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Gleeson D, Bornand R, Brownlee A, Dhaliwal H, Dyson JK, Hails J, Henderson P, Kelly D, Mells GF, Miquel R, Oo YH, Sutton A, Yeoman A, Heneghan MA. British Society of Gastroenterology guidelines for diagnosis and management of autoimmune hepatitis. Gut 2025:gutjnl-2024-333171. [PMID: 40169244 DOI: 10.1136/gutjnl-2024-333171] [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: 06/22/2024] [Accepted: 10/22/2024] [Indexed: 04/03/2025]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if untreated, often leads to cirrhosis, liver failure and death. The last British Society of Gastroenterology (BSG) guideline for the management of AIH was published in 2011. Since then, our understanding of AIH has advanced in many areas. This update to the previous guideline was commissioned by the BSG and developed by a multidisciplinary group. The aim of this guideline is to review and summarise the current evidence, in order to inform and guide diagnosis and management of patients with AIH and its variant syndromes. The main focus is on AIH in adults, but the guidelines should also be relevant to older children and adolescents.
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Affiliation(s)
- Dermot Gleeson
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Division of Clinical Medicine, School of Medicine and Population Science, University of Sheffield, Sheffield, UK
| | | | | | - Harpreet Dhaliwal
- Department of Gastroenterology, Manchester Royal Infirmary, Manchester, UK
| | - Jessica K Dyson
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Janeane Hails
- Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK
| | - Paul Henderson
- Royal Hospital for Children and Young People, Edinburgh, UK
| | - Deirdre Kelly
- Birmingham Women's & Children's Hospital, Birmingham, UK
- University of Birmingham, Birmingham, UK
| | - George F Mells
- Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Rosa Miquel
- Liver Histopathology Laboratory, Institute of Liver Studies, King's College London, London, UK
| | - Ye H Oo
- Centre for Liver and Gastroenterology research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- NIHR Biomedical Research Centre, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
- Centre for Rare Diseases, European Reference Network on Hepatological Diseases (ERN-RARE-LIVER) centre, Birmingham, UK
| | - Anthea Sutton
- Sheffield Centre for Health and Related Research, The University of Sheffield, Sheffield, UK
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Bolis F, Cazzaniga G, Pagni F, Invernizzi P, Carbone M, Gerussi A. The phenotypic landscape of primary biliary cholangitis and autoimmune hepatitis variants. GASTROENTEROLOGIA Y HEPATOLOGIA 2025; 48:502225. [PMID: 38950647 DOI: 10.1016/j.gastrohep.2024.502225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/21/2024] [Accepted: 06/21/2024] [Indexed: 07/03/2024]
Abstract
Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) stand as distinct diseases, yet occasionally intertwine with overlapping features, posing diagnostic and management challenges. This recognition traces back to the 1970s, with initial case reports highlighting this complexity. Diagnostic scoring systems like IAIHG and simplified criteria for AIH were introduced but are inherently limited in diagnosing variant syndromes. The so-called Paris criteria offer a diagnostic framework with high sensitivity and specificity for variant syndromes, although disagreements among international guidelines persist. Histological findings in AIH and PBC may exhibit overlapping features, rendering histology alone inadequate for a definitive diagnosis. Autoantibody profiles could be helpful, but similarly cannot be considered alone to reach a solid and consistent evaluation. Treatment strategies vary based on the predominant features observed. Individuals with overlapping characteristics favoring AIH ideally benefit from corticosteroids, while patients primarily manifesting PBC features should initially receive treatment with choleretic drugs like ursodeoxycholic acid (UDCA).
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MESH Headings
- Humans
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/drug therapy
- Hepatitis, Autoimmune/genetics
- Hepatitis, Autoimmune/classification
- Hepatitis, Autoimmune/pathology
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/drug therapy
- Liver Cirrhosis, Biliary/genetics
- Liver Cirrhosis, Biliary/pathology
- Liver Cirrhosis, Biliary/classification
- Phenotype
- Ursodeoxycholic Acid/therapeutic use
- Autoantibodies/blood
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Affiliation(s)
- Francesca Bolis
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Liver Unit, ASST Grande Ospedale Metropolitano (GOM) Niguarda, Milan, Italy
| | - Giorgio Cazzaniga
- Department of Pathology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Fabio Pagni
- Department of Pathology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Pietro Invernizzi
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Centre for Autoimmune Liver Diseases & Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, ERN-RARE LIVER, Monza, Italy.
| | - Marco Carbone
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Liver Unit, ASST Grande Ospedale Metropolitano (GOM) Niguarda, Milan, Italy
| | - Alessio Gerussi
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; Centre for Autoimmune Liver Diseases & Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, ERN-RARE LIVER, Monza, Italy
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Chang ML, Le PH, Chen WT, Chen TD, Su CW, Chen CJ, Lin CY, Wu CH, Kuo CJ, Sung KF, Chien RN. Distinct characteristics of various autoimmune liver diseases: A 22-year hospital-based study in Taiwan. J Gastroenterol Hepatol 2024; 39:2835-2844. [PMID: 39307997 DOI: 10.1111/jgh.16736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/13/2024] [Accepted: 08/27/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND AND AIM The characteristics of autoimmune liver diseases (AILDs), including primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and PBC-AIH overlap syndrome (OS), have rarely been investigated and compared in Asia. METHODS At the Taiwan tertiary referral center, 330 PBC patients (87% treated with ursodeoxycholic acid [UDCA]), 143 AIH patients (94.4% treated with immunosuppressive therapy [IST]) and 21 PBC-AIH OS patients (85.7% treated with UDCA and IST) were enrolled. RESULTS Compared with AIH patients, PBC patients were older at baseline and had greater female-to-male sex ratios, alkaline phosphatase (ALP) and γ-glutamyl transferase (γ-GT) levels, and liver cirrhosis (LC), dyslipidemia, and hepatic and cardiometabolic complication rates. PBC patients had the lowest transaminase levels, whereas AIH patients had the highest transaminase levels. PBC patients had greater 22-year all-cause mortality and liver transplantation (ACMaLT) (43.5 vs 25.4%, P = 0.004), LC (75 vs 58.5%, P < 0.01), dyslipidemia (54.4 vs 45.9%, P = 0.001), and cerebrovascular accident (11.3 vs 0.8%, P = 0.019) cumulative incidences (CIs) than did AIH patients; PBC-AIH OS patients had greater systemic lupus erythematosus (28.9 vs 8.9%, P = 0.009) CI than did PBC patients. Baseline ALP (hazard ratio: 1.001), albumin (0.514), platelet count (0.997), and LC (3.438) were associated with ACMaLT; age (1.110), albumin (0.350), cirrhosis (46.219), and hepatitis C virus antibody positivity (5.068) were associated with hepatocellular carcinoma (HCC); and female sex (2.183) and body mass index (1.054) were associated with autoimmune diseases. CONCLUSIONS Compared with AIH patients, PBC patients had greater cardiometabolic CI, and ACMaLT CI, which was associated with cholestasis, liver functional reserve and LC. Older AILD patients with LC and females with obesity demand special caution for the development of HCC and extrahepatic autoimmune diseases, respectively.
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Affiliation(s)
- Ming-Ling Chang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Puo-Hsien Le
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Ting Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tai-Di Chen
- Department of Anatomic Pathology, Chang Gung Memorial Hospital Linkou Main Branch, Taoyuan, Taiwan
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Chung-Wei Su
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Jen Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Yu Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chi-Huan Wu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Jung Kuo
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kei-Feng Sung
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Varadarajan A, Rastogi A, Maiwall R, Bihari C, Thomas S, Shasthry SM. Serum IgG level in autoimmune liver diseases and its significance: Is there a need to revisit existing criteria? Experience from a tertiary care center. INDIAN J PATHOL MICR 2024; 67:846-851. [PMID: 38847214 DOI: 10.4103/ijpm.ijpm_865_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 02/13/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Serum immunoglobulin G (IgG) level is elevated in autoimmune liver diseases (AILDs), especially autoimmune hepatitis (AIH). However, its utility is limited in current practice as different criteria propose different cut-off values leading to considerable ambiguity. MATERIALS AND METHODS A cross-sectional study was conducted among patients with AILD who underwent a liver biopsy over a ten-year period. From 17644 liver biopsies, 630 patients were included and divided into three groups-AIH (455 patients), primary biliary cholangitis (PBC) (97 patients), and overlap (78 patients). Clinical and laboratory details were collected and histological findings were reviewed. Non-cirrhotic non-alcoholic steatohepatitis (NASH) cases were taken as the control group for IgG level comparison. RESULTS Among AIH patients, IgG values of >2 times the upper limit of normal (ULN) were associated with significant elevation of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, and necroinflammatory activity. IgG level of >1.1 times ULN lacks specificity in differentiating AIH from the control group. The receiver operating characteristic (ROC) curve demonstrates maximum sensitivity and specificity at a cut-off value of >1.3 times ULN. CONCLUSION Serum IgG cut-off value for diagnosing AIH, either in isolation or as a component of overlap syndrome, needs revision and uniformity. IgG value of >2 times ULN in AIH is associated with severe AIH. A new cut-off value of >1.3 times ULN is proposed.
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Affiliation(s)
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Chaggan Bihari
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sherin Thomas
- Department of Biochemistry, Institute of Liver and Biliary Sciences, New Delhi, India
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Jayabalan D, Huang Y, Calzadilla-Bertot L, Janjua M, de Boer B, Joseph J, Cheng W, Hazeldine S, Smith BW, MacQuillan GC, Wallace MC, Garas G, Adams LA, Jeffrey GP. Predictors of survival in autoimmune liver disease overlap syndromes. World J Hepatol 2024; 16:1269-1277. [PMID: 39351512 PMCID: PMC11438591 DOI: 10.4254/wjh.v16.i9.1269] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 06/16/2024] [Accepted: 06/27/2024] [Indexed: 09/23/2024] Open
Abstract
BACKGROUND Survival in patients with autoimmune liver disease overlap syndromes (AILDOS) compared to those with single autoimmune liver disease is unclear. AIM To investigate the survival of patients with AILDOS and assess the accuracy of non-invasive serum models for predicting liver-related death. METHODS Patients with AILDOS were defined as either autoimmune hepatitis and primary biliary cholangitis overlap (AIH-PBC) or autoimmune hepatitis and primary sclerosing cholangitis overlap (AIH-PSC) and were identified from three tertiary centres for this cohort study. Liver-related death or transplantation (liver-related mortality) was determined using a population-based data linkage system. Prognostic scores for liver-related death were compared for accuracy [including liver outcome score (LOS), Hepascore, Mayo Score, model for end-stage liver disease (MELD) score and MELD incorporated with serum sodium (MELD-Na) score]. RESULTS Twenty-two AILDOS patients were followed for a median of 3.1 years (range, 0.35-7.7). Fourteen were female, the median age was 46.7 years (range, 17.8 to 82.1) and median Hepascore was 1 (range, 0.07-1). At five years post enrolment, 57% of patients remained free from liver-related mortality (74% AIH-PBC, 27% AIH-PSC). There was no significant difference in survival between AIH-PBC and AIH-PSC. LOS was a significant predictor of liver-related mortality (P < 0.05) in patients with AIH-PBC (n = 14) but not AIH-PSC (n = 8). A LOS cut-point of 6 discriminated liver-related mortality in AIH-PBC patients (P = 0.012, log-rank test, 100% sensitivity, 77.8% specificity) (Harrell's C-statistic 0.867). The MELD score, MELD-Na score and Mayo Score were not predictive of liver-related mortality in any group. CONCLUSION Survival in the rare, AILDOS is unclear. The current study supports the LOS as a predictor of liver-related mortality in AIH-PBC patients. Further trials investigating predictors of survival in AILDOS are required.
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Affiliation(s)
- Dujinthan Jayabalan
- Medical School, University of Western Australia, Nedlands 6009, Western Australia, Australia
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia, Australia.
| | - Yi Huang
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia, Australia
| | - Luis Calzadilla-Bertot
- Medical School, University of Western Australia, Nedlands 6009, Western Australia, Australia
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia, Australia
| | - Malik Janjua
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia, Australia
| | - Bastiaan de Boer
- Department of Anatomical Pathology, PathWest Laboratory Medicine, Nedlands 6009, Western Australia, Australia
| | - John Joseph
- Department of Anatomical Pathology, PathWest Laboratory Medicine, Nedlands 6009, Western Australia, Australia
| | - Wendy Cheng
- Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth 6000, Western Australia, Australia
| | - Simon Hazeldine
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Western Australia, Australia
| | - Briohny W Smith
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia, Australia
| | - Gerry C MacQuillan
- Medical School, University of Western Australia, Nedlands 6009, Western Australia, Australia
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia, Australia
| | - Michael C Wallace
- Medical School, University of Western Australia, Nedlands 6009, Western Australia, Australia
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia, Australia
| | - George Garas
- Medical School, University of Western Australia, Nedlands 6009, Western Australia, Australia
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia, Australia
| | - Leon A Adams
- Medical School, University of Western Australia, Nedlands 6009, Western Australia, Australia
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia, Australia
| | - Gary P Jeffrey
- Medical School, University of Western Australia, Nedlands 6009, Western Australia, Australia
- Department of Hepatology, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia, Australia
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Li M, Cao W, Jiang T, Deng W, Wang S, Wu S, Zhang L, Lu Y, Chang M, Liu R, Ding X, Shen G, Gao Y, Hao H, Chen X, Hu L, Xu M, Jiang Y, Yi W, Xie Y, Song R. Impact of ursodeoxycholic acid therapy in autoimmune liver disease patients with COVID-19 and its clinical prognosis. BIOSAFETY AND HEALTH 2024; 6:165-170. [PMID: 40078729 PMCID: PMC11895010 DOI: 10.1016/j.bsheal.2024.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 04/27/2024] [Accepted: 04/29/2024] [Indexed: 03/14/2025] Open
Abstract
To explore the impact of ursodeoxycholic acid (UDCA) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and clinical outcomes in patients with autoimmune liver disease (AILD). Patients diagnosed with AILD were enrolled and divided into a UDCA group and a non-UDCA group based on whether they received UDCA treatment. Relevant data were collected regarding AILD diagnosis, treatment, biochemical indicators, and imaging examination. The incidence of SARS-CoV-2 infection and the prognosis of AILD patients were observed. A total of 1,138 patients completed follow-up. The usage rate of hormone (P = 0.003) and immunosuppressant (P = 0.001) used for treating AILD in the non-UDCA group was markedly lower than in the UDCA group. The UDCA usage rate was markedly lower in SARS-CoV-2 infected patients than in uninfected patients (P = 0.003). The rate of SARS-CoV-2 infection in the non-UDCA group was significantly higher than in the UDCA group (P = 0.018). Logistic regression analysis showed that UDCA use (P = 0.003) was correlated to a lower incidence of SARS-CoV-2, while immunosuppressant use (P = 0.017) increased the incidence. Recovery time from SARS-CoV-2 infection was markedly longer for those receiving UDCA treatment than those in the non-UDCA group (P = 0.018). UDCA is associated with low SARS-CoV-2 incidence in AILD patients, while immunosuppressant increases its incidence instead. Patients receiving UDCA treatment have a longer recovery time after being infected.
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Affiliation(s)
- Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing 100015, China
| | - Weihua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Tingting Jiang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Shiyu Wang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xiaoyan Ding
- Department of Medical Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Yuanjiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Hongxiao Hao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xiaoxue Chen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Leiping Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Mengjiao Xu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Yuyong Jiang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Yi
- Department of Gynecology and Obstetrics, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing 100015, China
| | - Rui Song
- Department of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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Maurotti S, Geirola N, Frosina M, Mirarchi A, Scionti F, Mare R, Montalcini T, Pujia A, Tirinato L. Exploring the impact of lipid droplets on the evolution and progress of hepatocarcinoma. Front Cell Dev Biol 2024; 12:1404006. [PMID: 38818407 PMCID: PMC11137176 DOI: 10.3389/fcell.2024.1404006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 04/29/2024] [Indexed: 06/01/2024] Open
Abstract
Over the past 10 years, the biological role of lipid droplets (LDs) has gained significant attention in the context of both physiological and pathological conditions. Considerable progress has been made in elucidating key aspects of these organelles, yet much remains to be accomplished to fully comprehend the myriad functions they serve in the progression of hepatic tumors. Our current perception is that LDs are complex and active structures managed by a distinct set of cellular processes. This understanding represents a significant paradigm shift from earlier perspectives. In this review, we aim to recapitulate the function of LDs within the liver, highlighting their pivotal role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) (Hsu and Loomba, 2024) and their contribution to the progression towards more advanced pathological stages up to hepatocellular carcinoma (HC) (Farese and Walther, 2009). We are aware of the molecular complexity and changes occurring in the neoplastic evolution of the liver. Our attempt, however, is to summarize the most important and recent roles of LDs across both healthy and all pathological liver states, up to hepatocarcinoma. For more detailed insights, we direct readers to some of the many excellent reviews already available in the literature (Gluchowski et al., 2017; Hu et al., 2020; Seebacher et al., 2020; Paul et al., 2022).
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Affiliation(s)
- Samantha Maurotti
- Department of Clinical and Experimental Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Nadia Geirola
- Department of Clinical and Experimental Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Miriam Frosina
- Department of Medical and Surgical Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Angela Mirarchi
- Department of Medical and Surgical Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Francesca Scionti
- Department of Clinical and Experimental Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Rosario Mare
- Department of Medical and Surgical Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Tiziana Montalcini
- Department of Clinical and Experimental Medicine, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Arturo Pujia
- Department of Medical and Surgical Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
| | - Luca Tirinato
- Department of Medical and Surgical Sciences, University “Magna Græcia” of Catanzaro, Catanzaro, Italy
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8
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Yang F, Zhou L, Shen Y, Wang X, Fan X, Yang L. Multi-omics approaches for drug-response characterization in primary biliary cholangitis and autoimmune hepatitis variant syndrome. J Transl Med 2024; 22:214. [PMID: 38424613 PMCID: PMC10902991 DOI: 10.1186/s12967-024-05029-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 02/24/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) variant syndrome (VS) exhibit a complex overlap of AIH features with PBC, leading to poorer prognoses than those with PBC or AIH alone. The biomarkers associated with drug response and potential molecular mechanisms in this syndrome have not been fully elucidated. METHODS Whole-transcriptome sequencing was employed to discern differentially expressed (DE) RNAs within good responders (GR) and poor responders (PR) among patients with PBC/AIH VS. Subsequent gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted for the identified DE RNAs. Plasma metabolomics was employed to delineate the metabolic profiles distinguishing PR and GR groups. The quantification of immune cell profiles and associated cytokines was achieved through flow cytometry and immunoassay technology. Uni- and multivariable logistic regression analyses were conducted to construct a predictive model for insufficient biochemical response. The performance of the model was assessed by computing the area under the receiver operating characteristic (AUC) curve, sensitivity, and specificity. FINDINGS The analysis identified 224 differentially expressed (DE) mRNAs, 189 DE long non-coding RNAs, 39 DE circular RNAs, and 63 DE microRNAs. Functional pathway analysis revealed enrichment in lipid metabolic pathways and immune response. Metabolomics disclosed dysregulated lipid metabolism and identified PC (18:2/18:2) and PC (16:0/20:3) as predictors. CD4+ T helper (Th) cells, including Th2 cells and regulatory T cells (Tregs), were upregulated in the GR group. Pro-inflammatory cytokines (IFN-γ, TNF-α, IL-9, and IL-17) were downregulated in the GR group, while anti-inflammatory cytokines (IL-10, IL-4, IL-5, and IL-22) were elevated. Regulatory networks were constructed, identifying CACNA1H and ACAA1 as target genes. A predictive model based on these indicators demonstrated an AUC of 0.986 in the primary cohort and an AUC of 0.940 in the validation cohort for predicting complete biochemical response. CONCLUSION A combined model integrating genomic, metabolic, and cytokinomic features demonstrated high accuracy in predicting insufficient biochemical response in patients with PBC/AIH VS. Early recognition of individuals at elevated risk for insufficient response allows for the prompt initiation of additional treatments.
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Affiliation(s)
- Fan Yang
- Department of Gastroenterology and Hepatology and Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, #37 Guoxue Road, Chengdu, 610041, Sichuan, China
| | - Leyu Zhou
- Department of Gastroenterology and Hepatology and Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, #37 Guoxue Road, Chengdu, 610041, Sichuan, China
| | - Yi Shen
- Department of Gastroenterology and Hepatology and Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, #37 Guoxue Road, Chengdu, 610041, Sichuan, China
| | - Xianglin Wang
- Department of Gastroenterology and Hepatology and Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, #37 Guoxue Road, Chengdu, 610041, Sichuan, China
| | - Xiaoli Fan
- Department of Gastroenterology and Hepatology and Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, #37 Guoxue Road, Chengdu, 610041, Sichuan, China.
| | - Li Yang
- Department of Gastroenterology and Hepatology and Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, #37 Guoxue Road, Chengdu, 610041, Sichuan, China.
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Li M, Chen S, Li S, Lv T, Li B, Shan S, Li M, Zeng N, Wang Q, Kong Y, Ma H, Zhao X, Ou X, You H, Duan W, Jia J. Add-on immunosuppressive therapy may benefit selected patients with primary biliary cholangitis and autoimmune phenomena. Therap Adv Gastroenterol 2024; 17:17562848231224840. [PMID: 38250015 PMCID: PMC10798075 DOI: 10.1177/17562848231224840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 12/19/2023] [Indexed: 01/23/2024] Open
Abstract
Background Mildly elevated levels of transaminase and/or immunoglobulin G (IgG) are common in patients with primary biliary cholangitis (PBC). It is still unclear whether adding immunosuppressive therapy to ursodeoxycholic acid (UDCA) benefits those patients who are not fulfilling the diagnostic criteria of PBC with autoimmune hepatitis (AIH) features. Objectives To assess the efficacy of adding immunosuppressive therapy to UDCA for patients with PBC and autoimmune phenomena but not fulfilling the diagnostic criteria of PBC with AIH features. Design This is a retrospective-prospective cohort study in a tertiary medical center. Methods Patients with PBC and autoimmune phenomena were defined by the elevation of IgG and/or transaminase but did not fulfill the diagnostic criteria of PBC with AIH features. We grouped these patients based on with and without add-on immunosuppressive therapy and balanced their baseline characteristics using inverse probability treatment weighting (IPTW). Results A total of 652 patients with PBC and autoimmune phenomena were included, with a median follow-up of 4.08 years. After IPTW, the pseudo sample size in the add-on therapy and monotherapy groups was 558 and 655, respectively. After 1 year of observation, patients in the add-on therapy group had a higher biochemical response rate (normalization of transaminase and IgG levels) (49% versus 17%, p < 0.001). Furthermore, add-on therapy improved the transplant-free survival in the subgroup of patients with PBC and transaminase ⩾3 × upper limit of normal (ULN) or IgG ⩾1.3 × ULN (p = 0.033). Conclusion Add-on immunosuppressive therapy may improve the normalization rates of transaminase and IgG levels in all patients with PBC and mildly elevated transaminase and IgG levels and the long-term outcomes in the subgroup of the patients with transaminase ⩾3 × ULN or IgG ⩾1.3 × ULN.
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Affiliation(s)
- Mengqi Li
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Sha Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Shuxiang Li
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Tingting Lv
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Buer Li
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Shan Shan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Min Li
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Na Zeng
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Qianyi Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Hong Ma
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing 100050, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing 100050, China
- Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
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Varadarajan A, Rastogi A, Maiwall R, Bihari C, Thomas S, Sood V, Shasthry SM. Prevalence and clinicopathological Spectrum of Auto-Immune Liver Diseases & Overlap syndrome. INDIAN J PATHOL MICR 2024; 67:107-114. [PMID: 38358198 DOI: 10.4103/ijpm.ijpm_72_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024] Open
Abstract
Aims Autoimmune liver diseases (AILD) represent a spectrum of related yet distinct immune-mediated disorders. The literature on the prevalence of these AILDs in Indian population is scarce. This study aims to assess the prevalence and clinicopathological spectrum of various AILDs especially the overlap syndrome. Materials and Methods A 10-year (2011-2020) cross-sectional, retrospective observational study of histological proven cases of AILD was conducted. Clinical, demographic, and laboratory parameters were retrieved. Two pathologists independently reviewed the liver biopsies and reassessed 18 histopathological parameters. Results During the study period, 17664 liver biopsies were received, out of which 1060 (6%) biopsies of AILD were identified. After exclusion, we had 721 cases which revealed a distribution of autoimmune hepatitis (AIH)-64.7%, primary biliary cholangitis (PBC)-14.8%, primary sclerosing cholangitis (PSC)-7.6%, overlap AIH-PBC 11%, and overlap AIH-PSC 1.7%. AIH patients had significantly higher prevalence for severe lobular inflammation (27%, P ≤ 0.001), several lobular plasma cells (37%, P ≤ 0.001), central perivenulitis (30%, P ≤ 0.001), hepatic rosettes (51%, P ≤ 0.001), and necrosis (35.5%, P ≤ 0.001), while PBC patients had significantly higher frequency of florid duct lesions (11.2%, P ≤ 0.001), duct loss (83.17%, P ≤ 0.001), bile duct damage (76.6%, P ≤ 0.001), and periportal copper deposits (19.6%, P ≤ 0.001). Overlap AIH-PBC group had the highest proportion of severe portal inflammation (27.5%, P ≤ 0.001), prominent portal plasma cells (75%, P ≤ 0.001), moderate interface activity (53.7%, P ≤ 0.001), Mallory-Denk bodies (27.5%, P ≤ 0.001), and periportal cholate stasis (25%, P ≤ 0.001). Conclusion Prevalence of biopsy-proven AILDs in our study cohort is 6%. AIH (64.7%) is the most common AILD followed by PBC (14.8%). Overlap syndrome (AIH-PBC) showed prevalence of 11%.
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Affiliation(s)
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Chhagan Bihari
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sherin Thomas
- Department of Paediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vikrant Sood
- Department of Paediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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11
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Rodrigues Barbosa B, Pereira L, Campante F, Pona AP. Chronic Liver Disease, Not Everything Is What It Seems: Autoimmune Hepatitis/Primary Biliary Cholangitis Overlap Syndrome. Cureus 2024; 16:e51630. [PMID: 38313999 PMCID: PMC10837645 DOI: 10.7759/cureus.51630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2024] [Indexed: 02/06/2024] Open
Abstract
Overlap syndrome (OS) is a rare condition that shares characteristics of at least two other recognized diseases, whose early diagnosis impacts treatment decisions and prognosis since the unfavorable course of the OS seems to be worse than that of the diseases alone. OS in autoimmune liver diseases combines characteristic features of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis. AIH is a chronic, inflammatory disease of the liver that occurs predominantly in females. The disease may start as acute hepatitis and progress to chronic liver disease and cirrhosis. PBC is characterized by a T-lymphocyte-mediated attack on small intralobular bile ducts. A continuous assault on the bile duct epithelial cells leads to their gradual destruction and eventual disappearance. The sustained loss of intralobular bile ducts causes the signs and symptoms of cholestasis and eventually may result in cirrhosis and liver failure. With treatment with ursodeoxycholic acid, the majority of patients now have normal life expectancies. The authors report a subtype of OS, i.e., AIH-PBC overlap, characterized by elevated serum transaminases, cholestasis markers, antimitochondrial antibodies (AMAs), and histological findings compatible with AIH, including moderate-to-severe interface hepatitis. The authors present a clinical case referred for internal medicine consultation regarding a 73-year-old woman presenting pancytopenia and increased transaminases, along with weight loss, decreased appetite, and tiredness. Laboratory tests were positive for the following parameters: antinuclear antibody, anti-double-stranded DNA antibody, AMA, anti-glycoprotein-210, and anti-smooth muscle antibody (anti-actin). Computed tomography of the abdomen displayed chronic liver disease and evidence of small perihepatic ascites. The diagnosis was established with a liver biopsy revealing architectural alteration with severe advanced fibrosis, with bridges and parenchymal nodularity, and histological parenchymal changes of progressive chronic liver disease (chronic biliary disease/PBC) in the stage of cirrhosis. With proper treatment, the condition of the patient significantly improved.
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Affiliation(s)
| | - Laurinda Pereira
- Department of Internal Medicine, Centro Hospitalar Barreiro Montijo, Barreiro, PRT
| | - Fátima Campante
- Department of Internal Medicine, Centro Hospitalar Barreiro Montijo, Barreiro, PRT
| | - Ana Paula Pona
- Department of Internal Medicine, Centro Hospitalar Barreiro Montijo, Barreiro, PRT
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12
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Graf M, Lange CM, Langer MM, Schattenberg JM, Seessle J, Dietz J, Vermehren A, Michael FA, Mondorf A, Zeuzem S, Pathil A, Graf C. Primary Biliary Cholangitis (PBC)-Autoimmune Hepatitis (AIH) Variant Syndrome: Clinical Features, Response to Therapy and Long-Term Outcome. J Clin Med 2023; 12:7047. [PMID: 38002661 PMCID: PMC10672247 DOI: 10.3390/jcm12227047] [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: 08/06/2023] [Revised: 11/02/2023] [Accepted: 11/09/2023] [Indexed: 11/26/2023] Open
Abstract
INTRODUCTION Standardization of diagnostic criteria of autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) variant syndrome (AIH-PBC VS) has not been achieved so far and evidence-based recommendations for monitoring and treatment of the disease are still lacking. Our study aimed to assess the prevalence, biochemical, and serological features, as well as the clinical course, of VS. METHODS We performed a retrospective study including all patients with VS between 1999 and 2020 in four German centers. Data on demographic parameters, biochemical and serological tests, treatment, and outcome were collected. RESULTS Of 90 patients (3.1%) meeting Paris criteria for VS diagnosis, 65.6% showed AIH and PBC histological features, while biochemical Paris criteria were observed comparatively rarely. Further antibodies, which were not part of the diagnostic criteria of VS, were found in a subgroup of patients with available data (ACA: 30.0%; anti-CENP-A: 25.0%; anti-CENP-B: 33.3%; anti-SP100: 21.4%). Biochemical response was more frequently observed in patients treated with a combined therapy of ursodeoxycholic acid (UDCA) and immunosuppression (IS). Liver cirrhosis was detected in 31 patients (34.4%) and 25 patients (27.8%) developed clinical manifestations of portal hypertension. CONCLUSIONS Biochemical Paris criteria of VS were rarely detected, thus implying that these cut-off values should be redefined. Regarding pharmacological treatment, combined therapy of UDCA and IS appeared to be more effective than monotherapy with UDCA.
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Affiliation(s)
- Markus Graf
- Department of Internal Medicine I, University Hospital Frankfurt, 60596 Frankfurt am Main, Germany; (M.G.); (J.D.); (A.V.); (F.A.M.); (A.M.); (S.Z.); (A.P.)
| | - Christian M. Lange
- Department of Internal Medicine II, University Hospital Munich, 81377 Munich, Germany; (C.M.L.); (M.M.L.)
| | - Mona M. Langer
- Department of Internal Medicine II, University Hospital Munich, 81377 Munich, Germany; (C.M.L.); (M.M.L.)
| | - Jörn M. Schattenberg
- Department of Internal Medicine I, University Medical Center Mainz, 55131 Mainz, Germany;
| | - Jessica Seessle
- Department of Internal Medicine IV, University of Heidelberg, 69120 Heidelberg, Germany;
| | - Julia Dietz
- Department of Internal Medicine I, University Hospital Frankfurt, 60596 Frankfurt am Main, Germany; (M.G.); (J.D.); (A.V.); (F.A.M.); (A.M.); (S.Z.); (A.P.)
| | - Annika Vermehren
- Department of Internal Medicine I, University Hospital Frankfurt, 60596 Frankfurt am Main, Germany; (M.G.); (J.D.); (A.V.); (F.A.M.); (A.M.); (S.Z.); (A.P.)
| | - Florian A. Michael
- Department of Internal Medicine I, University Hospital Frankfurt, 60596 Frankfurt am Main, Germany; (M.G.); (J.D.); (A.V.); (F.A.M.); (A.M.); (S.Z.); (A.P.)
| | - Antonia Mondorf
- Department of Internal Medicine I, University Hospital Frankfurt, 60596 Frankfurt am Main, Germany; (M.G.); (J.D.); (A.V.); (F.A.M.); (A.M.); (S.Z.); (A.P.)
| | - Stefan Zeuzem
- Department of Internal Medicine I, University Hospital Frankfurt, 60596 Frankfurt am Main, Germany; (M.G.); (J.D.); (A.V.); (F.A.M.); (A.M.); (S.Z.); (A.P.)
| | - Anita Pathil
- Department of Internal Medicine I, University Hospital Frankfurt, 60596 Frankfurt am Main, Germany; (M.G.); (J.D.); (A.V.); (F.A.M.); (A.M.); (S.Z.); (A.P.)
| | - Christiana Graf
- Department of Internal Medicine I, University Hospital Frankfurt, 60596 Frankfurt am Main, Germany; (M.G.); (J.D.); (A.V.); (F.A.M.); (A.M.); (S.Z.); (A.P.)
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Çetinkaya NS, Cengiz M, Gül Aydın E. Autoimmune hepatitis and primary biliary cholangitis overlap syndrome after mRNA COVID-19 vaccination. GULHANE MEDICAL JOURNAL 2023; 65:141-144. [DOI: 10.4274/gulhane.galenos.2023.66376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
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14
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KASL clinical practice guidelines for management of autoimmune hepatitis 2022. Clin Mol Hepatol 2023; 29:542-592. [PMID: 37137334 PMCID: PMC10366804 DOI: 10.3350/cmh.2023.0087] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/27/2023] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
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15
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Sahu R, Goswami S, Narahari Sastry G, Rawal RK. The Preventive and Therapeutic Potential of the Flavonoids in Liver Cirrhosis: Current and Future Perspectives. Chem Biodivers 2023; 20:e202201029. [PMID: 36703592 DOI: 10.1002/cbdv.202201029] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 01/12/2023] [Indexed: 01/28/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) may vary from moderately mild non-alcohol fatty liver (NAFL) towards the malignant variant known as non-alcoholic steatohepatitis (NASH), which is marked by fatty liver inflammation and may progress to liver cirrhosis (LC), liver cancer, fibrosis, or liver failure. Flavonoids can protect the liver from toxins through their anti-inflammatory, antioxidant, anti-cancer, and antifibrogenic pharmacological activities. Furthermore, flavonoids protect against LC by regulation of hepatic stellate cells (HSCs) trans-differentiation, inhibiting growth factors like TGF-β and platelets-derived growth factor (PDGF), vascular epithelial growth factor (VEGF), viral infections like hepatitis-B, C and D viruses (HBV, HCV & HDV), autoimmune-induced, alcohol-induced, metabolic disorder-induced, causing by apoptosis, and regulating MAPK pathways. These flavonoids may be explored in the future as a therapeutic solution for hepatic diseases.
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Affiliation(s)
- Rakesh Sahu
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - Sourav Goswami
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - G Narahari Sastry
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
| | - Ravindra K Rawal
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
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Hussain N, Trivedi PJ. The Inconvenient Truth of Primary Biliary Cholangitis/Autoimmune Hepatitis Overlap Syndrome. Clin Liver Dis 2022; 26:657-680. [PMID: 36270722 DOI: 10.1016/j.cld.2022.06.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The term 'PBC/AIH-overlap' has been applied when features of autoimmune hepatitis (AIH), be they biochemical, serological or histological, coexist with primary biliary cholangitis (PBC), either at first presentation or sequentially during disease course. Several treatment paradigms have been proposed, extrapolated from those of the primary conditions. However, there are no randomised studies showing improved survival with combination therapy compared to bile acid monotherapy. In the absence of high-quality evidence, multidisciplinary patient-specific approaches must be used to individualise treatment pathways, with appreciation that disease phenotypes are not always static, differ in treatment responses, and have the potential to evolve over time.
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Affiliation(s)
- Nasir Hussain
- NIHR Birmingham BRC, Institute of Immunology and Immunotherapy, Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, United Kingdom
| | - Palak J Trivedi
- NIHR Birmingham BRC, Institute of Immunology and Immunotherapy, Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Birmingham, United Kingdom; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom.
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17
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Walsh K, Park J. Far From the Biliary Tree: A Case of Overlapping Autoimmune Liver Disease in a Patient Presenting With Sicca Symptoms. Cureus 2022; 14:e26760. [PMID: 35967173 PMCID: PMC9365501 DOI: 10.7759/cureus.26760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2022] [Indexed: 11/16/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic autoimmune condition with many extrahepatic manifestations that are commonly encountered as a patient's primary presenting complaints. Rarely, PBC co-exists as an “overlapping syndrome” with other liver-related autoimmune conditions such as autoimmune hepatitis (AIH). Presented is a rare case of PBC with features of AIH diagnosed in a patient who initially presented with hemoptysis and worsened sicca symptoms due to advanced Sjögren’s syndrome. The patient had a three-year evolution of abnormal liver biochemistry and was found to be a heterozygous carrier for hereditary hemochromatosis (H63D mutation). Given that patients with PBC-AIH are at an increased risk of complications compared to isolated disease from either disorder, early diagnosis and prompt management can help spare patients from cirrhosis, liver failure and transplantation, or even death.
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18
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Minimal hepatic encephalopathy may be present despite the absence of non-invasive and elastography evidence of cirrhosis in patients with primary biliary cholangitis. Adv Med Sci 2021; 66:293-301. [PMID: 34192643 DOI: 10.1016/j.advms.2021.06.001] [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: 12/21/2020] [Revised: 05/25/2021] [Accepted: 06/20/2021] [Indexed: 11/21/2022]
Abstract
PURPOSE Minimal hepatic encephalopathy (MHE) is an important complication of chronic liver disease (CLD); however, MHE burden in patients with primary biliary cholangitis (PBC) has not been determined yet. Therefore, our study aimed to assess the prevalence of MHE in a typical cohort of middle-aged, patients with PBC suspicion of liver fibrosis and to investigate the relationship between MHE, basic laboratory tests and the stage of liver fibrosis. PATIENTS AND METHODS Fifty-one patients (38 with PBC and 13 controls), were prospectively enrolled. Portosystemic Encephalopathy-Syndrome test was used to diagnose MHE. Elastography point qualification (ElastPQ) and non-invasive markers (APRI and FIB-4) were used to assess liver fibrosis. The severity of CLD was assessed using the Model of End-Stage Liver Disease (MELD) and Child-Pugh score. RESULTS MHE was diagnosed in 9 patients (24.3%) with PBC and none in the control group. As many as 44.4% of the patients with MHE had neither advanced fibrosis nor cirrhosis, as demonstrated using non-invasive markers of liver fibrosis or ElastPQ. The MELD score was the only predictor of MHE with cut-off value 8.5 [AUC = 0.753, CI95% = 0.569 to 0.938)] with sensitivity of 56%, specificity of 85% and accuracy of the test of 78%. Non-invasive markers of liver fibrosis and ElastPQ did not predict MHE. CONCLUSIONS MHE may occur in PBC despite no evidence of advanced liver fibrosis or cirrhosis. The slightly elevated MELD score may indicate a substantially increased risk of MHE in patients with PBC.
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Jiang Y, Xu BH, Rodgers B, Pyrsopoulos N. Characteristics and Inpatient Outcomes of Primary Biliary Cholangitis and Autoimmune Hepatitis Overlap Syndrome. J Clin Transl Hepatol 2021; 9:392-398. [PMID: 34221925 PMCID: PMC8237146 DOI: 10.14218/jcth.2021.00008] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 02/23/2021] [Accepted: 02/26/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND AIMS Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are hepatobiliary diseases of presumed immune-mediated origin that have been shown to overlap. The aim of this retrospective trial was to use national data to examine the characteristics and outcomes of patients hospitalized with overlapping PBC and AIH (PBC/AIH). METHODS The National Inpatient Sample was used to identify hospitalized adult patients with PBC, AIH, and PBC/AIH from 2010 to 2014 by International Classification of Diseases-Ninth Edition Revision codes; patients with hepatitis B virus and hepatitis C virus infection were excluded. Primary outcomes measures were in-hospital outcomes that included mortality, respiratory failure, septic shock, length of stay, and total hospital charges. Secondary outcomes were the clinical characteristics of PBC/AIH, including the comorbid extrahepatic autoimmune disease pattern and complications of cirrhosis. RESULTS A total of 3,478 patients with PBC/AIH were included in the study. PBC/AIH was associated with higher rates of Sjögren's syndrome (p<0.001; p<0.001), lower rates of Crohn's disease (p<0.05; p<0.05), and higher rates of cirrhosis-related complications when compared to PBC or AIH alone. There were similar rates of mortality between the PBC/AIH, PBC, and AIH groups. The PBC/AIH group had higher rates of septic shock when compared to the PBC group (p<0.05) and AIH group (p<0.05) after adjusting for possible confounders. CONCLUSIONS PBC/AIH is associated with a lower rate of Crohn's disease, a higher rate of Sjögren's syndrome, higher rates of cirrhosis-related complications, and significantly increased risk of septic shock compared to PBC and AIH individually.
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Affiliation(s)
- Yi Jiang
- Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA
- Correspondence to: Nikolaos Pyrsopoulos, Division of Gastroenterology and Hepatology, Rutgers-New Jersey Medical School, University Hospital, 185 S. Orange Avenue, Medical Science Building H level Room – 536, Newark, NJ 07101-1709, USA. ORCID: https://orcid.org/0000-0002-6950-8174. Tel: +1-973-972-5252, E-mail: ; Yi Jiang, Department of Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07101, USA. ORCID: https://orcid.org/0000-0001-5114-0183. Tel: +1-973-972-6056, E-mail:
| | - Bing-Hong Xu
- Liver Center & Center for Asian Health, RWJBH-Saint Barnabas Medical Center, Florham Park, New Jersey, USA
| | - Brandon Rodgers
- Department of Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA
| | - Nikolaos Pyrsopoulos
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, New Jersey, USA
- Correspondence to: Nikolaos Pyrsopoulos, Division of Gastroenterology and Hepatology, Rutgers-New Jersey Medical School, University Hospital, 185 S. Orange Avenue, Medical Science Building H level Room – 536, Newark, NJ 07101-1709, USA. ORCID: https://orcid.org/0000-0002-6950-8174. Tel: +1-973-972-5252, E-mail: ; Yi Jiang, Department of Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07101, USA. ORCID: https://orcid.org/0000-0001-5114-0183. Tel: +1-973-972-6056, E-mail:
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20
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Wen M, Men R, Fan X, Shen Y, Ni P, Hu Z, Yang L. Worse Response to Ursodeoxycholic Acid in Primary Biliary Cholangitis Patients with Autoimmune Hepatitis Features. Dig Dis 2020; 39:366-374. [PMID: 33238269 DOI: 10.1159/000513331] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 11/24/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND There is limited evidence on the treatment response of primary biliary cholangitis (PBC) with autoimmune hepatitis (AIH) features but not meet the criteria of PBC-AIH syndromes. The aim of this study was to elucidate the clinical characteristics of PBC patients with features of AIH. METHODS We included patients with diagnostic criteria of PBC. All patients were treated with ursodeoxycholic acid (UDCA) and without immunosuppressive agents for >1 year. The biochemical response was evaluated at 1 year after the treatment of UDCA. RESULTS Among 432 patients with PBC, 166 (38.4%) patients did not achieve biochemical response within 1 year of UDCA treatment. Nonresponders had a lower albumin level and higher immunoglobulin G, alanine transaminase (ALT), alanine aminotransferase (AST), alkaline phosphatase, glutamyl transpeptidase and total bilirubin levels (p < 0.05). The response rates were significantly lower in patients with elevated level of IgG or ALT or AST. Moreover, the higher the IgG or AST level was, the lower the response rate was in patients with PBC, regardless of cirrhosis. For patients with cirrhosis, there was no differences among patients with different levels of ALT. Patients in the PBC with AIH features group had a significant lower response rate than patients in the PBC-only group. Among the 139 patients who underwent liver biopsy, 54 were nonresponsive to UDCA and 48 (88.9%) shown mild interface hepatitis. CONCLUSION In conclusion, PBC patients with AIH features had a worse response to UDCA therapy.
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Affiliation(s)
- Maoyao Wen
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China.,Health Management Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ruoting Men
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoli Fan
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Shen
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Ping Ni
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Zhichao Hu
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Li Yang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China,
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21
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Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020; 72:671-722. [PMID: 31863477 DOI: 10.1002/hep.31065] [Citation(s) in RCA: 520] [Impact Index Per Article: 104.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Cara L Mack
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David Adams
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David N Assis
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Nanda Kerkar
- Golisano Children's Hospital at Strong, University of Rochester Medical Center, New York, NY
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX
| | - John M Vierling
- Medicine and Surgery, Baylor College of Medicine, Houston, TX
| | | | - Mohammad H Murad
- Mayo Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, MN
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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22
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Freedman BL, Danford CJ, Patwardhan V, Bonder A. Treatment of Overlap Syndromes in Autoimmune Liver Disease: A Systematic Review and Meta-Analysis. J Clin Med 2020; 9:jcm9051449. [PMID: 32414025 PMCID: PMC7291241 DOI: 10.3390/jcm9051449] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 04/30/2020] [Accepted: 05/07/2020] [Indexed: 12/13/2022] Open
Abstract
The treatment of overlap syndromes is guided by small observational studies whose data have never been synthesized in a rigorous, quantitative manner. We conducted a systematic review and meta-analysis to evaluate the efficacy of available treatments for these rare and morbid conditions. We searched the literature for studies comparing ≥2 therapies for autoimmune hepatitis (AIH)-primary biliary cholangitis (PBC), AIH-primary sclerosing cholangitis (PSC), PBC-PSC, AIH-PBC-PSC, autoimmune cholangitis (AIC), or autoimmune sclerosing cholangitis (ASC) with respect to various clinical outcomes, including biochemical improvement and transplant-free survival. A total of 28 studies met the inclusion criteria for AIH-PBC, AIH-PSC, AIC, and ASC. AIH-PBC patients tended to experience more biochemical improvement with ursodeoxycholic acid (UDCA) + [corticosteroids and/or antimetabolites], i.e., "combination therapy", than with corticosteroids ± azathioprine (RR = 4.00, 95% CI 0.93-17.18). AIH-PBC patients had higher transplant-free survival with combination therapy than with UDCA, but only when studies with follow-up periods ≤90 months were excluded (RR = 6.50, 95% CI 1.47-28.83). Combination therapy may therefore be superior to both UDCA and corticosteroids ± azathioprine for the treatment of AIH-PBC, but additional studies are needed to show this definitively and to elucidate optimal treatments for other overlap syndromes.
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Affiliation(s)
- Benjamin L. Freedman
- Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, USA;
| | - Christopher J. Danford
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Dana 603, Boston, MA 02215, USA;
| | - Vilas Patwardhan
- Liver Center, Autoimmune and Cholestatic Liver Disease Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis St. Suite 8E, Boston, MA 02215, USA;
| | - Alan Bonder
- Liver Center, Autoimmune and Cholestatic Liver Disease Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis St. Suite 8E, Boston, MA 02215, USA;
- Correspondence: ; Tel.: +1-617-632-1070
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23
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Huang Y, Joseph J, de Boer WB, Cheng W, Adams LA, MacQuillan G, Garas G, Raftopoulos S, Jeffrey GP. Long-term Liver-related Outcomes of Patients With Chronic Liver Diseases in Australia. Clin Gastroenterol Hepatol 2020; 18:496-504.e3. [PMID: 31319186 DOI: 10.1016/j.cgh.2019.07.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 07/04/2019] [Accepted: 07/09/2019] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Chronic liver disease is a major health burden that produces significant liver-related morbidity and mortality. We aimed to evaluate liver-related outcomes of patients with different causes of chronic liver disease in Australia. METHODS We collected data from 10,933 patients with chronic liver disease assessed by Hepascore (a serum fibrosis model) in Western Australia from 2004 through 2015. We obtained records of liver-related death, transplantation, decompensation, and hepatocellular carcinoma from WA Data Linkage Unit databases. Competing risk analysis was used to calculate the cumulative risk of each clinical endpoint, and risks for clinical endpoints were compared among all causes of chronic liver disease. RESULTS In our final cohort for analysis, 5566 patients had hepatitis C virus (HCV) infection, 1989 had HBV infection, 119 were infected with HBV and HCV, 955 had alcohol-associated liver disease, 1597 had non-alcoholic fatty liver disease (NAFLD), 123 had alcohol-associated liver disease and metabolic risk factors, 561 had autoimmune liver disease without overlap syndrome, and 23 autoimmune overlap syndrome. Significant differences among chronic liver diseases were observed in risk of all-cause death (P < .001), liver-related death (P < .001), liver transplantation (P < .001), and decompensation (P < .001) but not hepatocellular carcinoma (P=.095). Patients with alcohol-associated liver disease had the highest 5-year cumulative risk of liver-related death (17.1%) and the second-highest 5-year cumulative risk of decompensation (29.2%). Multivariate analysis found patients with alcohol-associated liver disease had significantly higher risks of liver-related death and decompensation than patients with HCV infection with hazard ratios (HRs) of 2.39 (95% CI, 1.88-3.03) and 3.42 (95% CI, 2.74-4.27), respectively. Patients with NAFLD had a significantly lower risk of liver related death and decompensation than patients with HCV infection, with HRs of 0.67 (95% CI, 0.48-0.95) and 0.70 (95% CI, 0.52-0.94) respectively. CONCLUSIONS In an analysis of patients in Western Australia, we found patients with alcohol-associated liver disease to have significantly higher risk of decompensation and liver-related death than patients with HCV infection, whereas patients with NAFLD have significantly lower risks of either outcome.
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Affiliation(s)
- Yi Huang
- School of Medicine and Pharmacology, University of Western Australia, Perth, Australia; Department of Hepatology, Sir Charles Gairdner Hospital, Perth, Australia
| | - John Joseph
- Department of Biochemistry, PathWest Laboratory Medicine, Perth, Australia
| | - W Bastiaan de Boer
- Department of Anatomical Pathology, PathWest Laboratory Medicine, Perth, Australia
| | - Wendy Cheng
- Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Australia
| | - Leon A Adams
- School of Medicine and Pharmacology, University of Western Australia, Perth, Australia; Department of Hepatology, Sir Charles Gairdner Hospital, Perth, Australia
| | - Gerry MacQuillan
- School of Medicine and Pharmacology, University of Western Australia, Perth, Australia; Department of Hepatology, Sir Charles Gairdner Hospital, Perth, Australia
| | - George Garas
- School of Medicine and Pharmacology, University of Western Australia, Perth, Australia; Department of Hepatology, Sir Charles Gairdner Hospital, Perth, Australia
| | - Spiro Raftopoulos
- Department of Hepatology, Sir Charles Gairdner Hospital, Perth, Australia
| | - Gary P Jeffrey
- School of Medicine and Pharmacology, University of Western Australia, Perth, Australia; Department of Hepatology, Sir Charles Gairdner Hospital, Perth, Australia.
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24
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Cristoferi L, Nardi A, Invernizzi P, Mells G, Carbone M. Individualizing Care: Management Beyond Medical Therapy. Surg Oncol Clin N Am 2019; 29:87-103. [PMID: 31757316 DOI: 10.1016/j.soc.2019.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The evolving research landscape, with advances in the omics technologies, availability of large-scale patient cohorts, and forthcoming availability of novel drugs in primary biliary cholangitis (PBC), is creating a unique opportunity for developing a precision medicine (PM) program. PM has potential to change the paradigm of management. Diagnostic work-up of PBC patients may include information on genetic variants and molecular signature to define a particular subtype of disease and provide an estimate of treatment response and survival. To reach this point, specific interventions, such as sequencing more genomes, creating bigger biobanks, and linking biological information to health data, are needed.
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Affiliation(s)
- Laura Cristoferi
- Division of Gastroenterology and Hepatology, Department of Medicine and Surgery, University of Milan Bicocca, Piazza dell'Ateneo Nuovo, 1, 20126 Milan, Italy
| | - Alessandra Nardi
- Department of Mathematics, Tor Vergata University of Rome, Via della Ricerca Scientifica 1, Rome, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Hepatology, Department of Medicine and Surgery, University of Milan Bicocca, Piazza dell'Ateneo Nuovo, 1, 20126 Milan, Italy
| | - George Mells
- Academic Department of Medical Genetics, University of Cambridge, Hills Road 1, Cambridge, UK
| | - Marco Carbone
- Division of Gastroenterology and Hepatology, Department of Medicine and Surgery, University of Milan Bicocca, Piazza dell'Ateneo Nuovo, 1, 20126 Milan, Italy; Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
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25
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Abstract
For many years the one-size-fits-all approach has been the only one available to manage patients affected by primary biliary cholangitis. The introduction of obeticholic acid in 2016 as a second-line treatment, together with the creation and validation of several biochemically based scores to stratify the risk of progressive disease, has opened up the need to redefine clinical practice by changing the actual paradigm. The precision medicine initiative is a model of patient-centered health care that aims to improve medicine based on genotypic and molecular characteristics that correlate to specific phenotypic, individual characteristics. In summary, the aim of the precision medicine is to define the right treatment for the right person at the right time. The availability of a second-line disease-modifying drug and new molecules in phase 2 or 3 trials makes this an exciting time for the precision medicine initiative in primary biliary cholangitis. In this review we describe the current risk stratification tools and we track a possible path towards the application of precision medicine in clinical daily life.
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Affiliation(s)
- Vincenzo Ronca
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Alessio Gerussi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Laura Cristoferi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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26
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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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27
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Dalekos GN, Koskinas J, Papatheodoridis GV. Hellenic Association for the Study of the Liver Clinical Practice Guidelines: Autoimmune hepatitis. Ann Gastroenterol 2019; 32:1-23. [PMID: 30598587 PMCID: PMC6302199 DOI: 10.20524/aog.2018.0330] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a relatively rare acute or chronic liver disease of unknown etiology characterized by large heterogeneity. Its distribution is global, covering all ages, both sexes and all ethnic groups. The aim of the present Clinical Practice Guidelines (CPG) of the Hellenic Association for the Study of the Liver was to provide updated guidance and help to gastroenterologists, hepatologists, internists and general practitioners for AIH diagnosis and management. AIH diagnosis is based on clinicopathological characteristics: namely, polyclonal hypergammaglobulinemia, particularly of immunoglobulin G (IgG), circulating autoantibodies, interface hepatitis on liver histology, absence of viral hepatitis, and a favorable response to immunosuppression. Clinical manifestations at disease onset are variable, ranging from asymptomatic to the acute/severe form. Aminotransferase and bilirubin levels vary, while the presence of hepatitis at the histological level is a prerequisite for diagnosis. Autoantibodies are the hallmark for AIH diagnosis; therefore, the CPG describe the appropriate serological algorithm for their detection. AIH therapy should aim to achieve complete biochemical (normalization of IgG and aminotransferases) and histological remission. All patients who have active disease, even those with cirrhosis, should be treated with individualized and response-guided induction therapy using prednisolone in combination with azathioprine or mycophenolate mofetil as first-line therapy. Immunosuppression should be given for at least 3 years and for at least 2 years after the achievement of complete biochemical response, while a liver biopsy should be recommended before treatment discontinuation. Current CPG are also provided for several specific conditions and difficult-to-treat patients.
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Affiliation(s)
- George N. Dalekos
- Institute of Internal Medicine and Hepatology, Larissa (George N. Dalekos)
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa (George N. Dalekos)
| | - John Koskinas
- Second Department of Internal Medicine, National and Kapodistrian University of Athens, “Hippokratio” General Hospital of Athens, Athens (John Koskinas)
| | - George V. Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, “Laiko” General Hospital of Athens, Athens (George V. Papatheodoridis), Greece
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28
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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: 394] [Impact Index Per Article: 65.7] [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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29
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Cristoferi L, Nardi A, Invernizzi P, Mells G, Carbone M. Individualizing Care: Management Beyond Medical Therapy. Clin Liver Dis 2018; 22:545-561. [PMID: 30259852 DOI: 10.1016/j.cld.2018.03.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The evolving research landscape, with advances in the omics technologies, availability of large-scale patient cohorts, and forthcoming availability of novel drugs in primary biliary cholangitis (PBC), is creating a unique opportunity for developing a precision medicine (PM) program. PM has potential to change the paradigm of management. Diagnostic work-up of PBC patients may include information on genetic variants and molecular signature to define a particular subtype of disease and provide an estimate of treatment response and survival. To reach this point, specific interventions, such as sequencing more genomes, creating bigger biobanks, and linking biological information to health data, are needed.
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Affiliation(s)
- Laura Cristoferi
- Division of Gastroenterology and Hepatology, Department of Medicine and Surgery, University of Milan Bicocca, Piazza dell'Ateneo Nuovo, 1, 20126 Milan, Italy
| | - Alessandra Nardi
- Department of Mathematics, Tor Vergata University of Rome, Via della Ricerca Scientifica 1, Rome, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Hepatology, Department of Medicine and Surgery, University of Milan Bicocca, Piazza dell'Ateneo Nuovo, 1, 20126 Milan, Italy
| | - George Mells
- Academic Department of Medical Genetics, University of Cambridge, Hills Road 1, Cambridge, UK
| | - Marco Carbone
- Division of Gastroenterology and Hepatology, Department of Medicine and Surgery, University of Milan Bicocca, Piazza dell'Ateneo Nuovo, 1, 20126 Milan, Italy; Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
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30
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To U, Silveira M. Overlap Syndrome of Autoimmune Hepatitis and Primary Biliary Cholangitis. Clin Liver Dis 2018; 22:603-611. [PMID: 30259856 DOI: 10.1016/j.cld.2018.03.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Overlap syndrome of autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) is typically defined as concomitant or serial presentation with clinical features of both of these 2 distinct diseases. The Paris criteria and variations of the International Autoimmune Hepatitis group scoring systems for the diagnosis of AIH have been used to diagnose overlap syndrome. If left untreated, patients with overlap syndrome will have higher rates of portal hypertension, gastrointestinal bleeding, ascites, death, and need for liver transplant. Therefore, early identification is essential in providing appropriate therapy to potentially prevent long-term adverse outcomes in patients with overlap syndrome.
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Affiliation(s)
- Uyen To
- Department of Digestive Diseases, Yale University, New Haven, CT, USA
| | - Marina Silveira
- Department of Digestive Diseases, Yale University, New Haven, CT, USA.
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31
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Schulz L, Sebode M, Weidemann SA, Lohse AW. Variant syndromes of primary biliary cholangitis. Best Pract Res Clin Gastroenterol 2018; 34-35:55-61. [PMID: 30343711 DOI: 10.1016/j.bpg.2018.06.003] [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: 02/13/2018] [Accepted: 06/08/2018] [Indexed: 02/07/2023]
Abstract
Patients with primary biliary cholangitis (PBC) can show biochemical, serological and/or histological features of autoimmune hepatitis (AIH). The term 'AIH-PBC overlap syndrome' has been used frequently for these cases and implies the coexistence of two separate diseases. However, the boundaries between 'classical' PBC, PBC with features of AIH and 'classical' AIH are difficult to define, and therefore the term 'variant syndrome' should be preferred. A variant syndrome must primarily be assumed in PBC patients showing pronounced hepatitic activity, either expressed by elevated transaminases and raised levels of serum IgG/gammaglobulins or more specifically by liver biopsy showing a modified hepatitis activity index (mHAI) score of >4/18. The presence of AIH-specific autoantibodies also supports the diagnosis of a variant syndrome. The diagnosis must not be missed because individually adapted immunosuppressive treatment, analogous to AIH therapy, appears to have an important beneficial impact on the prognosis and should therefore be offered to these patients.
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Affiliation(s)
- Lisa Schulz
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Marcial Sebode
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören A Weidemann
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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32
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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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33
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Zhang W, De D, Mohammed KA, Munigala S, Chen G, Lai JP, Bacon BR. New scoring classification for primary biliary cholangitis-autoimmune hepatitis overlap syndrome. Hepatol Commun 2018; 2:245-253. [PMID: 29507900 PMCID: PMC5831022 DOI: 10.1002/hep4.1148] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 11/03/2017] [Accepted: 12/17/2017] [Indexed: 02/05/2023] Open
Abstract
Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are two major immune‐mediated chronic liver diseases. Overlap syndrome (OS) is diagnosed if patients have features of both AIH and PBC; however, there is no consensus on the definition or diagnostic criteria for OS. Here, we report a new scoring classification for OS and evaluate its usefulness. This new scoring classification was developed by modifying the International Autoimmune Hepatitis Group classification by selecting histologic features of AIH and PBC along with modifications of biochemical and immunologic characteristics. We evaluated 272 patients with chronic liver disease, including 105 with AIH, 102 with PBC, and 65 with OS. The best performance for the diagnosis of OS was noted among patients with an overlap score of ≥21 who had a sensitivity of 98.5%, a specificity of 92.8%, a positive predictive value of 81.0%, and a negative predictive value of 99.5%. By using a cut‐off score of 21, 64 (98.5%) patients were diagnosed with OS as opposed to 9 (8.8%) and 6 (5.7%) with PBC and AIH, respectively. All patients with OS had an aggregate score of >19, whereas most patients with PBC or AIH scored <19, making this a safe discriminatory cut‐off point against OS. Conclusion: The new scoring system for the diagnosis of OS has a high sensitivity and specificity for scores ≥21, while a score <19 suggests a diagnosis other than OS. This classification can identify patients and diagnose OS with a reasonable amount of accuracy and may be superior to current OS scoring systems in detecting mild forms of OS. (Hepatology Communications 2018;2:245‐253)
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Affiliation(s)
- Wei Zhang
- Department of Internal Medicine Saint Louis University School of Medicine St Louis MO
| | - Debapriya De
- Division of Gastroenterology and Hepatology Saint Louis University School of Medicine St Louis MO
| | - Kahee A Mohammed
- Department of Internal Medicine Saint Louis University School of Medicine St Louis MO.,Saint Louis University Center for Outcomes Research St. Louis MO
| | - Satish Munigala
- Saint Louis University Center for Outcomes Research St. Louis MO
| | - Guilan Chen
- Department of Pathology Saint Louis University School of Medicine St. Louis MO
| | - Jin-Ping Lai
- Department of Pathology Saint Louis University School of Medicine St. Louis MO.,Department of Pathology, Immunology, and Laboratory Medicine University of Florida, College of Medicine Gainesville FL
| | - Bruce R Bacon
- Division of Gastroenterology and Hepatology Saint Louis University School of Medicine St Louis MO.,Saint Louis University Liver Center St Louis MO
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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: 864] [Impact Index Per Article: 108.0] [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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Omori K, Yoshida K, Yokota M, Daa T, Kan M. Familial occurrence of autoimmune liver disease with overlapping features of primary biliary cholangitis and autoimmune hepatitis in a mother and her daughter. Clin J Gastroenterol 2016; 9:312-8. [PMID: 27503128 PMCID: PMC5035326 DOI: 10.1007/s12328-016-0676-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 07/22/2016] [Indexed: 01/03/2023]
Abstract
We encountered two patients with overlapping features of primary biliary cholangitis and autoimmune hepatitis within the same family. A 68-year-old woman presented at our hospital from a previous medical institution because of the diagnosis of primary biliary cholangitis. Her 49-year-old daughter was admitted with liver dysfunction 4 years later. When compared, these two related patients were found to have overlapping features of primary biliary cholangitis and autoimmune hepatitis. Their human leukocyte antigen haplotype was DRB1*04:05/DRB1*15:02. The clinical and biochemical findings of these two patients immediately improved following treatment with a combination of prednisolone and ursodeoxycholic acid, in accordance with the Japanese guidelines. It is extremely important to identify such pathological conditions as quickly as possible, particularly with the appearance of severe liver dysfunction due to liver cirrhosis, as observed in our case. The Japanese guidelines are considered to be a realistic and useful clinical policy for the swift and efficient treatment of patients with overlapping features of primary biliary cholangitis and autoimmune hepatitis. We suggest that our two patients presented with a genetic predisposition to autoimmune liver disease with overlapping features of primary biliary cholangitis and autoimmune hepatitis within the same family.
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Affiliation(s)
- Kaoru Omori
- Department of Gastroenterology and Hepatology, Sato Daiichi Hospital, 77-1 Hokyoji, Usa, Oita, 879-0454, Japan.
| | - Kanako Yoshida
- Department of Gastroenterology and Hepatology, Sato Daiichi Hospital, 77-1 Hokyoji, Usa, Oita, 879-0454, Japan
| | - Masaki Yokota
- Department of Gastroenterology, Nakatsu Municipal Hospital, 173 Shimo-Ikenaga, Nakatsu, Oita, 871-8511, Japan
| | - Tsutomu Daa
- Department of Pathology, Graduate School of Medicine, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan
| | - Masahiro Kan
- Department of Gastroenterology and Hepatology, Sato Daiichi Hospital, 77-1 Hokyoji, Usa, Oita, 879-0454, Japan
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Mitra S, Minz RW. Autoantibodies in Autoimmune Liver Diseases-Methods of Detection and Interpretation: An Update for the Reporting Pathologist. Int J Surg Pathol 2016; 24:576-85. [PMID: 27388199 DOI: 10.1177/1066896916657643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Autoimmune liver disease (AILD) is a type of chronic liver disease with autoimmune etiology. The diagnosis of the disease is multipronged and detection of autoantibodies in AILDs is an important diagnostic tool and it also helps in the classification of the disease. There are multiple autoantibodies that are detected in AILDs but none is diagnostic. Moreover, these autoantibodies are detected in many other pathological and nonpathological conditions. So the significance of seropositivity for these autoantibodies should be known by both the pathologists as well as the clinicians. In addition, there is prognostic significance associated with some of the antibodies and they also sometimes help in the disease monitoring. The whole array of antibodies detected in AILDs is discussed in detail in this review along with their clinical significance and interpretation.
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Affiliation(s)
- Suvradeep Mitra
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Ranjana Walker Minz
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
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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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Affiliation(s)
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- EASL office, 7 Rue Daubin, CH 1203 Geneva, Switzerland,
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Reshetnyak VI. Primary biliary cirrhosis: Clinical and laboratory criteria for its diagnosis. World J Gastroenterol 2015; 21:7683-7708. [PMID: 26167070 PMCID: PMC4491957 DOI: 10.3748/wjg.v21.i25.7683] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 04/07/2015] [Accepted: 06/10/2015] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic granulomatous, and destructive inflammatory lesion of small intralobular and septal bile ducts, which is likely to be caused by an autoimmune mechanism with a the presence of serum antimitochondrial antibodies and a potential tendency to progress to cirrhosis. Despite the fact that the etiology of this disease has been unknown so far, there has been a considerable body of scientific evidence that can reveal the clinical and laboratory signs of PBC and the individual components of its pathogenesis and elaborate diagnostic criteria for the disease and its symptomatic therapy. Deficiencies in autoimmune tolerance are critical factors for the initiation and perpetuation of the disease. The purpose of this review is to summarize the data available in the literature and the author's findings on clinical and laboratory criteria for the diagnosis of PBC. This review describes the major clinical manifestations of the disease and the mechanisms of its development. It presents the immunological, biochemical, and morphological signs of PBC and their significance for its diagnosis. A great deal of novel scientific evidence for the problem of PBC has been accumulated. However, the inadequate efficiency of therapy for the disease lends impetus to the quest for its etiological factors and to further investigations of its pathogenetic mechanisms and, on this basis, to searches for new methods for its early diagnosis.
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Abstract
Overlapping features between autoimmune hepatitis (AIH) and cholestatic disorders (primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or indeterminate cholestasis), so-called overlap syndromes, usually have a progressive course toward cirrhosis and liver failure without adequate treatment. The diagnosis of overlap syndrome requires the prominent features of classic AIH and secondary objective findings of PBC or PSC. Empiric treatment for patients with AIH-PBC overlap is immunosuppressive therapy plus ursodeoxycholic acid. Empiric treatment for patients with AIH-PSC and AIH-cholestatic overlap is immunosuppressive therapy with or without ursodeoxycholic acid. Liver transplantation is indicated for patients who have end-stage liver disease.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA; Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA.
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Liu F, Pan ZG, Ye J, Xu D, Guo H, Li GP, Xu KS, Hou XH, Song YH. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: simplified criteria may be effective in the diagnosis in Chinese patients. J Dig Dis 2014; 15:660-668. [PMID: 25236944 DOI: 10.1111/1751-2980.12196] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To evaluate the Paris criteria, the revised diagnostic criteria and the simplified diagnostic scoring system in the diagnosis of primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome in Chinese patients. METHODS Medical records of the patients who were diagnosed with PBC at the Union Hospital and Tongji Hospital, Tongji Medical University, Huazhong University of Science and Technology (Wuhan, Hubei Province, China) from 2003 to 2012 were retrospectively reviewed. The overlap syndrome was diagnosed based on the Paris criteria, the revised criteria and the simplified criteria, respectively. Patients' clinical characteristics, laboratory examination results and histological findings were collected. The sensitivity and specificity of the three criteria for diagnosing PBC-AIH overlap syndrome were calculated. RESULTS PBC-AIH overlap syndrome was diagnosed in 2, 13 and 10 patients with PBC based on the Paris, the revised and the simplified criteria, respectively. The sensitivity and specificity of the simplified criteria in diagnosing the overlap syndrome was 90.0% and 98.2%, which were the highest among the three criteria, followed by the revised criteria. The Paris criteria showed a high specificity (100%) but a relatively low sensitivity (20.0%). In addition, some patients who did not fulfil the Paris criteria still benefited from the immunosuppressive agents. CONCLUSIONS For Chinese patients with the PBC-AIH overlap syndrome, the simplified criteria appear to be the most efficacious compared with the Paris criteria and the revised criteria. Further studies should be performed to confirm these observations with respect to long-term outcomes and therapeutic implications.
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Affiliation(s)
- Fang Liu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Cholestatic phenotypes of autoimmune hepatitis. Clin Gastroenterol Hepatol 2014; 12:1430-8. [PMID: 24013108 DOI: 10.1016/j.cgh.2013.08.039] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 08/21/2013] [Accepted: 08/21/2013] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis can have cholestatic features that are outside the codified diagnostic criteria. These features have uncertain effects on the clinical presentation and progression of disease. Patients with autoimmune hepatitis can have antimitochondrial antibodies and coincidental bile duct injury or loss (2%-13% of patients), focal biliary strictures and dilations based on cholangiography (2%-11%), or histologic changes of bile duct injury or loss in the absence of other features (5%-11%). These findings probably represent atypical manifestations of autoimmune hepatitis or variants of primary biliary cirrhosis or primary sclerosing cholangitis, depending on the predominant findings. Serum levels of alkaline phosphatase and γ-glutamyl transferase, histologic features of bile duct injury, and findings from cholangiography are associated with responsiveness to corticosteroid therapy and individualized alternative treatments. Corticosteroid therapy, in combination with low-dose ursodeoxycholic acid, has been promulgated by international societies, but these recommendations are not based on strong evidence. The frequency, variable outcomes, and uncertainties in diagnosis and management of the cholestatic phenotypes must be addressed by a collaborative investigational network. This network should define the genetic and pathologic features of these disorders, standardize their nomenclature, and establish a treatment algorithm. In this review, the different cholestatic phenotypes of autoimmune hepatitis, mechanisms of pathogenesis, current management strategies and outcomes, and opportunities for improving understanding and therapy are presented.
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Zhou WC, Zhang QB, Qiao L. Pathogenesis of liver cirrhosis. World J Gastroenterol 2014; 20:7312-7324. [PMID: 24966602 PMCID: PMC4064077 DOI: 10.3748/wjg.v20.i23.7312] [Citation(s) in RCA: 380] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 03/16/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.
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Abstract
BACKGROUND Primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome is used to describe the coexistence of both diseases, with either a sequential or a simultaneous presentation in the same patient. Available studies have focused on the simultaneous form, whereas there is limited information on sequential PBC-AIH. We carried out a retrospective study of patients who sequentially developed PBC-AIH overlap syndrome. METHODS The medical data of 1065 patients diagnosed with PBC (n=483) and AIH (n=582) were retrospectively analyzed. RESULTS A sequential development of PBC-AIH was observed in 19 (1.8%) patients after a mean of 6.5 (1-14) years of follow-up. AIH developed in 12 (2.5%) PBC patients, whereas PBC occurred in seven (1.2%) patients with AIH. The baseline serologic and histological findings of patients who developed PBC-AIH were similar to those of patients with typical PBC or AIH. Eighteen patients were treated with a combination of ursodeoxycholic acid (UDCA) and immunosuppression after the diagnosis of PBC-AIH was established. One patient showed a spontaneous resolution of hepatitic flare under UDCA therapy. Biochemical remission was achieved in 16 patients, whereas three progressed to decompensated cirrhosis and required liver transplantation. CONCLUSION The sequential overlap of PBC-AIH can occur during the follow-up of patients with pure PBC or AIH. In our cohort, we could not identify any factors that predicted the development of this rare condition. The combination of UDCA and immunosuppression seems to be an appropriate therapy in the setting of PBC-AIH.
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Factors associated with response to therapy and outcome of patients with primary biliary cirrhosis with features of autoimmune hepatitis. Clin Gastroenterol Hepatol 2014; 12:863-9. [PMID: 24076417 DOI: 10.1016/j.cgh.2013.09.021] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Revised: 09/09/2013] [Accepted: 09/10/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS For patients with primary biliary cirrhosis (PBC) with features of autoimmune hepatitis (AIH), treatment with ursodeoxycholic acid (UDCA) alone or in combination with immunosuppression is controversial. Little is known about the factors associated with initial response to therapy or outcome. We performed a retrospective analysis of treatment strategies and factors associated with outcomes of patients with PBC-AIH. METHODS We analyzed data from 88 patients who were diagnosed with PBC-AIH according to Paris criteria, from 7 centers in 5 countries. First-line therapies included UDCA alone (n = 30) or a combination of UDCA and immunosuppression (n = 58). RESULTS Of patients who received UDCA alone as the first-line therapy, 37% did not respond to treatment. Severe interface hepatitis was independently associated with lack of response to treatment (P = .024; odds ratio, 0.05; 95% confidence interval, 0.004-0.68). The combination of UDCA and immunosuppression was effective in 73% of patients who had not been previously treated or had not responded to UDCA. The presence of advanced fibrosis was associated with lack of response to the combination of UDCA and immunosuppression (P = .003; odds ratio, 0.13; 95% confidence interval, 0.03-0.48). Second-line immunosuppressive agents (cyclosporine, tacrolimus, and mycophenolate mofetil) led to biochemical remission in 54% of patients who did not respond to initial immunosuppression. Liver transplants were given to 4 patients with PBC-AIH. Five patients died during follow-up (3 from liver-related causes). CONCLUSIONS In a retrospective study of a large cohort of patients with PBC-AIH, UDCA alone did not produce a biochemical response in most patients with severe interface hepatitis; these patients require additional therapy with immunosuppression. Second-line immunosuppressive agents are effective in controlling disease activity in patients who do not respond to conventional immunosuppression.
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Diagnosis and management of the overlap syndromes of autoimmune hepatitis. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2014; 27:417-23. [PMID: 23862175 DOI: 10.1155/2013/198070] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Autoimmune hepatitis may have cholestatic features that are outside the classical phenotype and that resemble findings in other immune-mediated liver diseases. These cholestatic phenotypes have been designated 'overlap syndromes'. OBJECTIVES To recognize the overlap syndromes in adults and manage them appropriately. METHODS The MEDLINE database was reviewed for published experiences from 1984 to 2013. RESULTS Patients with autoimmune hepatitis may exhibit features of primary biliary cirrhosis (7% to 13%), primary sclerosing cholangitis (6% to 11%) or a cholestatic syndrome without other diagnostic features (5% to 11%). These mixed phenotypes may represent classical autoimmune hepatitis with atypical features, transition states in the evolution of classical cholestatic syndromes, concurrent separate diseases or pathogenically distinct disorders. The 'Paris criteria' have been endorsed for the diagnosis of the overlap syndrome with primary biliary cirrhosis, and treatment with conventional immunosuppressive therapy alone or in combination with low-dose ursodeoxycholic acid can be guided by the serum alkaline phosphatase level. The overlap syndrome with primary sclerosing cholangitis or with cholestasis without diagnostic features is commonly treated with immunosuppressive therapy and ursodeoxycholic acid. Responses are variable and commonly incomplete (20% to 100% improvement) depending on the degree of cholestasis. DISCUSSION The overlap syndromes are clinical descriptions rather than pathological entities, and the dominant component of the disease determines its designation and therapy. Cholestatic findings in autoimmune hepatitis influence the response to immunosuppressive therapy. CONCLUSION The overlap syndromes must be considered in patients with autoimmune hepatitis and cholestatic findings, concurrent inflammatory bowel disease or steroid-refractory disease.
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Abstract
The care of the patient with cholestasis hinges on identifying the etiology, treating reversible causes, and managing chronic cholestatic processes. PBC and PSC are important causes of chronic cholestasis, and are the most common causes of cholestatic liver disease. Effective therapy is available for patients with PBC, whereas none exists for patients with PSC. Awareness of the complications that may be associated with cholestasis and implementing the appropriate management are essential.
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Affiliation(s)
- Andrea A Gossard
- Cholestatic Liver Disease Study Group, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
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Abstract
Autoimmune hepatitis is a disease of the hepatic parenchyma that can present in acute or chronic forms. In common with many autoimmune diseases, autoimmune hepatitis is associated with non-organ-specific antibodies in the context of hepatic autoimmunity. This dichotomy has made definition of a unifying hypothesis in the pathophysiology of the disease difficult, although data from the past 8 years have drawn attention to the role of regulatory T cells. Several triggers have been identified, and the disease arises in genetically susceptible individuals. Clinical and biochemical remission is achievable in up to 85% of cases. For the remaining patients, alternative immunosuppression strategies are an option. Liver transplantation provides an excellent outcome for patients with acute liver failure or complications of end-stage liver disease, including hepatocellular carcinoma. Variant or overlapping syndromes are worthy of consideration when unexpected disease features arise.
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Affiliation(s)
- Michael A Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK.
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Novel insights into autoimmune liver diseases provided by genome-wide association studies. J Autoimmun 2013; 46:41-54. [PMID: 23931959 DOI: 10.1016/j.jaut.2013.07.004] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 07/08/2013] [Indexed: 12/14/2022]
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