.
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Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic autoimmune liver disease characterized by the destruction of small intrahepatic bile ducts and the presence of highly specific serum antimitochondrial antibodies (AMAs). In this article, we will review the clinical, serological and histopathological features of PBC as well as the advances in the diagnosis and differential diagnosis of PBC. In addition, this article systematically describes the advances in the treatment of PBC, and the treatments include ursodeoxycholic acid (UDCA), budesonide, methotrexate (MTX), farnesoid X receptor (FXR) agonists, cyclosporine A, bezafibrate, rituximab, bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation, and liver transplantation. At present, liver transplantation is the only option with known therapeutic benefit for end-stage PBC patients.
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36
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Nakanuma Y. Primary biliary cirrhosis: is there still a place for histological evaluation? Clin Res Hepatol Gastroenterol 2014; 38:e1-2. [PMID: 24029741 DOI: 10.1016/j.clinre.2013.07.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Accepted: 07/29/2013] [Indexed: 02/04/2023]
Affiliation(s)
- Yasuni Nakanuma
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
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37
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Patanwala I, McMeekin P, Walters R, Mells G, Alexander G, Newton J, Shah H, Coltescu C, Hirschfield GM, Hudson M, Jones D. A validated clinical tool for the prediction of varices in PBC: the Newcastle Varices in PBC Score. J Hepatol 2013; 59:327-35. [PMID: 23608623 DOI: 10.1016/j.jhep.2013.04.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Revised: 04/02/2013] [Accepted: 04/14/2013] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS Gastro-oesophageal varices (GOV) can occur in early stage primary biliary cirrhosis (PBC), making it difficult to identify the appropriate time to begin screening with oesophageo-gastro-duodenoscopy (OGD). Our aim was to develop and validate a clinical tool to predict the probability of finding GOV in PBC patients. METHODS A cross-sectional retrospective study analysing clinical data of 330 PBC patients who underwent an OGD at the Freeman Hospital, Newcastle was used to create a predictive tool, the Newcastle Varices in PBC (NVP) Score, that was externally validated in PBC patients from Cambridge (UK) and Toronto (Canada). RESULTS 48% of the Newcastle, 31% of the Cambridge, and 22% of the Toronto cohorts of PBC patients had GOV. Twenty-five percent (95% CI 18-32%) of the Newcastle cohort had GOV diagnosed at an index variceal bleed. Of the others, 37% (95% CI 28-46%) bled after a median of 1.5 years (IQR 3.75). Transplant-free survival was significantly better in those without GOV than in those with GOV (p<0.001), but similar in patients with GOV that bled and those that did not (p=0.1). The NVP score (%Probability)=1/[1+exp^-(9.186+0.001*alkaline phosphatase in IU-0.178*albumin in g/L-0.015*platelet × 10(9)) was validated in 2 external cohorts and was highly discriminant (AUROC 0.86). Cost consequences analyses revealed the NVP score to be as accurate as, but more economical than using either OGD directly or other risk scores for screening PBC patients. CONCLUSIONS The NVP score is an inexpensive, non-invasive, externally validated tool that accurately predicts GOV in PBC.
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Ikeda F, Okamoto R, Baba N, Fujioka SI, Shoji B, Yabushita K, Ando M, Matsumura S, Kubota J, Yasunaka T, Miyake Y, Iwasaki Y, Kobashi H, Okada H, Yamamoto K. Prevalence and associated factors with esophageal varices in early primary biliary cirrhosis. J Gastroenterol Hepatol 2012; 27:1320-1328. [PMID: 22414162 DOI: 10.1111/j.1440-1746.2012.07114.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Recent routine testing for anti-mitochondrial antibodies has increased the number of patients with early primary biliary cirrhosis (PBC). The prevalence and clinical significance of esophageal varices in those patients remains obscure. METHODS A systematic cohort analysis of 256 PBC patients was performed to clarify the prevalence, characteristics, and prognosis of the patients with early PBC and esophageal varices. RESULTS Twenty-two patients had esophageal varices at the time of diagnosis: 5.5% (12/217) with early disease of histological stage 1 or 2, and 25.6% (10/39) with advanced disease of stage 3 or 4. Immediate treatments were required for two patients with early PBC: one for bleeding varices, and the other for large varices. The overall survival of the patients with early PBC and esophageal varices at diagnosis did not significantly differ from that of patients without esophageal varices (P = 0.66). High alkaline phosphatase (ALP) ratios (odds ratio = 2.3) and low platelet counts (odds ratio = 0.77) were significantly associated with the presence of esophageal varices in the patients with early PBC. Significant associations of these two factors with the development of esophageal varices during follow-up were also revealed (odds ratio = 1.4 and 0.88, respectively). The patients with early PBC and high ALP ratios ≥ 1.9 had significantly high risks of developing esophageal varices during follow-up (P = 0.022). CONCLUSIONS High ALP ratios and low platelet counts at diagnosis and decreased platelet counts during follow-up are useful predictors of esophageal varices in patients with early PBC.
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Affiliation(s)
- Fusao Ikeda
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
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