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Yilmaz K, Haeberle S, Kim YO, Fritzler MJ, Weng SY, Goeppert B, Raker VK, Steinbrink K, Schuppan D, Enk A, Hadaschik EN. Regulatory T-cell deficiency leads to features of autoimmune liver disease overlap syndrome in scurfy mice. Front Immunol 2023; 14:1253649. [PMID: 37818371 PMCID: PMC10561387 DOI: 10.3389/fimmu.2023.1253649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 09/08/2023] [Indexed: 10/12/2023] Open
Abstract
Introduction Scurfy mice have a complete deficiency of functional regulatory T cells (Treg) due to a frameshift mutation in the Foxp3 gene. The impaired immune homeostasis results in a lethal lymphoproliferative disorder affecting multiple organs, including the liver. The autoimmune pathology in scurfy mice is in part accompanied by autoantibodies such as antinuclear antibodies (ANA). ANA are serological hallmarks of several autoimmune disorders including autoimmune liver diseases (AILD). However, the underlying pathogenesis and the role of Treg in AILD remain to be elucidated. The present study therefore aimed to characterize the liver disease in scurfy mice. Methods Sera from scurfy mice were screened for ANA by indirect immunofluorescence assay (IFA) and tested for a wide range of AILD-associated autoantibodies by enzyme-linked immunosorbent assay, line immunoassay, and addressable laser bead immunoassay. CD4+ T cells of scurfy mice were transferred into T cell-deficient B6/nude mice. Monoclonal autoantibodies from scurfy mice and recipient B6/nude mice were tested for ANA by IFA. Liver tissue of scurfy mice was analyzed by conventional histology. Collagen deposition in scurfy liver was quantified via hepatic hydroxyproline content. Real-time quantitative PCR was used to determine fibrosis-related hepatic gene expression. Hepatic immune cells were differentiated by flow cytometry. Results All scurfy mice produced ANA. AILD-associated autoantibodies, predominantly antimitochondrial antibodies, were detected at significantly higher levels in scurfy sera. CD4+ T cells from scurfy mice were sufficient to induce anti-dsDNA autoantibodies and ANA with an AILD-related nuclear envelope staining pattern. Liver histology revealed portal inflammation with bile duct damage and proliferation, as in primary biliary cholangitis (PBC), and interface hepatitis with portal-parenchymal necroinflammation, as found in autoimmune hepatitis (AIH). In scurfy liver, TNFα and fibrosis-related transcripts including Col1a1, Timp1, Acta2, Mmp2, and Mmp9 were upregulated. The level of proinflammatory monocytic macrophages (Ly-6Chi) was increased, while M2-type macrophages (CD206+) were downregulated compared to wildtype controls. Despite severe hepatic inflammation, fibrosis did not develop within 25 days, which is close to the lifespan of scurfy mice. Discussion Our findings suggest that Treg-deficient scurfy mice spontaneously develop clinical, serological, and immunopathological characteristics of AILD with overlapping features of PBC and AIH.
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Affiliation(s)
- Kaan Yilmaz
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
- Department of Dermatology, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Stefanie Haeberle
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
| | - Yong Ook Kim
- Institute of Translational Immunology, University Medical Center of Johannes Gutenberg University Mainz, Mainz, Germany
| | - Marvin J. Fritzler
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Shih-Yen Weng
- Institute of Translational Immunology, University Medical Center of Johannes Gutenberg University Mainz, Mainz, Germany
- Smart Healthcare Interdisciplinary College, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
| | - Benjamin Goeppert
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
- Institute of Pathology and Neuropathology, RKH Klinikum Ludwigsburg, Ludwigsburg, Germany
| | - Verena K. Raker
- Department of Dermatology, University Hospital Muenster, Muenster, Germany
| | - Kerstin Steinbrink
- Department of Dermatology, University Hospital Muenster, Muenster, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology, University Medical Center of Johannes Gutenberg University Mainz, Mainz, Germany
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Alexander Enk
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
| | - Eva N. Hadaschik
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
- Department of Dermatology, University Hospital of Essen, Essen, Germany
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Massironi S, Pirola L, Mulinacci G, Ciaccio A, Viganò C, Palermo A, Zilli A, Invernizzi P, Danese S. Use of IBD Drugs in Patients With Hepatobiliary Comorbidities: Tips and Tricks. Inflamm Bowel Dis 2023; 29:1477-1487. [PMID: 36040402 DOI: 10.1093/ibd/izac189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Indexed: 12/09/2022]
Abstract
Advanced therapies (biologic agents and small molecules) for inflammatory bowel diseases (IBD) have radically changed the management of these diseases during the last decade. Data about these drugs in patients with hepatic disorders derive mainly from real-life studies, as these conditions often represent an exclusion criterion from pivotal drug developmental trials. However, IBD patients sometimes have concomitant liver diseases. Nonalcoholic fatty liver disease is the most prevalent hepatic comorbidity, whereas viral hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, and hepatic vascular disorders are less frequent. This review aimed at describing the real-life data about the use of advanced therapies for IBD in patients with concomitant hepatobiliary disorders. Hepatitis B virus and hepatitis C virus infections do not represent an absolute contraindication for novel IBD therapeutic agents. Data from the literature suggest a safe hepatobiliary profile of biologic agents and small molecules in the case of nonalcoholic fatty liver disease, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, and portal vein thrombosis. Consequently, although the liver disease does not affect a different therapeutic approach in patients with concomitant IBD and liver disease, a close risk/benefit analysis for each drug should be performed in these patients, especially in cirrhotic patients and in the postliver transplant setting.
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Affiliation(s)
- Sara Massironi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Lorena Pirola
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Giacomo Mulinacci
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Antonio Ciaccio
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Chiara Viganò
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Andrea Palermo
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Alessandra Zilli
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
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Heckroth MA, Eisa M, Cave M. Resolution of Autoimmune Hepatitis Following Total Colectomy in Severe Ulcerative Colitis: A Rare Presentation Associated With Leaky Gut. Cureus 2021; 13:e19276. [PMID: 34900465 PMCID: PMC8648171 DOI: 10.7759/cureus.19276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/05/2021] [Indexed: 11/25/2022] Open
Abstract
Liver disease is a common manifestation of inflammatory bowel disease. Although less common than other hepatic manifestations, autoimmune hepatitis can be seen in patients with ulcerative colitis. One possible mechanism in the relationship between the two is through the leaky gut where defects in the colonic mucosal barrier increase exposure to gut-derived toxins and bacterial products leading to immune activation. We report two cases of autoimmune hepatitis with concomitant severe ulcerative colitis in which complete remission of autoimmune hepatitis was seen following total colectomy.
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Affiliation(s)
- Matthew A Heckroth
- Department of Internal Medicine, University of Louisville School of Medicine, Louisville, USA
| | - Mohamed Eisa
- Department of Gastroenterology and Hepatology, University of Louisville School of Medicine, Louisville, USA
| | - Matthew Cave
- Department of Gastroenterology and Hepatology, University of Louisville School of Medicine, Louisville, USA
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Ballotin VR, Bigarella LG, Riva F, Onzi G, Balbinot RA, Balbinot SS, Soldera J. Primary sclerosing cholangitis and autoimmune hepatitis overlap syndrome associated with inflammatory bowel disease: A case report and systematic review. World J Clin Cases 2020; 8:4075-4093. [PMID: 33024765 PMCID: PMC7520795 DOI: 10.12998/wjcc.v8.i18.4075] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 04/23/2020] [Accepted: 07/30/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND A previously healthy 22-year-old woman presented with abdominal pain and jaundice. She had a reagent antinuclear factor (1:640, with a homogeneous nuclear pattern) and hypergammaglobulinemia (2.16 g/dL). Anti-smooth muscle, anti-mitochondrial and anti-liver-kidney microsomal antibody type 1 antibodies were negative. Magnetic resonance cholangiography showed a cirrhotic liver with multiple focal areas of strictures of the intrahepatic bile ducts, with associated dilations. Liver biopsy demonstrated periportal necroinflammatory activity, plasmocyte infiltration and advanced fibrosis. Colonoscopy showed ulcerative pancolitis and mild activity (Mayo score 1), with a spared rectum. Treatment with corticosteroids, azathioprine, ursodeoxycholic acid and mesalamine was initiated, with improvement in laboratory tests. The patient was referred for a liver transplantation evaluation. AIM To report the case of a female patient with autoimmune hepatitis and primary sclerosing cholangitis (PSC) overlap syndrome associated with ulcerative colitis and to systematically review the available cases of autoimmune hepatitis and PSC overlap syndrome. METHODS In accordance with preferred reporting items for systematic reviews and meta-analysis protocols guidelines, retrieval of studies was based on medical subject headings and health sciences descriptors, which were combined using Boolean operators. Searches were run on the electronic databases Scopus, Web of Science, MEDLINE (PubMed), Biblioteca Regional de Medicina, Latin American and Caribbean Health Sciences Literature, Cochrane Library for Systematic Reviews and Opengray.eu. Languages were restricted to English, Spanish and Portuguese. There was no date of publication restrictions. The reference lists of the studies retrieved were searched manually. RESULTS The search strategy retrieved 3349 references. In the final analysis, 44 references were included, with a total of 109 cases reported. The most common clinical finding was jaundice and 43.5% of cases were associated with inflammatory bowel disease. Of these, 27.6% were cases of Crohn's disease, 68% of ulcerative colitis, and 6.4% of indeterminate colitis. Most patients were treated with steroids. All-cause mortality was 3.7%. CONCLUSION PSC and autoimmune hepatitis overlap syndrome is generally associated with inflammatory bowel disease and has low mortality and good response to treatment.
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Affiliation(s)
| | | | - Floriano Riva
- CPM Laboratório de Caxias do Sul, Caxias do Sul 95070561, Brazil
| | - Georgia Onzi
- Clinical Gastroenterology, Universidade de Caxias do Sul (UCS), Caxias do Sul 95070560, Brazil
| | - Raul Angelo Balbinot
- Clinical Gastroenterology, Universidade de Caxias do Sul (UCS), Caxias do Sul 95070560, Brazil
| | | | - Jonathan Soldera
- Clinical Gastroenterology, Universidade de Caxias do Sul (UCS), Caxias do Sul 95070560, Brazil
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Kim JM, Cheon JH. Pathogenesis and clinical perspectives of extraintestinal manifestations in inflammatory bowel diseases. Intest Res 2020; 18:249-264. [PMID: 32295331 PMCID: PMC7385581 DOI: 10.5217/ir.2019.00128] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/25/2019] [Accepted: 03/06/2020] [Indexed: 12/13/2022] Open
Abstract
A considerable number of patients with inflammatory bowel disease (IBD) experience extraintestinal manifestations (EIMs), which can present either before or after IBD diagnosis. Unraveling the pathogenic pathways of EIMs in IBD is challenging because of the lack of reliable criteria for diagnosis and difficulty in distinguishing EIMs from external pathologies caused by drugs or other etiologies. Optimizing treatment can also be difficult. Early diagnosis and management of EIM revolve around multidisciplinary teams, and they should have the resources necessary to make and implement appropriate decisions. In addition, specialists of the affected organs should be trained in IBD treatment. Furthermore, patient awareness regarding the extraintestinal symptoms of IBD is of paramount importance for improving patient understanding of disease and health outcomes. Herein, we review the pathogenesis and clinical perspectives of EIMs in IBD.
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Affiliation(s)
- Jung Min Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Avison Biomedical Research Center, Severance Hospital, Seoul, Korea
- Affiliate Faculty, Pohang University of Science and Technology (POSTECH), Pohang, Korea
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Abstract
Obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) both cause an inflammatory response and hypoxia. Patients who have both conditions (overlap syndrome) have increased morbidity and mortality. This article aims to increase awareness of the potential effects that untreated OSA can have on COPD and the importance of treating patients with overlap syndrome.
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Restellini S, Chazouillères O, Frossard JL. Hepatic manifestations of inflammatory bowel diseases. Liver Int 2017; 37:475-489. [PMID: 27712010 DOI: 10.1111/liv.13265] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 09/27/2016] [Indexed: 12/18/2022]
Abstract
Inflammatory bowel diseases are associated with various hepatobiliary disorders, reported both in Crohn's disease and ulcerative colitis. They may occur at any moment in the natural course of the disease. The prevalence of liver dysfunction rises from 3% to 50% accordingly to definitions used in different studies. Fatty liver is considered as the most common hepatobiliary complication in inflammatory bowel diseases while primary sclerosing cholangitis is the most specific one. Less frequently, inflammatory bowel diseases-associated hepatobiliary disorders include: autoimmune hepatitis/ primary sclerosing cholangitis overlap syndrome, IgG4-associated cholangiopathy, primary biliary cholangitis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis and liver abscess. The spectrum of these manifestations varies according to the type of inflammatory bowel diseases. Treatments of inflammatory bowel diseases may cause liver toxicity, although incidence of serious complications remains low. However, early diagnosis of drug-induced liver injury is of major importance as it affects future clinical management. When facing abnormal liver tests, clinicians should undertake a full diagnostic work-up in order to determine whether the hepatic abnormalities are related to the inflammatory bowel diseases or not. Management of hepatic manifestations in inflammatory bowel diseases usually involves both hepatologists and gastroenterologists because of the complexity of some situations.
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Affiliation(s)
- Sophie Restellini
- Service de Gastroentérologie et Hépatologie, Hôpitaux Universitaires de Genève, Genève, Suisse
| | - Olivier Chazouillères
- Division d'Hépatologie, Centre de Référence des Maladies Inflammatoires des Voies Biliaires, et Université de Sorbonne, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Jean-Louis Frossard
- Service de Gastroentérologie et Hépatologie, Hôpitaux Universitaires de Genève, Genève, Suisse
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Rönnblom A, Holmström T, Tanghöj H, Rorsman F, Sjöberg D. Appearance of hepatobiliary diseases in a population-based cohort with inflammatory bowel diseases (Inflammatory Bowel Disease Cohort of the Uppsala Region). J Gastroenterol Hepatol 2015; 30:1288-92. [PMID: 25777994 DOI: 10.1111/jgh.12947] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/21/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM To prospectively follow the evolution of hepatobiliary diseases in a population-based cohort of patients with inflammatory bowel diseases. METHODS Between 2005 and 2009, 790 incident cases of ulcerative colitis and Crohn's disease were registered in the Uppsala Health Region, corresponding to an average incidence of 20.0 and 9.9 new cases/100 000 inhabitants/year, respectively. Liver function tests were analyzed in 97.1% and the results of ensuing investigations were summarized. RESULTS Seventeen patients with primary sclerosing cholangitis were diagnosed corresponding to an overall prevalence of 2.2% (ulcerative colitis 1.7% and Crohn's disease 3.0%, respectively). The median age at diagnosis was 25 years (interquartile range: 17.0-34.0). Among the 92 patients below 17 years of age, three had autoimmune hepatitis and three primary sclerosing cholangitis, summing up to a prevalence of 6.5% immune-mediated hepatobiliary diseases among the pediatric patients. Three patients have undergone liver transplantation and one died of colonic carcinoma. Ten patients have demonstrated persistent elevation of alkaline phosphatases but had a normal magnetic resonance cholangiopancreatography (two patients) or refused further investigation (one patient). CONCLUSION In this first large prospective population-based cohort of 526 patients with ulcerative colitis (UC) and 264 with Crohn's disease, 17 cases of primary sclerosing cholangitis were found, among whom three (17%) so far have been liver transplanted and one has died of colon carcinoma. The average age of those affected by primary sclerosing cholangitis is considerably lower than usually reported. Ten patients had or have had elevated alkaline phosphatase without confirmed liver or biliary disease.
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Affiliation(s)
- Anders Rönnblom
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Hans Tanghöj
- Department of Internal Medicine, Mälar Hospital, Eskilstuna, Sweden
| | - Fredrik Rorsman
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Daniel Sjöberg
- Department of Internal Medicine, Falu Hospital, Falun, Sweden
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Abstract
Research related to primary sclerosing cholangitis (PSC) has since 1980 been a major activity at the Oslo University Hospital Rikshospitalet. The purpose of this publication is to describe the development of this research, the impact of this research on the clinical handling of the patients, and finally to describe what we believe are the most urgent, remaining problems to be solved. During the early years, our research dealt primarily with clinical aspects of the disease. The concomitant inflammatory bowel disease (IBD) seen in most patients with PSC was a major interest and we also started looking into genetic associations of PSC. Prognosis, malignancy development and treatment with special emphasis on transplantation have later been dealt with. These activities has had impact on several aspects of PSC management; when and how to diagnose PSC and variant forms of PSC, how to handle IBD in PSC and how to deal with the increased rate of malignancy? The problems remaining to be solved are many. What is the role of the gut and the gut microbiota in the development of PSC? Do the PSC patients have an underlying disturbance in the bile homeostasis? And how does the characteristic type of fibrosis in PSC develop? The genetic studies have supported a role for the adaptive immune system in the disease development, but how should this be dealt with? Importantly, the development of malignancy in PSC is still not understood, and we lack appropriate medical treatment for our patients.
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Affiliation(s)
- Erik Schrumpf
- Norwegian PSC research center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet , Oslo , Norway
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HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1. Genes Immun 2015; 16:247-52. [PMID: 25611558 DOI: 10.1038/gene.2014.82] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Revised: 12/16/2014] [Accepted: 12/16/2014] [Indexed: 12/20/2022]
Abstract
The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.
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Yoshioka Y, Taniai M, Hashimoto E, Haruta I, Shiratori K. Clinical profile of primary biliary cirrhosis with features of autoimmune hepatitis: Importance of corticosteroid therapy. Hepatol Res 2014; 44:947-55. [PMID: 23879195 DOI: 10.1111/hepr.12210] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Revised: 07/16/2013] [Accepted: 07/17/2013] [Indexed: 12/13/2022]
Abstract
AIM The aim of this study was to elucidate the clinical and histological features, response to corticosteroid therapy and long-term outcome of primary biliary cirrhosis (PBC) with features of autoimmune hepatitis (AIH). METHODS Among 280 PBC patients under ursodeoxycholic acid administration, we identified 28 patients with AIH features fulfilling the following criteria: sustained high levels of serum aminotransferases and high immunoglobulin G levels with positivity for antinuclear antibodies or anti-smooth muscle antibodies (ASMA) and/or histological features of moderate to severe interface hepatitis or moderate to severe lobular hepatitis. We analyzed PBC patients with AIH features, focusing mainly on therapeutic responses to corticosteroids. RESULTS Patients with PBC with AIH features included 26 women (93%). Their median age was 55 years, and the median follow-up period was 7.5 years. Eight of these 28 patients were not actually treated with corticosteroids due to medical conditions. Among the 20 patients receiving corticosteroid therapy, 15 were responders and five were non-responders. A high alkaline phosphatase (ALP) level, negativity for ASMA and positivity for gp210 were identified as risk factors for lack of a response to corticosteroid therapy. Among 28 PBC patients with AIH features, the responders to corticosteroids had an excellent prognosis, while those who could not be treated with corticosteroids and non-responders to corticosteroids had a poor outcome. CONCLUSION Patients with PBC with AIH features benefit from corticosteroid therapy. Features of PBC such as high ALP level, negativity for ASMA and positivity for gp210 appear to predict a poor response to corticosteroids.
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Affiliation(s)
- Youko Yoshioka
- Division of Internal Medicine, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
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12
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de Boer YS, van Gerven NMF, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ, Beuers U, van Buuren HR, Drenth JPH, den Ouden JW, Verdonk RC, Koek GH, Brouwer JT, Guichelaar MMJ, Vrolijk JM, Kraal G, Mulder CJJ, van Nieuwkerk CMJ, Fischer J, Berg T, Stickel F, Sarrazin C, Schramm C, Lohse AW, Weiler-Normann C, Lerch MM, Nauck M, Völzke H, Homuth G, Bloemena E, Verspaget HW, Kumar V, Zhernakova A, Wijmenga C, Franke L, Bouma G. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology 2014; 147:443-52.e5. [PMID: 24768677 DOI: 10.1053/j.gastro.2014.04.022] [Citation(s) in RCA: 223] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 03/17/2014] [Accepted: 04/09/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. METHODS We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. RESULTS We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. CONCLUSIONS In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.
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Affiliation(s)
- Ynto S de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Nicole M F van Gerven
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Antonie Zwiers
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands; Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Bart J Verwer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Karel J van Erpecum
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Henk R van Buuren
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Jannie W den Ouden
- Department of Gastroenterology and Hepatology, Haga Hospital, The Hague, The Netherlands
| | - Robert C Verdonk
- University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, The Netherlands; Department of Gastroenterology and Hepatology, St Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands
| | - Ger H Koek
- Department of Gastroenterology and Hepatology, University Medical Center Maastricht, Maastricht, The Netherlands
| | - Johannes T Brouwer
- Department of Gastroenterology and Hepatology, Reinier de Graaf Hospital, Delft, The Netherlands
| | - Maureen M J Guichelaar
- Department of Gastroenterology and Hepatology, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Jan M Vrolijk
- Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, The Netherlands
| | - Georg Kraal
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - Chris J J Mulder
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Carin M J van Nieuwkerk
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Janett Fischer
- Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany
| | - Thomas Berg
- Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany
| | - Felix Stickel
- Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | | | - Christoph Schramm
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Markus M Lerch
- Department of Internal Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Matthias Nauck
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Georg Homuth
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
| | - Elisabeth Bloemena
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
| | - Hein W Verspaget
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Vinod Kumar
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Alexandra Zhernakova
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Cisca Wijmenga
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Lude Franke
- University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands; Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
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Abstract
The interaction between inflammatory bowel disease (IBD) and hepatobiliary manifestations represents a classic example of liver-gut crosstalk. The importance of liver-gut crosstalk in IBD is demonstrated in the pathogenesis and outcome of primary sclerosing cholangitis (PSC) in IBD patients. Immunoglobulin G4-associated cholangitis (IAC), which has recently been described in UC patients, may also illustrate the significance of gut-liver interaction in these patients. Presence of these hepatobiliary manifestations influences the outcome of associated IBD, in particular ulcerative colitis (UC), and vice versa. The pathogenesis of PSC is postulated to be related to gut inflammation in IBD that results in inflammation in the portal tracts (the 'leaky gut'). Enterohepatic circulation of lymphocytes from the gut to the liver is also of potential relevance to PSC pathogenesis and outcomes. The presence of PSC and gut inflammation in IBD influences the course and outcomes of both diseases. Further research is required, to understand the mutual effect of liver-gut crosstalk in the outcomes of UC patients, and highlights the importance of an interdisciplinary approach-involving gastroenterologists, hepatologists, advanced endoscopists and liver transplant surgeons-in the management of these patients.
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Affiliation(s)
- Udayakumar Navaneethan
- Department of Gastroenterology/Hepatology, Digestive Disease Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
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Rojas-Feria M, Castro M, Suárez E, Ampuero J, Romero-Gómez M. Hepatobiliary manifestations in inflammatory bowel disease: The gut, the drugs and the liver. World J Gastroenterol 2013; 19:7327-7340. [PMID: 24259964 PMCID: PMC3831215 DOI: 10.3748/wjg.v19.i42.7327] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 08/07/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
Abnormal liver biochemical tests are present in up to 30% of patients with inflammatory bowel disease (IBD), and therefore become a diagnostic challenge. Liver and biliary tract diseases are common extraintestinal manifestations for both Crohn’s disease and ulcerative colitis (UC), and typically do not correlate with intestinal activity. Primary sclerosing cholangitis (PSC) is the most common hepatobiliary manifestation of IBD, and is more prevalent in UC. Approximately 5% of patients with UC develop PSC, with the prevalence reaching up to 90%. Cholangiocarcinoma and colon cancer risks are increased in these patients. Less common disorders include autoimmune hepatitis/PSC overlap syndrome, IgG4-associated cholangiopathy, primary biliary cirrhosis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis, liver abscess, and non-alcoholic fatty liver disease. Hepatitis B reactivation during immunosuppressive therapy is a major concern, with screening and vaccination being recommended in serologically negative cases for patients with IBD. Reactivation prophylaxis with entecavir or tenofovir for 6 to 12 mo after the end of immunosuppressive therapy is mandatory in patients showing as hepatitis B surface antigen (HBsAg) positive, independently from viral load. HBsAg negative and anti-HBc positive patients, with or without anti-HBs, should be closely monitored, measuring alanine aminotransferase and hepatitis B virus DNA within 12 mo after the end of therapy, and should be treated if the viral load increases. On the other hand, immunosuppressive therapy does not seem to promote reactivation of hepatitis C, and hepatitis C antiviral treatment does not influence IBD natural history either. Most of the drugs used for IBD treatment may induce hepatotoxicity, although the incidence of serious adverse events is low. Abnormalities in liver biochemical tests associated with aminosalicylates are uncommon and are usually not clinically relevant. Methotrexate-related hepatotoxicity has been described in 14% of patients with IBD, in a dose-dependent manner. Liver biopsy is not routinely recommended. Biologics-related hepatotoxicity is rare, but has been shown most frequently in patients treated with infliximab. Thiopurines have been associated with veno-occlusive disease, regenerative nodular hyperplasia, and liver peliosis. Routine liver biochemical tests are recommended, especially during the first month of treatment. All these conditions should be considered in IBD patients with clinical or biochemical features suggestive of hepatobiliary involvement. Diagnosis and management of these disorders usually involve hepatologists and gastroenterologists due to its complexity.
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15
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Fallatah HI, Akbar HO. Autoimmune hepatitis as a unique form of an autoimmune liver disease: immunological aspects and clinical overview. Autoimmune Dis 2012; 2012:312817. [PMID: 23304455 PMCID: PMC3530748 DOI: 10.1155/2012/312817] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Revised: 09/09/2012] [Accepted: 10/12/2012] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a unique form of immune-mediated disease that attacks the liver through a variety of immune mechanisms. The outcomes of AIH are either acute liver disease, which can be fatal, or, more commonly, chronic progressive liver disease, which can lead to decompensated liver cirrhosis if left untreated. AIH has characteristic immunological, and pathological, features that are important for the establishment of the diagnosis. More importantly, most patients with AIH have a favorable response to treatment with prednisolone and azathioprine, although some patients with refractory AIH or more aggressive disease require more potent immune-suppressant agents, such as cyclosporine or Mycophenolate Mofetil. In this paper, we discuss the immunological, pathological and clinical features of AIH, as well as the standard and alternative treatments for AIH.
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Affiliation(s)
- Hind I. Fallatah
- Medical Department, Arab Board and Saudi Board of Internal Medicine, MACP, King Abdul Aziz University Hospital, P.O. Box 9714, Jeddah 21423, Saudi Arabia
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16
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Núñez Martínez Ó, Marquina Ibáñez I, Ruiz Bravo-Burguillos E, Encinas Sotillos A, Erdozaín Sosa JC. [Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome in a patient with chronic hepatitis B infection]. GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 36:382-7. [PMID: 23084258 DOI: 10.1016/j.gastrohep.2012.07.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 07/17/2012] [Accepted: 07/24/2012] [Indexed: 12/26/2022]
Abstract
We describe the case of a female patient with a previous diagnosis of primary biliary cirrhosis (PBC) and chronic hepatitis B in inactive phase who developed increased transaminase levels with no evidence of hepatitis B virus reactivation while receiving ursodeoxycholic acid treatment. A liver biopsy showed changes compatible with overlapping autoimmune hepatitis (AIH). Budesonide treatment achieved normalization of transaminase levels. We provide a review of PBC and AIH overlap syndrome and discuss the particular features of this case that led us to this diagnosis, as well as the treatment provided.
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Affiliation(s)
- Óscar Núñez Martínez
- Unidad de Digestivo, Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Madrid, España.
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17
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Trivedi PJ, Hirschfield GM. Review article: overlap syndromes and autoimmune liver disease. Aliment Pharmacol Ther 2012; 36:517-33. [PMID: 22817525 DOI: 10.1111/j.1365-2036.2012.05223.x] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Revised: 03/30/2012] [Accepted: 07/01/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) all nestle within the family of autoimmune liver diseases, whereby the result of immune-mediated liver injury gives rise to varied clinical presentations. Some patients demonstrate a phenotype whereby there is evidence of either PBC or PSC together with overlapping features of AIH. Due to an absence of well-validated diagnostic criteria and a lack of large therapeutic trials, treatment of overlap conditions is empiric and extrapolated from data derived from the primary autoimmune liver diseases. AIMS To review overlaps in the context of autoimmune liver diseases. METHODS General and specific review of published articles using PubMed, Medline and Ovid search engines, alongside pre-existing clinical management protocols, guidelines, and the authors' own knowledge of the published literature. RESULTS The challenges in diagnosis, clinical presentation, determining natural history and outcome of overlaps are presented, as well as present-day management suggestions, some based on evidence, others on consensus and opinion. CONCLUSIONS Overlapping autoimmune features, be they clinical, serological, histological or radiological are not infrequent, but appropriate diagnosis remains hindered by a lack of standardised diagnostic criteria. Optimum care for those with suspected overlap should thus focus on attention to detail over the fundamental aspects of timely secure diagnosis of the dominant disease entity. Clinicians should counsel patients carefully with regard to the risks and benefits of treatment, bearing in mind the paucity of randomised and controlled outcome data for medical interventions.
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Affiliation(s)
- P J Trivedi
- Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK
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18
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Niu GC, Liu L, Zhang XL. Hepatobiliary complications of inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2012; 20:662-669. [DOI: 10.11569/wcjd.v20.i8.662] [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
Inflammatory bowel disease (IBD) is a chronic idiopathic immune-mediated inflammatory disease of the gastrointestinal tract, including ulcerative colitis (UC) and Crohn's disease (CD). Extraintestinal manifestations (EIMs) are frequently encountered in IBD patients. Hepatobiliary manifestations are common extraintestinal manifestations of IBD, including primary sclerosing cholangitis (PSC), nonalcoholic fatty liver, cholelithiasis, primary biliary cirrhosis (PBC), small-duct PSC, IgG4-associated cholangitis (IAC), granulomatous hepatitis, amyloidosis, autoimmune hepatitis (AIH), PSC/AIH overlap syndrome, and portal vein thrombosis. In this paper, we describe the progress in understanding the hepatobiliary complications associated with IBD.
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19
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Liver disorders in inflammatory bowel disease. Gastroenterol Res Pract 2012; 2012:642923. [PMID: 22474447 PMCID: PMC3296398 DOI: 10.1155/2012/642923] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2011] [Accepted: 11/30/2011] [Indexed: 02/07/2023] Open
Abstract
Disorders of the hepatobiliary system are relatively common extraintestinal manifestations of inflammatory bowel disease (IBD). These disorders are sometimes due to a shared pathogenesis with IBD as seen in primary sclerosing cholangitis (PSC) and small-duct primary sclerosing cholangitis (small-duct PSC). There are also hepatobiliary manifestations such as cholelithiasis and portal vein thrombosis that occur due to the effects of chronic inflammation and the severity of bowel disease. Lastly, medications used in IBD such as sulfasalazine, thiopurines, and methotrexate can adversely affect the liver. It is important to be cognizant of these disorders as some do have serious long-term consequences. The management of these disorders often requires the expertise of multidisciplinary teams to achieve the best outcomes.
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20
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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.
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Affiliation(s)
| | - Hisham O Akbar
- King Abdul Aziz University Hospital, Jeddah, Saudi Arabia
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21
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Abstract
One of typical examples of liver-gut cross talk is the interaction and impact of inflammatory bowel disease (IBD) and hepatobiliary (HB) abnormalities on each other's disease course. There are several layers of association between IBD and HB diseases: (i) HB diseases and IBD share pathogenetic mechanisms; (ii) HB diseases parallel structural and pathophysiological changes seen with IBD; and (iii) hepatic toxicity is associated with medical therapy for IBD. Interdisciplinary approach, involving gastroenterologists, hepatologists and, in advanced cases, general, colorectal, and liver transplant surgeons, is advocated.
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Affiliation(s)
- Preethi Gk Venkatesh
- Department of Gastroenterology/Hepatology, Digestive Disease Institute, the Cleveland Clinic Foundation, Cleveland, Ohio, USA
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22
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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.
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23
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Navaneethan U, Shen B. Hepatopancreatobiliary manifestations and complications associated with inflammatory bowel disease. Inflamm Bowel Dis 2010; 16:1598-619. [PMID: 20198712 DOI: 10.1002/ibd.21219] [Citation(s) in RCA: 145] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diseases involving the hepatopancreatobiliary (HPB) system are frequently encountered in patients with inflammatory bowel disease (IBD). Hepatobiliary manifestations constitute some of the most common extraintestinal manifestations of IBD. They appear to occur with similar frequency in patients with Crohn's disease or ulcerative colitis. HPB manifestations may occur in following settings: 1) disease possibly associated with a shared pathogenetic mechanism with IBD including primary sclerosing cholangitis (PSC), small-duct PSC/pericholangitis and PSC/autoimmune hepatitis overlap, acute and chronic pancreatitis related to IBD; 2) diseases which parallel structural and physiological changes seen with IBD, including cholelithiasis, portal vein thrombosis, and hepatic abscess; and 3) diseases related to adverse effects associated with treatment of IBD, including drug-induced hepatitis, pancreatitis (purine-based agents), or liver cirrhosis (methotrexate), and reactivation of hepatitis B, and biologic agent-associated hepatosplenic lymphoma. Less common HPB manifestations that have been described in association with IBD include autoimmune pancreatitis (AIP), IgG4-associated cholangitis (IAC), primary biliary cirrhosis (PBC), fatty liver, granulomatous hepatitis, and amyloidosis. PSC is the most significant hepatobiliary manifestation associated with IBD and poses substantial challenges in management requiring a multidisciplinary approach. The natural disease course of PSC may progress to cirrhosis and ultimately require liver transplantation in spite of total proctocolectomy with ileal-pouch anal anastomosis. The association between AIP, IAC, and elevated serum IgG4 in patients with PSC is intriguing. The recently reported association between IAC and IBD may open the door to investigate these complex disorders. Further studies are warranted to help understand the pathogenesis of HPB manifestations associated with IBD, which would help clinicians better manage these patients. An interdisciplinary approach, involving gastroenterologists, hepatologists, and, in advanced cases, general, colorectal, and transplant surgeons is advocated.
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Hyslop WB, Kierans AS, Leonardou P, Fritchie K, Darling J, Elazazzi M, Semelka RC. Overlap syndrome of autoimmune chronic liver diseases: MRI findings. J Magn Reson Imaging 2010; 31:383-9. [PMID: 20099347 DOI: 10.1002/jmri.22048] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
PURPOSE To describe the MR findings of overlap syndromes of autoimmune chronic liver diseases. METHODS Review of clinical and radiological databases between March 2001 and July 2008 for patients with a clinical diagnosis and liver biopsy features compatible with overlap syndrome who had also undergone an abdominal MRI yielded 15 adult patients. MR features of overlap syndrome were reviewed by two radiologists by consensus. Two radiologists independently reviewed the studies in a blinded fashion for primary sclerosing cholangitis (PSC)-type or non-PSC-type features to assess interobserver agreement. RESULTS PSC-type and non-PSC-type overlap syndrome had distinctive MR features. In the consensus review, all 12 patients with PSC-type overlap syndrome were correctly identified. Imaging findings included central macroregeneration (N = 9), peripheral atrophy (N = 7), biliary duct beading (N = 12), biliary dilation (N = 10), or a combination of all four findings (N = 7). The presence of any of the first three features had 100% specificity for a PSC-type overlap syndrome. Patients with non-PSC-type overlap (N = 3) showed relatively normal liver morphology (N = 3) and minimal biliary ductal dilatation in one patient. There was good interobserver agreement (kappa = 0.76). CONCLUSION Patients with serologic or pathologic evidence of AIH or PBC with imaging features of PSC may have PSC-type overlap syndrome.
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Affiliation(s)
- W Brian Hyslop
- Department of Radiology, University of North Carolina, Chapel Hill, North Carolina, USA.
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25
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Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010; 51:660-78. [PMID: 20101749 DOI: 10.1002/hep.23294] [Citation(s) in RCA: 833] [Impact Index Per Article: 55.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Chazouillères O. [A case of autoimmune hepatitis]. GASTROENTEROLOGIE CLINIQUE ET BIOLOGIQUE 2009; 33:F36-F43. [PMID: 19762185 DOI: 10.1016/j.gcb.2009.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Autoimmune hepatitis (AIH) is a disorder of unknown aetiology that occurs in children and adults of all ages with a female predominance. The spectrum of presentation is wide, ranging from no symptoms to acute liver failure. The diagnosis is based on high level or serum gammaglobulins, characteristic circulating autoantibodies and histologic abnormalities (necrosis and inflammation) in the absence of other causes. AIH is classified on the basis of the autoantibody pattern: type 1 (antinuclear and/or smooth muscle antibodies) is the classic form whereas type 2 (liver-kidney microsome 1 antibody) is much less common and occurs mainly in childhood. Mixed forms of AIH that share features with other putative autoimmune liver diseases, primary biliary cirrhosis and primary sclerosing cholangitis, have been described. Because of therapeutic issues, it is important to distinguish AIH from other forms of hepatitis and the use of diagnostic scoring systems may be helpful. Treatment basis of AIH have not changed for the last 30 years. Initial treatment consists of corticosteroids associated with azathioprine. Budesonide may be at least as effective as systemic corticosteroids and reduces the frequency of side effects in non-cirrhotic patients. Long-term treatment consists of azathioprine. This treatment is rapidly effective but usually only suspensive since relapse after treatment withdrawal is the rule (80 % of cases). The probability of relapse is lower in case of complete biochemical response defined by normalization of transaminases, gamma-globulins and IgG and in case of histological response defined by the lack of interface hepatitis. The frequency of side effects justifies an attempt of drug discontinuation provided that criteria of clinical, biochemical and histological remission are achieved after at least 2 years of treatment.
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Affiliation(s)
- O Chazouillères
- INSERM U680, service d'hépatologie, pôle digestif, centre de référence des maladies inflammatoires des voies biliaires, hôpital Saint-Antoine, université Pierre-et-Marie-Curie Paris-VI, 184 rue du Faubourg-Saint-Antoine, Paris, France.
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27
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MESH Headings
- Adult
- Child
- Cholangitis/diagnosis
- Cholangitis/immunology
- Cholangitis/therapy
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/therapy
- Cholestasis, Intrahepatic/diagnosis
- Cholestasis, Intrahepatic/etiology
- Cholestasis, Intrahepatic/prevention & control
- Cholestasis, Intrahepatic/therapy
- Cystic Fibrosis/complications
- Female
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/therapy
- Humans
- Immunoglobulin G/metabolism
- Infant
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/therapy
- Male
- Osteoporosis/etiology
- Osteoporosis/therapy
- Pregnancy
- Pregnancy Complications/diagnosis
- Pregnancy Complications/therapy
- Syndrome
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Collaborators
Ulrich Beuers, Kirsten M Boberg, Roger W Chapman, Olivier Chazouillères, Pietro Invernizzi, David E J Jones, Frank Lammert, Albert Parès, Michael Trauner,
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Lewin M, Vilgrain V, Ozenne V, Lemoine M, Wendum D, Paradis V, Ziol M, Arrivé L, Beaugrand M, Poupon R, Valla D, Chazouillères O, Corpechot C. Prevalence of sclerosing cholangitis in adults with autoimmune hepatitis: a prospective magnetic resonance imaging and histological study. Hepatology 2009; 50:528-37. [PMID: 19575454 DOI: 10.1002/hep.23024] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED The development of sclerosing cholangitis (SC) is observed in up to 50% of children followed up for autoimmune hepatitis (AIH). In adults, the prevalence is less known, although a recent study found evidence of SC in 10% of AIH patients using magnetic resonance cholangiopancreatography (MRCP). The aim of this study was to assess prospectively the prevalence of SC in adults with AIH. Fifty-nine consecutive patients with AIH diagnosed according to International Autoimmune Hepatitis Group score (women, 71%; mean age, 48 years; cirrhosis, 23%) underwent both MRCP and percutaneous liver biopsy. Twenty-seven patients with cirrhosis of nonbiliary or non-autoimmune etiology served as controls. Fourteen AIH patients (24%) showed mild MRCP abnormalities of intrahepatic bile ducts (IHBDs). None had abnormal common bile duct or convincing evidence of SC on MRCP or biopsy. A diagnosis of overlapping SC was nevertheless retained in one patient with MRCP abnormalities who subsequently developed symptomatic cholestasis despite corticosteroid therapy. Fibrosis score was the only independent parameter associated with bile duct abnormalities on MRCP (odds ratio 2.4; 95% confidence interval 1.4-4.7) and the percentage of patients with IHBD MRCP abnormalities was not different among F3-F4 AIH patients (n = 24) and cirrhotic controls (46% versus 59%; NS). CONCLUSION In this cohort of adult patients with AIH, the prevalence of SC was much lower than previously reported (1.7%). Mild MRCP abnormalities of IHBD were seen in a quarter of patients, but these abnormalities resulted from hepatic fibrosis and not SC. In the absence of cholestatic presentation, MRCP screening does not seem justified in adult-onset AIH.
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Affiliation(s)
- Maïté Lewin
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
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Zepeda-Gomez S, Montaño-Loza A, Zapata-Colindres JC, Paz F, Olivera-Martinez M, López-Reyes A, Granados J, Vargas-Alarcón G. HLA-DR Allele Frequencies in Mexican Mestizos with Autoimmune Liver Diseases Including Overlap Syndromes. Immunol Invest 2009; 38:276-83. [DOI: 10.1080/08820130902846282] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Lindgren S, Glaumann H, Almer S, Bergquist A, Björnsson E, Broomé U, Danielsson A, Lebrun B, Prytz H, Olsson R. Transitions between variant forms of primary biliary cirrhosis during long-term follow-up. Eur J Intern Med 2009; 20:398-402. [PMID: 19524182 DOI: 10.1016/j.ejim.2008.12.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2008] [Revised: 11/14/2008] [Accepted: 12/18/2008] [Indexed: 12/12/2022]
Abstract
BACKGROUND Conditions exhibiting features of two different autoimmune liver diseases are designated overlap syndromes. Variant forms display some, but not all, characteristics of a distinct autoimmune liver disease. We describe transitions over time between variant forms of PBC, i.e. AMA-negative PBC, autoimmune hepatitis (AIH)-PBC overlap and autoimmune cholangitis (AIC) in a large cohort of PBC patients in Sweden. METHODS We retrieved all patients with variant forms of PBC in six university hospitals in Sweden, covering 60% of the Swedish population. The diagnosis of PBC and its variants was based on laboratory findings and compatible histological features. The revised autoimmune hepatitis scoring system proposed by the International Autoimmune Hepatitis Group was used to establish the diagnosis of AIH. RESULTS In a population of 800 patients with PBC, we identified 35 (5%) variant forms; 25 patients with AIH-PBC overlap, 8 with AIC and 2 with AMA-negative PBC at the time of our study. The initial diagnoses were PBC (3 patients), AIH (3), AIH-PBC overlap (16), AIC (8) and AMA-negative PBC with (1) or without (4) concomitant AIH. The median follow-up was 125 (41-360) months. Immunosuppression and ursodeoxycholic acid induced a complete or good regression of increased aminotransferases in about half of the patients who were given one or both of these treatments. CONCLUSIONS Variant forms of PBC are seen in approximately 5% of PBC patients in Sweden. Transition between different forms may occur, emphasizing the value of repeat biopsies, but established overlapping AIH-PBC seems to be stable over time.
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Affiliation(s)
- Stefan Lindgren
- Department of Medicine, University Hospital MAS, Malmö, Sweden.
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31
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Hong J, Song MK, Ko JS, Kang GH, Kim WS, Seo JK. Autoimmune hepatitis-primary sclerosing cholangitis overlap syndrome in a 10-year-old girl with ulcerative colitis. KOREAN JOURNAL OF PEDIATRICS 2009. [DOI: 10.3345/kjp.2009.52.4.504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Jeana Hong
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Mi Kyoung Song
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Woo Sun Kim
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Kee Seo
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
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Toyoda M, Yokomori H, Kaneko F, Yoshida H, Hoshi K, Takeuchi H, Tahara K, Takahashi A, Kudo T, Motoori T, Ohbu M, Kondo H, Hibi T. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome concomitant with systemic sclerosis, immune thrombocytopenic purpura. Intern Med 2009; 48:2019-23. [PMID: 19952485 DOI: 10.2169/internalmedicine.48.2687] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
A 58-year-old Japanese woman presented with chronic fluctuating liver dysfunction with purpura. Raynaud's phenomenon had been diagnosed 4 years previously. At the initial examination, skin biopsy showed limited cutaneous systemic sclerosis (SSc). Laboratory investigations revealed liver dysfunction. Anti-nuclear antibodies, anti-mitochondria M2 antibody, anti-thyroglobulin antibody, and platelet-associated IgG were positive. Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) were diagnosed serologically, clinically and histologically. Immune thrombocytopenic purpura (ITP) was diagnosed by bone marrow puncture, clinical and laboratory findings, and Helicobacter pylori IgG was positive. She was treated with prednisolone 30 mg/day, ursodeoxycholic acid 600 mg/day, and a 7-day course of lansoprazole plus amoxicillin and clarithromycin. Thrombocytes increased rapidly and transaminase improved at day 7. We report a rare case of PBC-AIH overlap syndrome with concurrent ITP and SSc which suggest the presence of shared genetic susceptibility factors in multiple autoimmune conditions including PBC, AIH, ITP and SSc.
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MESH Headings
- Female
- Hepatitis, Autoimmune/complications
- Hepatitis, Autoimmune/diagnosis
- Humans
- Liver Cirrhosis, Biliary/complications
- Liver Cirrhosis, Biliary/diagnosis
- Middle Aged
- Purpura, Thrombocytopenic, Idiopathic/complications
- Purpura, Thrombocytopenic, Idiopathic/diagnosis
- Scleroderma, Systemic/complications
- Scleroderma, Systemic/diagnosis
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Affiliation(s)
- Megumi Toyoda
- Division of Gastroenterology, Kitasato University, Kitasato Medical Center Hospital, Kitamoto
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Al-Chalabi T, Portmann BC, Bernal W, McFarlane IG, Heneghan MA. Autoimmune hepatitis overlap syndromes: an evaluation of treatment response, long-term outcome and survival. Aliment Pharmacol Ther 2008; 28:209-20. [PMID: 18433467 DOI: 10.1111/j.1365-2036.2008.03722.x] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Primary sclerosing cholangitis/autoimmune hepatitis (PSC/AIH) and primary biliary cirrhosis/AIH (PBC/AIH) overlap syndromes are poorly defined variants of AIH. Few large patient series exist, and there are little data on long-term outcomes. AIM To compare presentation, clinical course and outcome of patients with PSC/AIH and PBC/AIH, with patients with definite AIH. Methods Two hundred and thirty-eight AIH patients were compared with 10 PBC/AIH patients and 16 PSC/AIH patients presenting consecutively between 1971 and 2005 at a single centre. RESULTS Autoimmune hepatitis patients were significantly more likely to present with jaundice (69.4% vs. 25%; P = 0.0145) than PBC/AIH patients. Median serum aspartate aminotransferase activity at presentation was higher in AIH patients compared with PBC/AIH and PSC/AIH patients respectively (620 vs. 94 vs. 224 IU/L; P < 0.05). PBC/AIH patients demonstrated no response to standard AIH therapy more frequently than AIH patients (25% vs. 0.8%; P = 0.0057). Significant reduction in survival was identified between patients with PSC/AIH and those without (hazard ratio: PSC/AIH vs. AIH = 2.08, PSC/AIH vs. PBC/AIH = 2.14; P = 0.039). CONCLUSIONS Patients with PSC/AIH have severe disease and significantly worse prognosis than patients with AIH or PBC/AIH. Recognition and close follow-up of this cohort are warranted.
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Affiliation(s)
- T Al-Chalabi
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, UK
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34
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Wörns MA, Teufel A, Kanzler S, Shrestha A, Victor A, Otto G, Lohse AW, Galle PR, Höhler T. Incidence of HAV and HBV infections and vaccination rates in patients with autoimmune liver diseases. Am J Gastroenterol 2008; 103:138-46. [PMID: 17970833 DOI: 10.1111/j.1572-0241.2007.01609.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Hepatitis A virus (HAV) or hepatitis B virus (HBV) superinfection is associated with an increased mortality in patients with chronic liver diseases (CLD). Despite official recommendations, it was reported that the vaccination rate against HAV is low in patients with chronic hepatitis C infection. To evaluate the situation in patients with autoimmune liver diseases, we conducted a retrospective cohort study. METHODS Susceptibility to HAV and HBV infections, course of HAV and HBV infections, vaccination rates against HAV and HBV, and efficacy of hepatitis A/B vaccines were evaluated by antibody testing in 225 patients with autoimmune liver diseases during 1,677 person-years. RESULTS Susceptibility to HAV/HBV infection was 51/86%. Incidence of HAV/HBV infection was 1.3/1.4 per 1,000 person-years. One HAV infection occurred, but the patient recovered spontaneously. Two patients were HBV-infected after receiving an anti-HBc-positive (antibody to hepatitis B core antigen) donor graft during orthotopic liver transplantation, and one of them developed chronic HBV infection. Vaccination rates were 11% (HBV) and 13% (HAV), respectively. Seventy-six percent of the vaccinated patients (HBV vaccine) developed anti-HBs (antibody to hepatitis surface antigen) >or=10 UI/L. Ten out of 13 vaccinated patients, showing a low or nonresponse to hepatitis B vaccine, had concomitant immunosuppressive therapy. Anti-HAV was detectable in all patients after administration of HAV vaccine. CONCLUSIONS Patients with autoimmune liver diseases have a high susceptibility to HAV and HBV infections. Vaccination rates are low in this patient cohort and efficacy of hepatitis B vaccine is reduced due to immunosuppressive therapy. Improving adherence to vaccine recommendations is essential to prevent HAV and HBV infections in patients with autoimmune liver diseases.
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Affiliation(s)
- Marcus A Wörns
- Department of Internal Medicine I, Johannes Gutenberg-University, Mainz, Germany
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35
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Silveira MG, Lindor KD. Overlap syndromes with autoimmune hepatitis in chronic cholestatic liver diseases. Expert Rev Gastroenterol Hepatol 2007; 1:329-40. [PMID: 19072425 DOI: 10.1586/17474124.1.2.329] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Conditions exhibiting features of two different autoimmune liver diseases are commonly designated overlap syndromes, although there is no current agreement on what constitutes an overlap syndrome or specific diagnostic criteria. As in the classic autoimmune liver diseases, such as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), the etiology is unknown but presumed to be related to alterations of immune regulation. Distinction of these clinical entities is important for management as outcomes may differ from outcomes of patients with diagnosis of classic autoimmune liver diseases. Due to their presumed rarity, no large therapeutic trials are available and treatment of overlap conditions is empirical and based upon extrapolation of data from the primary autoimmune liver diseases. PBC-AIH overlap is the most frequently described overlap syndrome and may be associated with a poor prognosis. This may represent an important and unrecognized cause of resistance to ursodeoxycholic acid in patients with PBC. PSC-AIH overlap is less commonly reported. Prognosis may be better than in patients with PSC alone; however, worse than in patients with AIH alone. Further studies are needed for determining diagnosis, natural history and optimal therapeutic strategies of overlap syndromes of autoimmune liver disease.
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Affiliation(s)
- Marina G Silveira
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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36
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Chazouillères O. [Primary biliary cirrhosis--autoimmune hepatitis overlap syndrome: middle age?]. GASTROENTEROLOGIE CLINIQUE ET BIOLOGIQUE 2007; 31:7-9. [PMID: 17273126 DOI: 10.1016/s0399-8320(07)89321-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
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Poupon R, Chazouilleres O, Corpechot C, Chrétien Y. Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis. Hepatology 2006; 44:85-90. [PMID: 16799997 DOI: 10.1002/hep.21229] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome is a clinical entity characterized by the occurrence of both conditions at the same time in the same patient. In addition to PBC-AIH overlap syndrome, transitions from one autoimmune disease to another have been reported, but no systematic series have been published. We report a series of 12 patients with consecutive occurrence of PBC and AIH (i.e., PBC followed by AIH). Among 282 PBC patients, 39 were identified who fulfilled criteria for probable or definitive AIH. AIH developed in 12 patients (4.3%). The baseline characteristics of the patients were similar to those of patients with classical PBC. Time elapsed between the diagnosis of PBC and the diagnosis of AIH varied from 6 months to 13 years. Patients with multiple flares of hepatitis at the time of diagnosis of AIH had cirrhosis on liver biopsy. Ten patients were given prednisone +/- azathioprine; short-term as well as sustained remissions were obtained in 8 of these, while two had multiple relapses and eventually died 8 and 7 years after diagnosis of AIH. In conclusion, the development of superimposed AIH could not be predicted from baseline characteristics and initial response to UDCA therapy. If not detected early, superimposed AIH can result in rapid progression toward cirrhosis and liver failure in PBC patients.
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Affiliation(s)
- Raoul Poupon
- Hôpital Saint-Antoine, AP-HP, Hôpitaux de Paris, Faculté et Université PM Curie, INSERM U680, Paris, France.
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Terjung B, Spengler U. Role of auto-antibodies for the diagnosis of chronic cholestatic liver diseases. Clin Rev Allergy Immunol 2006; 28:115-33. [PMID: 15879618 DOI: 10.1385/criai:28:2:115] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Auto-antibodies are an integral part of the diagnostic armentarium in chronic cholestatic liver disorders, such as primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC),auto-immune cholangitis, or overlap syndromes among these disorders. However, care should be taken not to overestimate the diagnostic specificity. Auto-antibodies to mitochondrial antigens(AMAs) with reactivity to the E2 subunit of the pyruvate dehydrogenase complex represent the hallmark antibody for the diagnosis of PBC, whereas antinuclear antibodies (ANAs)with low disease specificity are found in up to 50% of these sera. Antibodies that recognize nuclear envelope proteins exert a similarly high diagnostic specificity as AMA in PBC but occur at a rather low prevalence. The role of auto-antibodies is less well-studied for patients with PSC, but there is growing evidence that only antineutrophil cytoplasmic antibodies(ANCAs) are of relevant diagnostic significance. In contrast, auto-antibodies-particularlyAMAs-do not contribute to the diagnosis of auto-immune cholangitis, whereas ANCAs,ANAs, smooth muscle antibodies, and AMAs are of varying significance in PBC-auto-immune hepatitis (AIH) or PSC-AIH overlap syndromes. It has been widely accepted that the course of the auto-antibody serum end point titers are not suited for the clinical management of patients with chronic cholestatic liver disorders. Additionally, auto-antibodies in these disorders usually do not contribute to the immunopathogenesis of the disease.
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MESH Headings
- Antigens, Bacterial/immunology
- Antigens, Nuclear/immunology
- Autoantibodies/blood
- Autoantibodies/immunology
- Autoantigens/immunology
- Autoimmune Diseases/diagnosis
- Autoimmune Diseases/immunology
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Humans
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Mitochondria, Liver/immunology
- Muscle, Smooth/immunology
- Transglutaminases/immunology
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Affiliation(s)
- Birgit Terjung
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.
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39
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Schramm C, Lohse AW. Overlap syndromes of cholestatic liver diseases and auto-immune hepatitis. Clin Rev Allergy Immunol 2006; 28:105-14. [PMID: 15879617 DOI: 10.1385/criai:28:2:105] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Approximately 18% of patients with auto-immune liver disease present with features characteristic of a second auto-immune liver disease. These cases have been termed "overlap syndromes."The pathogenesis of overlap syndromes is poorly understood, and few data are available regarding the clinical characteristics and outcome of this disease. Therefore, a consensus on the definition of overlap syndromes has not been reached. A common genetic background between auto-immune hepatitis (AIH) and its overlap with primary biliary cirrhosis(PBC) or primary sclerosing cholangitis (PSC) might confer susceptibility to a more inflammatory phenotype, probably requiring combined immunosuppressive treatment. This article focuses on the prevalence, diagnosis, and treatment of the overlap syndrome of AIH and PBC or PSC.
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MESH Headings
- Autoantibodies/immunology
- Cholagogues and Choleretics/therapeutic use
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/drug therapy
- Cholangitis, Sclerosing/epidemiology
- Cholangitis, Sclerosing/immunology
- Diagnosis, Differential
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/drug therapy
- Hepatitis, Autoimmune/epidemiology
- Hepatitis, Autoimmune/immunology
- Humans
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/drug therapy
- Liver Cirrhosis, Biliary/epidemiology
- Liver Cirrhosis, Biliary/immunology
- Prevalence
- Ursodeoxycholic Acid/therapeutic use
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Affiliation(s)
- Christoph Schramm
- Medizinische Klinik I, Universitätsulinikum Hamburg-Eppendorf, Hamburg, Germany.
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40
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Chazouillères O, Wendum D, Serfaty L, Rosmorduc O, Poupon R. Long term outcome and response to therapy of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. J Hepatol 2006; 44:400-6. [PMID: 16356577 DOI: 10.1016/j.jhep.2005.10.017] [Citation(s) in RCA: 128] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2005] [Revised: 09/27/2005] [Accepted: 10/10/2005] [Indexed: 12/20/2022]
Abstract
BACKGROUND/AIMS Whether primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome requires immunosuppressive therapy in addition to ursodeoxycholic acid (UDCA) is a controversial issue. METHODS Seventeen patients with simultaneous form of strictly defined overlap were followed for 7.5 years. First-line treatment was UDCA alone (UDCA) in 11 and combination of immunosuppressors and UDCA (UDCA + IS) in 6. RESULTS Characteristics at presentation were not significantly different between the 2 groups. In the UDCA + IS group (f-up 7.3 years), biochemical response in terms of AIH features (ALT<2ULN and IgG < 16 g/L) was achieved in 4/6 and fibrosis did not progress. In the UDCA group, biochemical response was observed in three patients together with stable or decreased fibrosis (f-up 4.5 years) whereas the eight others were non-responders with increased fibrosis in four (f-up 1.6 years). Seven of these eight patients subsequently received combined therapy for 3 years. Biochemical response was obtained in 6/7 and no further increase of fibrosis was demonstrated. Overall, fibrosis progression in non-cirrhotic patients occurred more frequently under UDCA monotherapy (4/8) than under combined therapy (0/6) (P = 0.04). CONCLUSIONS Combination of UDCA and immunosuppressors appears to be the best therapeutic option for strictly defined PBC-AIH overlap syndrome.
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Affiliation(s)
- Olivier Chazouillères
- Centre de référence des maladies inflammatoires du foie et des voies biliaires, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine Pierre et Marie Curie, Paris, France.
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Li Y, Ayata G, Baker SP, Banner BF. Cholangitis: a histologic classification based on patterns of injury in liver biopsies. Pathol Res Pract 2005; 201:565-72. [PMID: 16259109 DOI: 10.1016/j.prp.2005.06.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory disorders of the biliary tract present difficult diagnostic problems in liver needle biopsies. The aim of this study was to perform a detailed histologic analysis of liver biopsies from patients with biliary tract disorders, classify them by pattern of inflammation, and determine the accuracy of the histologic classification by clinical follow-up. Percutaneous liver needle biopsies from the surgical pathology files of UmassMemorial Healthcare (UMMHC) from 2000 to 2003 with a diagnosis suggesting a biliary tract process (n = 32) and four biopsies from cases with systemic non-biliary tract disorders were analyzed for multiple histologic features and classified as one of five patterns: acute cholangitis/pericholangitis (ACP), lymphocytic cholangitis (LC), granulomatous (G), ductopenia (D), or non-specific (NS). When compared to the "gold standard" diagnosis based on all clinical data, the concordance between the histologic classification and the clinical diagnosis was: 50% for ACP and bile duct obstruction; 77% for LC and immune-mediated cholangitis NOS; 100% for G and G cholangitis; 100% for D and idiopathic adulthood D; and 50% for NS and non-biliary tract disorders. Our findings suggest that classifying biopsies by pattern of injury is helpful in guiding the subsequent clinical work-up. ACP pattern correlates with bile duct obstruction, infection, and ischemia. LC correlates with serologic studies supporting immune-mediated processes. G pattern suggests further work-up for PBC, drug, tuberculosis, or sarcoidosis. D pattern establishes the clinical diagnosis. NS pattern includes cases of primary sclerosing cholangitis, which cannot be diagnosed by biopsy alone.
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Affiliation(s)
- Yanhua Li
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA
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42
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Kingham JGC, Abbasi A. Co-existence of primary biliary cirrhosis and primary sclerosing cholangitis: a rare overlap syndrome put in perspective. Eur J Gastroenterol Hepatol 2005; 17:1077-80. [PMID: 16148553 DOI: 10.1097/00042737-200510000-00011] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Overlap syndromes between autoimmune hepatitis and both primary biliary cirrhosis and primary sclerosing cholangitis are well described, but overlap between primary biliary cirrhosis and primary sclerosing cholangitis is not recognized. We present two cases of an unusual autoimmune liver disease, both of which included an overlap between primary biliary cirrhosis and primary sclerosing cholangitis, while one had features of all three conditions. The diagnoses were based on clinical, biochemical, serological, histological and cholangiographic findings. The two cases were identified from a consecutive cohort of 261 patients with autoimmune liver disease followed prospectively in secondary care over a 20-year period, which gives perspective to this uncommon overlap syndrome.
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Batres LA, Russo P, Mathews M, Piccoli DA, Chuang E, Ruchelli E. Primary sclerosing cholangitis in children: a histologic follow-up study. Pediatr Dev Pathol 2005; 8:568-76. [PMID: 16220233 DOI: 10.1007/s10024-005-0020-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2005] [Accepted: 06/10/2005] [Indexed: 02/08/2023]
Abstract
Primary sclerosing cholangitis (PSC) is rare in the pediatric population. Little information exists on the progression of the disease in children. This study evaluated the experience with PSC at the Children's Hospital of Philadelphia over the past 20 years, with an emphasis on the histologic features at presentation, during disease progression, and after liver transplantation. We retrospectively reviewed the medical records of patients diagnosed with PSC between 1981 and 2001. Nineteen patients met the inclusion criteria with classic radiographic evidence of PSC. One additional patient with normal biliary imaging was subsequently diagnosed at the time of liver transplantation. The 20 patients with PSC (14 males) ranged in age from 1 month to 15 years at time of presentation. Inflammatory bowel disease was evident in 50% of patients. Initial histology revealed advanced disease (bridging fibrosis or cirrhosis) in 13 patients and an earlier histologic stage in 7 patients. Of the latter, 3 remain stable, 2 required transplantation, and 2 were lost to follow-up. Seven of the 13 patients with advanced disease required orthotopic liver transplantation, and 3 of these subsequently showed recurrence of primary disease in the allograft. Thus, most subjects presented insidiously at an advanced stage that required transplantation. Subjects who presented at an earlier stage progressed or remained stable, but the histologic findings at diagnosis were generally not predictive of disease progression. Recurrence of PSC after transplantation is a significant complication in children.
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Affiliation(s)
- L Arturo Batres
- Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
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45
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Choudhuri G, Somani SK, Baba CS, Alexander G. Autoimmune hepatitis in India: profile of an uncommon disease. BMC Gastroenterol 2005; 5:27. [PMID: 16098234 PMCID: PMC1236920 DOI: 10.1186/1471-230x-5-27] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2004] [Accepted: 08/15/2005] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Autoimmune hepatitis (AIH) has been reported to show considerable geographical variation in frequency and clinical manifestations. It is considered a rare cause of liver disease in India. The present study was undertaken to determine the incidence, clinical, biochemical and histological profile of AIH in this part of the world. METHODS Patients presenting with acute or chronic liver disease between January 1999 and June 2002 were evaluated prospectively. AIH was diagnosed using the international autoimmune hepatitis group criteria. Workup included clinical, biochemical, USG, viral markers, UGI endoscopy, AI markers (ANA, SMA, Anti-LKM, AMA, RF, p-ANCA) using indirect immunofluorescence and liver biopsy if possible. RESULTS Forty-one of 2401 (1.70%) patients were diagnosed to have autoimmune liver disease. Out of these, 38 had autoimmune hepatitis and the rest 3 had primary biliary cirrhosis. The mean age of the patients of autoimmune hepatitis was 36.2 (15.9) years, 34 (89.4%) were females, and the duration of symptoms was 20.3 (20.5) months. Nineteen (50%) of them presented with chronic hepatitis, 13 (34.2%) as cirrhosis, 5 (13.1%) with acute hepatitis and 1 (2.6%) with cholestatic hepatitis. The presentations were jaundice in 21 (55.2%), pedal edema and hepatomegaly in 17 (44.7%), splenomegaly in 13 (34.2%), encephalopathy, abdominal pain in 9 (23.6%) and fever in 8 (21%). Twelve had esophageal varices and 3 had bled. Biochemical parameters were ALT 187 (360) U/L, AST 157 (193) U/L, ALP 246 (254) U/L, globulin 4.1 (1.6) g/dL, albumin 2.8 (0.9) g/dL, bilirubin 5.2 (7.4) mg/dL, prothrombin time 17 (7) sec and ESR 47 (17) sec. The autoimmune markers were SMA (24), ANA (15), both SMA and ANA (4), AMA (1), rheumatoid factor (2), pANCA (1), and Anti-LKM in none. Thirty (79%) patients had definite AIH and eight (21%) had probable AI hepatitis. Associated autoimmune diseases was seen in 15/38 (39.4%), diabetes 4, hypothyroidism 3, vitiligo 2, thrombocytopenia 2, rheumatoid arthritis 2, Sjogren's syndrome 1 and autoimmune polyglandular syndrome III in 1. Viral markers were positive in two patients, one presenting as acute hepatitis and HEV-IgM positive and another anti-HCV positive. CONCLUSION In India, autoimmune hepatitis is uncommon and usually presents with chronic hepatitis or cirrhosis, acute hepatitis being less common. Age at presentation was earlier but clinical parameters and associated autoimmune diseases were similar to that reported from the west. Primary biliary cirrhosis is rare. Type II AIH was not observed.
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Affiliation(s)
- Gourdas Choudhuri
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014 (UP), India
| | - Sanjay K Somani
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014 (UP), India
| | - Chalamalasetty S Baba
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014 (UP), India
| | - George Alexander
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014 (UP), India
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Affiliation(s)
- Ulrich Beuers
- Department of Medicine II-Grosshadern, Ludwig Maximilians-University of Munich, Marchioninistrasse 15, 81377 Munich, Germany.
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Floreani A, Rizzotto ER, Ferrara F, Carderi I, Caroli D, Blasone L, Baldo V. Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. Am J Gastroenterol 2005; 100:1516-22. [PMID: 15984974 DOI: 10.1111/j.1572-0241.2005.41841.x] [Citation(s) in RCA: 149] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED Autoimmune hepatitis/primary sclerosing cholangitis (AIH/PSC) overlap syndrome is a relatively uncommon variant of PSC. AIM To evaluate the natural history of AIH/PSC overlap syndrome compared to a group of "classical" PSC. METHODS Forty-one consecutive PSC patients, with a regular follow-up of at least 2 years, were prospectively included in the study. Among these, 7 fulfilled the criteria for AIH/PSC overlap syndrome. RESULTS The AIH/PSC overlap group significantly differed from the "classical" PSC group in the following parameters: mean age at presentation (21.4 +/- 5.0 vs 32.3 +/- 10 years, p < 0.01), AST 191.0 +/- 14.8 vs 48.9 +/- 34.5 U/L, p < 0.005), ALT (357.0 +/- 26.5 vs 83.7 +/- 60.7 U/L, p < 0.005) and serum IgG (25.6 +/- 4.7 vs 12.9 +/- 6.0 mg/dl, p < 0.0001). The mean follow-up was similar in the 2 groups (93.3 +/- 65.9 vs 98.1 +/- 65.9 months respectively). Treatment included immunosuppression + ursodeoxycholic acid (UDCA) in the AIH/PSC overlap patients, and UDCA in the "classical" PSC group. Deaths were recorded only in the classical PSC group. The median survival in the latter group was 207 months (95% C.I. 87.6-326.4). The major events during the follow-up included: OLTx (1/7 vs 6/34), and neoplasms (only in the group of "classical" PSC). The new Mayo score prognostic index only increased significantly during follow-up in the "classical" PSC group (r2 0.8117, p < 0.01) CONCLUSION Patients with AIH/PSC overlap syndrome seem to benefit from immunosuppression + UDCA therapy, survival is apparently better than in "classical" PSC condition.
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Affiliation(s)
- Annarosa Floreani
- Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
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Gheorghe L, Iacob S, Gheorghe C, Iacob R, Simionov I, Vadan R, Becheanu G, Parvulescu I, Toader C. Frequency and predictive factors for overlap syndrome between autoimmune hepatitis and primary cholestatic liver disease. Eur J Gastroenterol Hepatol 2004; 16:585-92. [PMID: 15167161 DOI: 10.1097/00042737-200406000-00012] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
OBJECTIVES To evaluate the frequency of cholestatic pattern in patients with autoimmune hepatitis (AIH) and to identify predictive factors associated with the development of the overlap syndrome. METHODS Eighty-two consecutive patients diagnosed with AIH at the referral centre between January 1998 and June 2002 were included in the study. The new scoring system modified by the International Autoimmune Hepatitis Group was used to classify patients as definite/probable. Overlap syndrome was considered when the patient had clinical, serological and histological characteristics of two conditions: AIH and primary biliary cirrhosis (PBC) or AIH and primary sclerosing cholangitis (PSC). RESULTS From the 82 AIH patients (76 female and six male), 84.1% presented definite AIH (> 15 points) and 15.9% probable AIH (10 - 15 points). The frequency of the overlap syndrome was 20%: 13% with PBC and 7% with PSC. In the univariate analysis the overlap syndrome was associated with male gender (P = 0.01), age < 35 years (P < 0.0001), histopathological aspect of cholestasis (P < 0.0001), suboptimal response to treatment (P < 0.0001) and probable AIH (P < 0.0001). Age < 35 years, probable AIH and the absence of anti-nuclear antibody (ANA) have been identified as independent indicators of the overlap diagnosis by the logistic regression analysis. CONCLUSION Patients with overlap syndrome between AIH and primary cholestatic liver disease are frequently diagnosed in clinical practice, representing 20% of AIH cases in our study. The independent predictive factors associated with the diagnosis of overlap syndrome are young age, ANA(-) profile, and probable diagnosis according with the scoring system for AIH.
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Affiliation(s)
- Liana Gheorghe
- Centre of Gastroenterology and Hepatology, Fundeni Clinical Institute, Bucharest, Romania.
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Habior A. Association of autoimmune liver diseases. Eur J Gastroenterol Hepatol 2004; 16:503; author reply 503. [PMID: 15097044 DOI: 10.1097/00042737-200405000-00011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
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Floreani A, Baragiotta A, Leone MG, Baldo V, Naccarato R. Primary biliary cirrhosis and hepatitis C virus infection. Am J Gastroenterol 2003; 98:2757-62. [PMID: 14687829 DOI: 10.1111/j.1572-0241.2003.08717.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The aim of this study was to describe the clinical characteristics of hepatitis C virus (HCV)-infected patients with primary biliary cirrhosis (PBC) by comparison to patients with both antimitochondrial (AMA) positive and AMA negative PBC. METHODS All patients consecutively diagnosed as having PBC between 1973 and 1999 who had a regular follow-up of at least 2 yr were prospectively included in the study. The mean follow-up was 8.3 +/- 5.7 yr. Survival was calculated according to Kaplan-Meier curves. RESULTS A total of 170 patients with PBC were considered. The syndrome with PBC and HCV infection (HCV-infected PBC patients) was recorded in 14 patients (13 women and one man), whereas 135 patients had AMA positive PBC and 18 had AMA negative PBC. Only three patients fulfilled the criteria for overlap syndrome involving PBC and autoimmune hepatitis. At presentation, the HCV-infected PBC group had significantly lower levels of ALP, gamma-glutamyl transpeptidase, and IgM than the AMA positive or AMA negative PBC patients (p < 0.01). With regard to the autoantibody profile, there was a significant association with LKM and HCV-infected PBC patients (21.4%), whereas ANA was significantly higher in AMA negative PBC patients than in the other two groups (83% vs 21.4% in the HCV-infected PBC patients and 38.5% in the AMA positive PBC group). No differences were found regarding the association with autoimmune conditions. During follow-up, hepatocellular carcinoma (HCC) developed more frequently in the PBC/HCV overlap group (i.e., three of 14 vs four of 135 patients with AMA positive PBC, p < 0.05). Survival curves were similar in HCV-infected PBC patients and AMA positive PBC, whereas the AMA negative group had a significantly slower decline (relative risk (RR) = 2.44, p < 0.05). CONCLUSION HCV-infected PBC patients are characterized by a biochemical profile with a modest rise in cholestatic enzymes but a high risk of developing HCC during follow-up.
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Affiliation(s)
- Annarosa Floreani
- Department of Surgical and Gastroenterological Sciences, University of Padua, Via Giustiniani 2, 35128 Padua, Italy
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