|
1
|
Ronca V, Parente A, Lytvyak E, Hansen BE, Hirschfield G, Bonder A, Ebadi M, Elwir S, Alsaed M, Milkiewicz P, Janik MK, Marschall HU, Burza MA, Efe C, Rıza Calışkan A, Harputluoglu M, Kabaçam G, Terrabuio D, de Quadros Onofrio F, Selzner N, Parés A, Llovet L, Akyıldız M, Arikan C, Manns MP, Taubert R, Weber AL, Schiano TD, Haydel B, Czubkowski P, Socha P, Ołdak N, Akamatsu N, Tanaka A, Levy C, Martin EF, Goel A, Sedki M, Jankowska I, Ikegami T, Rodriguez M, Sterneck M, Sebode M, Schramm C, Donato MF, Colapietro F, Lohse A, Andrade RJ, Patwardhan VR, van Hoek B, Biewenga M, Kremer AE, Ueda Y, Deneau M, Pedersen M, Mayo MJ, Floreani A, Burra P, Secchi MF, Terziroli Beretta-Piccoli B, Sciveres M, Maggiore G, Jafri SM, Debray D, Girard M, Lacaille F, Heneghan M, Mason AL, Oo Y, Montano-Loza AJ. Recurrence of autoimmune hepatitis cholestatic variant syndromes after liver transplantation affects graft and patient survival. JHEP Rep 2025; 7:101332. [PMID: 40276483 PMCID: PMC12018556 DOI: 10.1016/j.jhepr.2025.101332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 04/26/2025] Open
Abstract
Background & Aims A significant proportion of patients with variant syndromes (VSs), namely autoimmune hepatitis/primary biliary cholangitis or autoimmune hepatitis/primary sclerosing cholangitis, require liver transplantation (LT) despite treatment. The frequency of disease recurrence and the effect on graft survival are yet to be clarified. The aim of this international, multicentric, retrospective study is to evaluate the risk factors associated with recurrence and the impact of the disease recurrence after LT on graft and patient survival. Methods We evaluated 166 patients undergoing LT for VS in 33 centers in North America, South America, Europe, and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients with a higher risk of recurrence of autoimmune disease based on a histological and radiological diagnosis. Cumulative probabilities of graft and overall survival after LT were calculated using a semi-Markov model. Results The autoimmune pattern of recurrence resembled the original VS in 19 cases (61%). Recurrence of autoimmune liver disease (rALD) after LT was observed in 23% and 33% of patients after 5 and 10 years, respectively. Increased alkaline phosphatase (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.13-2.25, p <0.01) and alanine aminotransferase (HR 1.25, 95% CI 1.01-1.53, p = 0.03) at 12 months after LT and acute rejection (HR 3.58, 95% CI 1.60-7.73, p <0.01) were associated with a higher risk of VS recurrence, whereas the use of predniso(lo)ne was associated with a reduced risk (HR 0.30, 95% CI 0.14-0.64, p <0.01). After adjusting for alanine aminotransferase and alkaline phosphatase at 12 months, the use of predniso(lo)ne was found to be independently and negatively associated with recurrent disease. The rALD was found to be significantly associated with graft loss and patient survival in the multivariate Cox regression analysis with a time-dependent covariate. The 5- and 10-year probabilities of graft survival were 68% and 41% in patients with recurrent VS compared with 83% and 60% in patients without recurrent disease, respectively (p = 0.01). The overall survival was significantly reduced in patients with recurrent disease (p = 0.01), with event probability at 5 and 10 years of 75% and 49% vs. 84% and 60% in patients without recurrence, respectively. Conclusions rALD after LT is frequent and is associated with elevation in liver enzymes within the first year after LT and rejection episodes. According to our data, VS recurrence appears to be associated with poorer graft and patient survival. Further studies are needed to explore strategies that can prevent VS recurrence or mitigate its potential impact. Impact and implications This study investigated the recurrence of autoimmune liver diseases (rALD) in patients transplanted for variant syndromes (VSs) and its effect on graft and patient survival. The findings reveal a significant association between rALD and poorer graft and overall survival, highlighting the need for preventive strategies. This research is crucial for transplant physicians and healthcare providers, as it underscores the impact of early liver enzyme monitoring and tailored immunosuppressive therapy on long-term outcomes. These insights can inform more effective post-LT management protocols, potentially improving patient prognosis.
Collapse
Affiliation(s)
- Vincenzo Ronca
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Alessandro Parente
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, Denmark Hill, SE59RS, London, UK
| | - Ellina Lytvyak
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Bettina E. Hansen
- Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
| | - Gideon Hirschfield
- Toronto Center for Liver Disease, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Alan Bonder
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Maryam Ebadi
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada
| | - Saleh Elwir
- Baylor University Medical Center, Dallas, TX, USA
| | | | - Piotr Milkiewicz
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
| | - Maciej K. Janik
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
| | - Hanns-Ulrich Marschall
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Maria Antonella Burza
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Department of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Gothenburg, Sweden
| | - Cumali Efe
- Department of Gastroenterology, Harran University Hospital, Şanlıurfa, Turkey
| | - Ali Rıza Calışkan
- Department of Gastroenterology, Adiyaman University School of Medicine, Adiyaman, Turkey
| | - Murat Harputluoglu
- Department of Gastroenterology, Inönü University School of Medicine, Malatya, Turkey
| | - Gökhan Kabaçam
- Clinic of Gastroenterology and Liver Transplantation, Guven Hospital, Ankara, Turkey
| | - Débora Terrabuio
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | | | - Nazia Selzner
- Toronto Center for Liver Disease, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Albert Parés
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona Spain
| | - Laura Llovet
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona Spain
| | - Murat Akyıldız
- Koç University School of Medicine, Department of Gastroenterology and Liver Transplantation Center, Istanbul, Turkey
| | - Cigdem Arikan
- Koc University School of Medicine Pediatric Gastroenterology and Hepatology, Organ Transplantation Center, Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey
| | - Mihael P. Manns
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Anna-Lena Weber
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Thomas D. Schiano
- Recanati/Miller Transplantation Institute/Division of Liver Diseases, Mount Sinai Medical Center, New York, NY, USA
| | - Brandy Haydel
- Recanati/Miller Transplantation Institute/Division of Liver Diseases, Mount Sinai Medical Center, New York, NY, USA
| | - Piotr Czubkowski
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Piotr Socha
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Natalia Ołdak
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Nobuhisa Akamatsu
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Cynthia Levy
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Eric F. Martin
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Aparna Goel
- Division of Gastroenterology & Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Mai Sedki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Irena Jankowska
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Maria Rodriguez
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- UKE Hamburg, Hamburg, Germany
| | - Martina Sterneck
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- UKE Hamburg, Hamburg, Germany
| | - Marcial Sebode
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- UKE Hamburg, Hamburg, Germany
| | - Christoph Schramm
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- UKE Hamburg, Hamburg, Germany
| | - Maria Francesca Donato
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Liver Transplant Hepatology Unit, Division of Gastroenterology and Hepatology, Milan, Italy
| | - Francesca Colapietro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Ansgar Lohse
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- UKE Hamburg, Hamburg, Germany
| | - Raul J. Andrade
- Gastroenterology Service—IBIMA, University Hospital and CIBERehd, University of Málaga, Málaga, Spain
| | - Vilas R. Patwardhan
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Bart van Hoek
- Leiden University Medical Center, Leiden, The Netherlands
| | | | - Andreas E. Kremer
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Department of Medicine, University Hospital Erlangen and Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
- Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Mark Deneau
- University of Utah and Intermountain Healthcare Primary Children's Hospital, Salt Lake City, Utah, USA
| | - Mark Pedersen
- The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Marlyn J. Mayo
- The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Annarosa Floreani
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Patrizia Burra
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Maria Francesca Secchi
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- University of Padova, Padova, Italy
| | | | | | - Giuseppe Maggiore
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Hepatogastroenterology, Nutrition and Liver Transplant IRCCS Bambino Gesù Pediatric Hospital, Rome Italy
| | | | - Dominique Debray
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Pediatric Liver Unit, Paris Descartes University and French National Reference Center for Rare Diseases BA and Genetic Cholestasis, Hôpital Necker, Paris, France
| | - Muriel Girard
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Pediatric Liver Unit, Paris Descartes University and French National Reference Center for Rare Diseases BA and Genetic Cholestasis, Hôpital Necker, Paris, France
| | - Florence Lacaille
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Pediatric Liver Unit, Paris Descartes University and French National Reference Center for Rare Diseases BA and Genetic Cholestasis, Hôpital Necker, Paris, France
| | - Michael Heneghan
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, Denmark Hill, SE59RS, London, UK
| | - Andrew L. Mason
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada
| | - Ye Oo
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
- Centre for Liver and Gastro Research, Birmingham NIHR Inflammation Biomedical Research, Birmingham, UK
- Centre Liver Unit, Queen Elizabeth University Hospital Birmingham, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Aldo J. Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
|
2
|
Srinath VBS, Shahid F, Saddique MN, Mumtaz H, Iqbal J. Cholestatic Phenotype in Autoimmune Hepatitis: A Rare Presentation. Dig Dis Sci 2025:10.1007/s10620-025-08927-x. [PMID: 40019586 DOI: 10.1007/s10620-025-08927-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 02/14/2025] [Indexed: 03/01/2025]
Affiliation(s)
| | - Fatima Shahid
- King Edward Medical University, Lahore, 54000, Pakistan
| | | | | | - Javed Iqbal
- Nursing Department Communicable Disease Centre, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
| |
Collapse
|
|
3
|
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.
Collapse
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
| |
Collapse
|
|
4
|
Waldron O, Kim A, Daoud D, Zhu J, Patel J, Butler T, Zhou S, Jain A. A Comparative Review of Standardized Incidence Ratios of De Novo Malignancies Post Liver Transplantation in Males Versus Females. Transplant Proc 2024; 56:1365-1373. [PMID: 39003208 DOI: 10.1016/j.transproceed.2024.01.065] [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: 09/18/2023] [Revised: 12/05/2023] [Accepted: 01/24/2024] [Indexed: 07/15/2024]
Abstract
After liver transplantation (LTx), the most common cause of death in the long-term is de-novo malignancy (DNM). The aim is to review the gender differences in the standardized incidence ratio (SIR) of DNM within the same geographical locations. METHODS Four studies were identified comparing post-LTx SIR between males and females. RESULTS From 6663 males and 2780 females LTx recipients, the mean SIR from each of the four studies for males is 2.8, 2.0, 1.94, and 3.4, and 3.5, 1.3, 1.95, and 2.3 for females. On meta-analysis using a random effect model for each gender group. No significant difference was revealed after logarithmic transformation and subgroup meta-analysis. Overall mean SIR with 95% Confidence Interval (CI) for males is 2.53 (95% CI 1.65-3.88) and 2.3 (1.25-4.24) for females. lung malignancy, 1.97 (1.14-3.41) for males and 2.65 (0.67-10.47) for females. For colorectal malignancy, the combined SIR for males is 1.98 (0.58-6.78) and 1.85 (1.02-3.37) for females. The SIR for female gender-specific malignancies; SIR for breast is 1.1 ± 4.4, cervix 2.9 ± 1.9, uterus 2.8, and ovarian 0.7, and for males, testis 1.6 ± 1.3, prostate 1.2 ± 0.4. However, rare malignancies, male breast cancers (n = 1, SIR, 22.6), and Kaposi's sarcoma, in males (n = 6) and in females (n = 1), had SIR 120. and 212.7, respectively. CONCLUSION Overall, there are no statistical differences between male and female DNM. Female-specific cervix, uterus, ovarian, and male-specific testis and prostate have similar SIR. Rare malignancies have very high SIR.
Collapse
Affiliation(s)
| | - Andrew Kim
- Penn State College of Medicine, Hershey, PA
| | - Deborah Daoud
- Department of General Surgery, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Junjia Zhu
- Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Hershey, PA
| | - Jay Patel
- Department of General Surgery, VCU Medical Center, Richmond, VA
| | - Thomas Butler
- Department of General Surgery, Division of Transplant Surgery, The Pennsylvania State University College of Medicine, Hershey, PA
| | - Shouhao Zhou
- Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Hershey, PA
| | - Ashokkumar Jain
- Department of General Surgery, Division of Transplant Surgery, The Pennsylvania State University College of Medicine, Hershey, PA.
| |
Collapse
|
|
5
|
Lee DU, Ponder R, Lee K, Menegas S, Fan GH, Chou H, Jung D, Lee K, Hastie DJ, Urrunaga NH. The differences in post-liver transplant outcomes of patients with autoimmune hepatitis who present with overlapping autoimmune liver diseases. Hepatol Int 2023; 17:720-734. [PMID: 36575337 PMCID: PMC10225314 DOI: 10.1007/s12072-022-10468-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/03/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND Patients with autoimmune hepatitis (AIH) may co-present with features of primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC). Using a national transplant registry, the outcomes of patients with these autoimmune liver conditions were compared. METHODS The UNOS-STAR registry was used to select a study population of AIH, PSC, and PBC liver transplant (LT) patients. Living and multi-organ transplant cases were excluded. Using the UNOS-registered diagnoses, the study population was subdivided into those with nonoverlapping autoimmune liver diseases and those with overlapping forms (e.g., AIH-PBC). Outcomes were compared, using endpoints such as all-cause mortality, graft failure, and organ-system specific causes of death. RESULTS The main analysis featured 2048 entries, with 1927 entries having nonoverlapping AIH, 52 entries having PSC overlap, and 69 entries having PBC overlap. Patients with PBC overlap were more likely to have graft failure (adjusted hazard ratio [aHR] 3.46 95% CI 1.70-7.05), mortality secondary to respiratory causes (aHR 3.57 95% CI 1.23-10.43), and mortality secondary to recurrent disease (aHR 9.53 95% CI 1.85-49.09). Case incidence rates reflected these findings, expressed in events per 1000 person-years. For patients with PBC overlap and nonoverlapping AIH cases, respectively. Graft failure: 28.87 events vs. 9.42 events, mortality secondary to respiratory causes: 12.83 deaths vs. 3.77 deaths, mortality secondary to recurrent disease: 6.42 deaths vs. 1.26 deaths. Those with AIH-PSC overlap experienced a higher risk of death from graft infection (aHR 10.43 95% CI 1.08-100.37; case-incidence rate: 3.89 vs. 0.31 mortalities per 1000 person-years). Supplementary analysis showed similar findings, in which overlapping autoimmune conditions were associated with higher adverse outcome rates. CONCLUSION Patients with AIH-PBC overlap have higher risk of mortality due to recurrent liver disease and respiratory causes, and patients with AIH-PSC overlap have higher risk of mortality due to graft infection. While further prospective studies are needed to clarify the underlying mechanisms related to these findings, our study characterizes the prognostic implications of AIH overlap on post-LT mortality and graft failure risks.
Collapse
Affiliation(s)
- David Uihwan Lee
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, 22 S. Greene St N3W50, Baltimore, MD, 21201, USA.
| | - Reid Ponder
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA, 02111, USA
| | - Kijung Lee
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA, 02111, USA
| | - Samantha Menegas
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, 22 S. Greene St N3W50, Baltimore, MD, 21201, USA
| | - Gregory Hongyuan Fan
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA, 02111, USA
| | - Harrison Chou
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA, 02111, USA
| | - Daniel Jung
- Department of Medicine, University of Missouri-Kansas City School of Medicine, Boston, MA, USA
| | - Keeseok Lee
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA, 02111, USA
| | - David Jeffrey Hastie
- Department of Medicine, Tufts University School of Medicine, Washington St, Boston, MA, 02111, USA
| | - Nathalie Helen Urrunaga
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, 22 S. Greene St N3W50, Baltimore, MD, 21201, USA
| |
Collapse
|
|
6
|
Fuchs S, Bayer M, Taubert R, Manns MP, Pfeilschifter JM, Christen U, Hintermann E. Effects of adenovirus-induced hepatocyte damage on chronic bile duct inflammation in a sclerosing cholangitis mouse model. Liver Int 2019; 39:2330-2340. [PMID: 31225929 DOI: 10.1111/liv.14183] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 05/10/2019] [Accepted: 06/15/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Four major autoimmune diseases target the liver. They develop because of bile duct destruction, leading to chronic cholestasis or result from hepatocyte damage like autoimmune hepatitis (AIH). Interestingly, some patients simultaneously show features of both cholangitis and AIH. Our goal was to mimic such concurrent characteristics in a mouse model that would help deciphering mechanisms possibly involved in an inflammatory crosstalk between cholestatic disease and hepatitis. METHODS Mdr2-/- mice, which spontaneously develop sclerosing cholangitis because of accumulation of toxic bile salts, were infected with adenovirus (Ad) encoding human Cytochrome P4502D6 (hCYP2D6), the major target autoantigen in type-2 AIH, to trigger hepatocyte injury. Wild type FVB mice were controls. RESULTS Resulting Ad-Mdr2-/- mice presented with cholangitis, fibrosis and cellular infiltrations that were higher than in Mdr2-/- or Ad-FVB mice. Increased levels of anti-neutrophil cytoplasmic antibodies but similar anti-hCYP2D6 antibody titres were detected in Ad-Mdr2-/- compared to Mdr2-/- and Ad-FVB mice respectively. IFNγ-expressing hCYP2D6-specific CD4 T cells declined, whereas hCYP2D6-specific CD8 T cells increased in Ad-Mdr2-/- compared to Ad-FVB mice. The overall T cell balance in Ad-Mdr2-/- mice was a combination of a type 17 T cell response typically found in Mdr2-/- mice with a type 1 dominated T cell response characteristic for Ad-FVB mice. Simultaneously, the type 2 T cell compartment was markedly reduced. CONCLUSIONS Experimental hepatitis induction in a mouse with sclerosing cholangitis results in a disorder which represents not simply the sum of the individual characteristics but depicts a more complex entity which urges on further analysis.
Collapse
Affiliation(s)
- Sina Fuchs
- Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Monika Bayer
- Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Josef M Pfeilschifter
- Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Urs Christen
- Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Edith Hintermann
- Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| |
Collapse
|
|
7
|
Floreani A, De Martin S, Secchi MF, Cazzagon N. Extrahepatic autoimmunity in autoimmune liver disease. Eur J Intern Med 2019; 59:1-7. [PMID: 30360943 DOI: 10.1016/j.ejim.2018.10.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 10/16/2018] [Indexed: 02/07/2023]
Abstract
The most important autoimmune liver disease include: autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis. In general, about one in three patients with an autoimmune liver disease have a concomitant extrahepatic autoimmune disease, which may include rheumatological, endocrinological, gastrointestinal, pulmonary or dermatological conditions. The pathogenesis of these conditions includes the production of both innate and adaptive immune responses targeting cholangiocytes as well as different extrahepatic tissues. In this sense, extrahepatic autoimmunity represent a continuous spectrum of autoimmunity involving liver and extrahepatic tissues. This review aims to focus the clinical and pathophysiological aspects of extrahepatic autoimmunity associated to autoimmune liver diseases.
Collapse
Affiliation(s)
- Annarosa Floreani
- Dept of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, 35128, Italy.
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Maria Francesca Secchi
- Dept of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, 35128, Italy
| | - Nora Cazzagon
- Dept of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, 2, 35128, Italy
| |
Collapse
|
|
8
|
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.
Collapse
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
| |
Collapse
|
|
9
|
Liu XM, Xu Y, Bao J, Gao SJ, Hua J, Kang GL. Ursodeoxycholic acid combined with glucocorticoids for treatment of primary biliary cirrhosis with characteristics of autoimmune hepatitis. Shijie Huaren Xiaohua Zazhi 2017; 25:456-462. [DOI: 10.11569/wcjd.v25.i5.456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To observe the efficacy of ursodeoxycholic acid (UDCA) combined with glucocorticoids in the treatment of primary biliary cirrhosis (PBC) with characteristics of autoimmune hepatitis (AIH).
METHODS Thirty-one patients with PBC with AIH characteristics were divided into two group: a UDCA alone group and a UDCA combined with glucocorticoid group. Blood biochemical indexes before and after treatment were retrospectively analyzed. Immunoglobulin indexes, liver pathological changes, and the status of response to treatment were also observed.
RESULTS In both groups, the levels of alkaline phosphatase (ALP), γ-glutamyl transferase (GGT) and immunoglobulin M (IgM) decreased after therapy, and the improvement of ALP and IgM had statistical significance (P < 0.05). In the combination group, alanine transaminase, aspartate transaminase, GGT, ALP, globulin, and immunoglobulin obviously improved compared with baseline values. Biochemical responses showed no significant difference between the two groups, although the combination group had a higher response rate. In patients with different pathological stages of disease, ALP response rate was statistically significant (P < 0.05). The degree and extent of liver inflammation or fibrosis and bile duct damage significantly improved after treatment in the combination group.
CONCLUSION For patients with PBC with AIH characteristics, a definitive diagnosis should be achieved as early as possible. UDCA plus glucocorticoid treatment is recommended to better control the progression of the disease.
Collapse
|
|
10
|
Ali AH, Carey EJ, Lindor KD. The management of autoimmunity in patients with cholestatic liver diseases. Expert Rev Gastroenterol Hepatol 2016; 10:73-91. [PMID: 26523975 DOI: 10.1586/17474124.2016.1095088] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cholestatic liver diseases are rare diseases that often lead to cirrhosis and its consequent complications. In addition to liver-related morbidity, patients with cholestatic liver diseases often suffer from autoimmune diseases that affect several organs and tissues. The robust and efficient data collection and collaboration between hepatologists and rheumatologists have led to significant advancements in understanding the relationship between the cholestatic liver diseases and associated autoimmune diseases. In this paper, we discuss the cholestatic liver diseases (primary biliary cirrhosis, primary sclerosing cholangitis and immunoglobulin G4 associated cholangitis) and associated autoimmune diseases.
Collapse
Affiliation(s)
- Ahmad H Ali
- a 1 Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Elizabeth J Carey
- a 1 Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Keith D Lindor
- a 1 Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA.,b 2 Arizona State University, College of Health Solutions, Phoenix, AZ, USA
| |
Collapse
|
|
11
|
van Gerven NMF, de Boer YS, Mulder CJJ, van Nieuwkerk CMJ, Bouma G. Auto immune hepatitis. World J Gastroenterol 2016; 22:4651-4661. [PMID: 27217697 PMCID: PMC4870072 DOI: 10.3748/wjg.v22.i19.4651] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 03/29/2016] [Accepted: 04/20/2016] [Indexed: 02/06/2023] Open
Abstract
To provide an update of the latest trends in epidemiology, clinical course, diagnostics, complications and treatment of auto immune hepatitis (AIH). A search of the MEDLINE database was performed using the search terms: “auto immune hepatitis”, “clinical presentation”, “symptoms”, “signs”, “diagnosis”, “auto antibodies”, “laboratory values”, “serology”, “histopathology”, “histology”, “genetics”, “HLA genes”, “non-HLA genes”, “environment”, “epidemiology”, “prevalence”, “incidence”, “demographics”, “complications”, “HCC”, “PBC”, “PSC”, “corticosteroid”, “therapy”, “treatment”, “alternative treatment”. English-language full-text articles and abstracts were considered. Articles included reviews, meta-analysis, prospective retrospective studies. No publication date restrictions were applied. AIH is an immune meditated progressive inflammatory liver disease that predominantly affects middle-aged females but may affect people of all ages. The clinical spectrum of AIH is wide, ranging from absent or mild symptoms to fulminant hepatic failure. The aetiology of AIH is still unknown, but is believed to occur as the consequence of an aberrant immune response towards an un-known trigger in a genetically susceptible host. In the absence of a gold standard, diagnosis is based on the combination of clinical, biochemical and histopathological criteria. Immunosuppressive treatment has been the cornerstone of treatment since the earliest description of the disease in 1950 by Waldenström. Such treatment is often successful at inducing remission and generally leads to normal life expectancy. Nevertheless, there remain significant areas of unmet aetiological a clinical needs including fundamental insight in disease pathogenesis, optimal therapy, duration of treatment and treatment alternatives in those patients unresponsive to standard treatment regimens.
Collapse
|
|
12
|
van Gerven NMF, Verwer BJ, Witte BI, van Erpecum KJ, van Buuren HR, Maijers I, Visscher AP, Verschuren EC, van Hoek B, Coenraad MJ, Beuers UHW, de Man RA, Drenth JPH, den Ouden JW, Verdonk RC, Koek GH, Brouwer JT, Guichelaar MMJ, Vrolijk JM, Mulder CJJ, van Nieuwkerk CMJ, Bouma G. Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands. Scand J Gastroenterol 2014; 49:1245-54. [PMID: 25123213 DOI: 10.3109/00365521.2014.946083] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Epidemiological data on autoimmune hepatitis (AIH) are scarce. In this study, we determined the clinical and epidemiological characteristics of AIH patients in the Netherlands (16.7 million inhabitants). METHODS Clinical characteristics were collected from 1313 AIH patients (78% females) from 31 centers, including all eight academic centers in the Netherlands. Additional data on ethnicity, family history and symptoms were obtained by the use of a questionnaire. RESULTS The prevalence of AIH was 18.3 (95% confidential interval [CI]: 17.3-19.4) per 100,000 with an annual incidence of 1.1 (95% CI: 0.5-2) in adults. An incidence peak was found in middle-aged women. At diagnosis, 56% of patients had fibrosis and 12% cirrhosis in liver biopsy. Overall, 1% of patients developed HCC and 3% of patients underwent liver transplantation. Overlap with primary biliary cirrhosis and primary sclerosing cholangitis was found in 9% and 6%, respectively. The clinical course did not differ between Caucasian and non-Caucasian patients. Other autoimmune diseases were found in 26% of patients. Half of the patients reported persistent AIH-related symptoms despite treatment with a median treatment period of 8 years (range 1-44 years). Familial occurrence was reported in three cases. CONCLUSION This is the largest epidemiological study of AIH in a geographically defined region and demonstrates that the prevalence of AIH in the Netherlands is uncommon. Although familial occurrence of AIH is extremely rare, our twin data may point towards a genetic predisposition. The high percentage of patients with cirrhosis or fibrosis at diagnosis urges the need of more awareness for AIH.
Collapse
Affiliation(s)
- Nicole M F van Gerven
- Department of Gastroenterology and Hepatology, VU University Medical Center , Amsterdam , The Netherlands
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Zhang Y, Lu J, Dai W, Wang F, Shen M, Yang J, Zhu R, Zhang H, Chen K, Cheng P, He L, Wang C, Xu L, Zhou Y, Guo C. Combination therapy of ursodeoxycholic Acid and corticosteroids for primary biliary cirrhosis with features of autoimmune hepatitis: a meta-analysis. Gastroenterol Res Pract 2013; 2013:490731. [PMID: 24369456 PMCID: PMC3867832 DOI: 10.1155/2013/490731] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Accepted: 10/09/2013] [Indexed: 12/12/2022] Open
Abstract
A meta-analysis was performed of RCTs comparing therapies that combine UDCA and corticosteroids with UDCA monotherapy. In this paper, we found that the combination therapy of UDCA and corticosteroids was more effective for PBC-AIH.
Collapse
Affiliation(s)
- Yan Zhang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Weiqi Dai
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Fan Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Miao Shen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jing Yang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Rong Zhu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Huawei Zhang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Ping Cheng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Lei He
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Chengfen Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Ling Xu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| |
Collapse
|
|
14
|
Epigenetic considerations and the clinical reevaluation of the overlap syndrome between primary biliary cirrhosis and autoimmune hepatitis. J Autoimmun 2013. [DOI: 10.1016/j.jaut.2012.10.004] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
|
|
15
|
Trivedi PJ, Chapman RW. PSC, AIH and overlap syndrome in inflammatory bowel disease. Clin Res Hepatol Gastroenterol 2012; 36:420-36. [PMID: 22306055 DOI: 10.1016/j.clinre.2011.10.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2011] [Revised: 10/08/2011] [Accepted: 10/14/2011] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a progressive, cholestatic disorder characterised by chronic inflammation and stricture formation of the biliary tree. Symptoms include pruritus, fatigue and in advanced cases ascending cholangitis, cirrhosis and end-stage hepatic failure. Patients are at an increased risk of malignancy arising from the bile ducts, gallbladder, liver and colon. The majority (>80%) of Northern European patients with PSC also have inflammatory bowel disease (IBD), usually ulcerative colitis (UC). IBD commonly presents before the onset of PSC, although the opposite can occur and the onset of both conditions can be separated by many years. The colitis associated with PSC is characteristically mild although frequently involves the whole colon. Despite the majority of patients having relatively inactive colonic disease, paradoxically the risk of colorectal malignancy is substantially increased. Patients may also develop dominant, stenotic lesions of the biliary tree which may be difficult to differentiate from cholangiocarcinoma and the coexistence of IBD may influence the development of this complication. Ursodeoxycholic acid may offer a chemoprotective effect against colorectal malignancy and improve liver biochemical indices. Evidence of any beneficial effect on histological progression of hepatobiliary disease is less clear. High doses (∼25-30 mg/kg/d) may be harmful and should be avoided. Autoimmune hepatitis (AIH) is less common in patients with IBD than PSC, however, an association has been observed. A small subgroup may have an overlap syndrome between AIH and PSC and management should be individualised dependant on liver histology, serum immunoglobulin levels, autoantibodies, degree of biochemical cholestasis and cholangiography.
Collapse
Affiliation(s)
- P J Trivedi
- Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Wolfson Drive, Edgbaston, Birmingham, B15 2TT United Kingdom.
| | | |
Collapse
|
|
16
|
Fallatah HI, Akbar HO. Autoimmune liver disease - are there spectra that we do not know? COMPARATIVE HEPATOLOGY 2011; 10:9. [PMID: 21910861 PMCID: PMC3179434 DOI: 10.1186/1476-5926-10-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2010] [Accepted: 09/12/2011] [Indexed: 12/12/2022]
Abstract
Autoimmune liver diseases (AILDs) are common leading causes for liver cirrhosis and terminal stage of liver disease. They have variable prevalence among patients with liver disease and have two major clinical and biochemical presentations. Autoimmune hepatitis (AIH) is the typical example of hepatocellular AILD, but it can also be presented under a cholestatic pattern. AIH has a scoring diagnostic system and respond in most cases to the treatment with prednisolone and azathioprine. Primary biliary cirrhosis (PBC) is the second most common AILD, with a cholestatic presentation and characterized by positive antimitochondrial antibody (AMA). It has an excellent response and long term outcome with the administration of ursodeoxycholic acid (UDCA). Another AILD that is thought to be a variant of PBC is the autoimmune cholangitis, being a disease that has biochemical and histological features similar to PBC; but the AMA is negative. Primary sclerosing cholangitis (PSC) is a rare entity of AILD that has a cholestatic presentation and respond poorly to the treatment, with the ultimate progression to advance liver cirrhosis in most patients. Other forms of AILD include the overlap syndromes (OS), which are diseases with mixed immunological and histological patterns of two AILD; the most commonly recognized one is AIH-PBC overlap (AIH-PSC overlap is less common). The treatment of OS involves the trial of UDCA and different immunosuppressants. Here we present three case reports of unusual forms of chronic liver diseases that most likely represent AILD. The first two patients had a cholestatic picture, whereas the third one had a hepatocellular picture at presentation. We discussed their biochemical, immunological and histological features as well as their response to treatment and their outcomes. Then, we compared them with other forms of AILD.
Collapse
Affiliation(s)
| | - Hisham O Akbar
- King Abdul Aziz University Hospital, Jeddah, Saudi Arabia
| |
Collapse
|
|
17
|
Jothimani D, Cramp ME, Mitchell JD, Cross TJS. Treatment of autoimmune hepatitis: a review of current and evolving therapies. J Gastroenterol Hepatol 2011; 26:619-27. [PMID: 21073674 DOI: 10.1111/j.1440-1746.2010.06579.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Autoimmune hepatitis (AIH) is an immune-mediated necroinflammatory condition of the liver. Presentation can vary from the asymptomatic individual with abnormal liver function test to fulminant liver failure. The diagnosis is based on the combination of biochemical, autoimmune, and histological parameters, and exclusion of other liver diseases. Standard therapy consists of a combination of corticosteroids and azathioprine, which is efficacious in 80% of patients. Alternative therapies are increasingly being explored in patients who do not respond to the standard treatment and/or have unacceptable adverse effects. This review examines the role of alternative drugs (second-line agents) available for AIH treatment non-responders. These agents include budesonide, mycophenolate mofetil, cyclosporin, tacrolimus, 6-mercaptopurine, 6-thioguanine, rituximab, ursodeoxycholic acid, rapamycin, and methotrexate. In addition, the risk of opportunistic infections and malignancies are discussed. A treatment algorithm is proposed for the management of patients with AIH treatment non-responders.
Collapse
Affiliation(s)
- Dinesh Jothimani
- The Southwest Liver Unit, Derriford Hospital, Plymouth, Devon, UK
| | | | | | | |
Collapse
|
|
18
|
Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011; 54:374-85. [PMID: 21067838 DOI: 10.1016/j.jhep.2010.09.002] [Citation(s) in RCA: 324] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2010] [Revised: 08/30/2010] [Accepted: 09/02/2010] [Indexed: 12/12/2022]
Abstract
Some patients present with overlapping features between disorders within the spectrum of autoimmune liver diseases (i.e. autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC)) and are commonly classified as having an "overlap syndrome". Standardized definitions of "overlap syndromes" are lacking. The aim of this report by the International Autoimmune Hepatitis Group (IAIHG) is to evaluate if there are important reasons to classify conditions with overlapping features between autoimmune liver diseases as separate diagnostic entities. Definition of diagnostic criteria for overlap conditions can only be arbitrary. The IAIHG scoring system for diagnosis of AIH has been widely used to diagnose "overlap syndromes", but was not intended for such use and has not proven to be an efficient tool for this purpose. Some patients with overlapping features between a cholestatic and hepatitic disorder appear to benefit from treatment with a combination of ursodeoxycholic acid and immunosuppressants, but this strategy is not evidence-based, and it seems unjustified to define new diagnostic groups in this regard. The IAIHG suggests that patients with autoimmune liver disease should be categorized according to the predominating feature(s) as AIH, PBC, and PSC/small duct PSC, respectively, and that those with overlapping features are not considered as being distinct diagnostic entities. The IAIHG scoring system should not be used to establish subgroups of patients. Patients with PBC and PSC with features of AIH should be considered for immunosuppressive treatment. Due to the low prevalence of such "overlap syndromes", prospective interventional therapeutic trials cannot be expected in the foreseeable future.
Collapse
|
|
19
|
Abstract
BACKGROUND Although the pathomechanisms of autoimmune diseases in various organs remain unresolved, an accumulation of autoimmune diseases in individual patients has been observed. An overlap of autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) or primary sclerosing cirrhosis has been well documented. However, the overlap of autoimmune diseases other than PBC or PSC has not yet been investigated in a large cohort. GOAL The goal of our analysis was to investigate the incidence of concurrent autoimmune diseases in patients with AIH. STUDY We analyzed our cohort of 278 patients with AIH for concurrent autoimmune diseases. RESULTS A total of 111 patients (40%) were diagnosed with additional autoimmune diseases. Besides overlap syndromes for PBC and PSC, autoimmune thyroiditis was the most common concurrent disease (28 patients, 10%). Other concurrent autoimmune diseases comprised vitiligo (5 patients), rheumatoid arthritis (5 patients), Sjogren syndrome (4 patients), ulcerative colitis (4 patients), conjunctivitis (4 patients), celiac disease (3 patients), systemic lupus erythematodes (2 patients), type I diabetes (2 patients), multiple sclerosis (2 patients), polymyalgia rheumatica (2 patients), and urticaria (2 patients). One patient each was diagnosed with Crohn's disease, autoimmune gastritis, collagenous colitis, hypophysitis, and sarcoidosis. Investigating 100 patients with polyglandular syndrome and autoimmune thyroid disease for the occurrence of autoantibodies associated with AIH, we identified AIH-associated antibodies only in 1 patient. CONCLUSIONS Concurrent autoimmune diseases are common in patients with AIH and mirror the full range of known autoimmune diseases. Therefore, an extended diagnostic screening for accumulating autoimmune diseases, especially autoimmune thyroiditis, seems reasonable in patients with AIH.
Collapse
|