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Pietri O, Chicaud M, Andreani T, Chrétien Y, Limousin W, Lemoinne S, Chazouilleres O, Wendum D. Unexplained Chronically Elevated Aminotransferases: Liver Biopsy Gives Major Information with Therapeutic Implication in One Patient Out of Seven. Dig Dis Sci 2025; 70:1178-1189. [PMID: 39681748 DOI: 10.1007/s10620-024-08730-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 11/03/2024] [Indexed: 12/18/2024]
Abstract
BACKGROUND & AIMS Liver biopsy contribution in patients with unexplained elevation of transaminases is not clearly established. The aim was to study liver biopsy contribution in patients with unexplained elevated transaminases strictly defined according to the current guidelines, reflecting the present clinical practice. METHODS In a retrospective study, we identified all the liver biopsies performed in patients with elevated transaminases for at least six months. Patients with a particular context, or with an identified cause of liver disease were excluded. The biopsies were classified according to the 4 following injury patterns: hepatitic, biliary, steatotic, vascular. RESULTS 87 patients were included. Liver biopsy showed minimal changes or a normal histology in 48%, a steatotic pattern in 21%, a hepatitic pattern in 13%, a vascular pattern in 8%, a biliary pattern in 1%, and a mixed pattern in 8%. A cause could be determined in 21% of patients with normal histology, 85% with steatosis, 56% with hepatitis, 75% with biliary, but in none with isolated vascular pattern. Liver biopsy had important clinical and therapeutic implications in 15% of patients, with a diagnosis of autoimmune hepatitis, primary biliary cholangitis or metabolic dysfunction-associated steatohepatitis. Elevation of transaminases > 10 upper normal limit was present in all the patients with confirmed autoimmune hepatitis, but in only 7% of others. CONCLUSION Liver biopsy had important clinical and therapeutic implications in 15% of patients. However, the majority of patients had minimal changes without a cause, or minor vascular lesions of uncertain significance.
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Affiliation(s)
- Olivia Pietri
- AP-HP, Saint-Antoine Hospital, Department of Hepatology, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis (CRMR MIVB-H), ERN RARE-LIVER, Sorbonne Université, Paris, France
| | - Matthieu Chicaud
- AP-HP, Hôpital Saint Antoine, Department of Pathology, Paris, France
| | - Tony Andreani
- AP-HP, Saint-Antoine Hospital, Department of Hepatology, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis (CRMR MIVB-H), ERN RARE-LIVER, Sorbonne Université, Paris, France
| | - Yves Chrétien
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, Paris, France
| | - Wendy Limousin
- AP-HP, Saint-Antoine Hospital, Department of Hepatology, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis (CRMR MIVB-H), ERN RARE-LIVER, Sorbonne Université, Paris, France
| | - Sara Lemoinne
- AP-HP, Saint-Antoine Hospital, Department of Hepatology, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis (CRMR MIVB-H), ERN RARE-LIVER, Sorbonne Université, Paris, France
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, Paris, France
| | - Olivier Chazouilleres
- AP-HP, Saint-Antoine Hospital, Department of Hepatology, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis (CRMR MIVB-H), ERN RARE-LIVER, Sorbonne Université, Paris, France
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, Paris, France
| | - Dominique Wendum
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, Paris, France.
- AP-HP, Hôpital Saint Antoine, Department of Pathology, Paris, France.
- AP-HP, Hôpital Saint Antoine, Service d'Anatomie et Cytologie Pathologiques, 184 rue du faubourg Saint-Antoine, F-75012, Paris, France.
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Ellez HI, Danis N, Akarca US. Evaluation of patients with positive anti-mitochondiral antibody and normal alkaline phosphatase levels for primary biliary cholangitis. Acta Gastroenterol Belg 2024; 87:282-286. [PMID: 39210760 DOI: 10.51821/87.2.12041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Primary Biliary Cholangitis (PBC) is a chronic cholestatic liver disease typically diagnosed by elevated cholestatic liver enzymes and a positive anti-mitochondrial antibody (AMA) test. The clinical importance of AMA positivity in patients with normal cholestatic liver enzymes is unclear. The aim of this study was to determine the relationship between PBC and AMA positivity detected in individuals with normal cholestatic enzyme levels. The files of patients with AMA and/or AMA-M2 positivity between 2009 and 2018 and whose alkaline phosphatase (ALP) levels were below upper limit of normal (ULN) at initial admission were retrospectively analyzed. The ALP levels were normal in all patients. All patients had AMA positivity demonstrated by indirect immunofluorescence (IIF) or AMA-M2 positivity demonstrated by ELISA. A total of 16 patients underwent liver biopsy and seven (43.75%) showed changes consistent with those with PBC. A total of 12 patients were diagnosed with PBC and were treated and followed up with this diagnosis. People with AMA positivity and normal cholestasis enzyme levels are closely associated with PBC. Some of these patients were diagnosed with PBC as a result of biopsy and some were diagnosed by clinical and laboratory findings during follow-up.. The patients with an AMA titration of 1/20 were not associated with PBC. In our study, results similar to the studies confirmed by biopsies were obtained. In this regard, there is a need for prospective and retrospective studies with longer follow-up periods.
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Affiliation(s)
- Halil Ibrahim Ellez
- Department of Internal Medicine, Division of Medical Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Nilay Danis
- Department of Internal Medicine, Division of Gastroenterology, Dokuz Eylul University, Izmir, Turkey
| | - Ulus Salih Akarca
- Department of Internal Medicine, Division of Gastroenterology, Ege University, Izmir, Turkey
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SORRENTINO MC, a nome del GdS-AI SIPMeL, CARBONE T, CINQUANTA L, ALESSIO MG, INFANTINO M, DELEONARDI G, TREVISAN MT, PORCELLI B, TERZUOLI L, PLATZGUMMER S, BRUSCA I, ANTICO A, TAMPOIA M, PESCE G, VILLALTA D, BIZZARO N. Linee guida SIPMeL per la determinazione degli autoanticorpi nella diagnosi delle malattie autoimmuni del fegato. LA RIVISTA ITALIANA DELLA MEDICINA DI LABORATORIO 2024; 20. [DOI: 10.23736/s1825-859x.24.00226-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Rigopoulou EI, Bogdanos DP. Role of autoantibodies in the clinical management of primary biliary cholangitis. World J Gastroenterol 2023; 29:1795-1810. [PMID: 37032725 PMCID: PMC10080701 DOI: 10.3748/wjg.v29.i12.1795] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/04/2023] [Accepted: 03/14/2023] [Indexed: 03/28/2023] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by immune-driven destruction of small intrahepatic bile ducts leading a proportion of patients to hepatic failure over the years. Diagnosis at early stages in concert with ursodeoxycholic acid treatment has been linked with prevention of disease progression in the majority of cases. Diagnosis of PBC in a patient with cholestasis relies on the detection of disease-specific autoantibodies, including anti-mitochondrial antibodies, and disease-specific anti-nuclear antibodies targeting sp100 and gp210. These autoantibodies assist the diagnosis of the disease, and are amongst few autoantibodies the presence of which is included in the diagnostic criteria of the disease. They have also become important tools evaluating disease prognosis. Herein, we summarize existing data on detection of PBC-related autoantibodies and their clinical significance. Moreover, we provide insight on novel autoantibodies and their possible prognostic role in PBC patients.
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Affiliation(s)
- Eirini I Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa 41110, Greece
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa 41110, Greece
| | - Dimitrios P Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa 41110, Greece
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Bozward A, Ce M, Dell'oro L, Oo YH, Ronca V. Breakdown in hepatic tolerance and its relation to autoimmune liver diseases. Minerva Gastroenterol (Torino) 2023; 69:10-22. [PMID: 33793157 DOI: 10.23736/s2724-5985.21.02853-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The liver is a complex immunological organ. It has both immunogenic and tolerogenic capacity. Tolerogenic potential of human liver with its protective firewalls is required to guard the body against the continuous influx of microbial product from the gut via the sinusoids and biliary tree. Immunotolerance and anergic state is maintained by a combined effort of both immune cells, parenchyma cells, epithelial and endothelial cells. Despite this, an unknown trigger can ignite the pathway towards breakdown in hepatic tolerance leading to autoimmune liver diseases. Understanding the initial stimulus which causes the hepatic immune system to switch from the regulatory arm towards self-reactive effector arm remains challenging. Dissecting this pathology using the current technological advances is crucial to develop curative immune based therapy in autoimmune liver diseases. We discuss the hepatic immune cells and non-immune cells which maintain liver tolerance and the evidence of immune system barrier breach which leads to autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis.
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Affiliation(s)
- Amber Bozward
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK
| | - Maurizio Ce
- Department of Health Sciences, University of Milan, Milan, Italy
| | | | - Ye H Oo
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK
| | - Vincenzo Ronca
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK - .,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK
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6
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Leung KK, Hirschfield GM. Autoantibodies in Primary Biliary Cholangitis. Clin Liver Dis 2022; 26:613-627. [PMID: 36270719 DOI: 10.1016/j.cld.2022.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is a chronic immune-mediated liver disease characterized by a lymphocytic cholangitis, with subsequent cholestasis, progressive liver fibrosis, and ultimately complications arising from end-stage liver disease. Testing for autoantibodies is important in the diagnosis of PBC, as well as stratifying prognosis. This review focuses on the role of autoantibodies in the diagnosis of PBC, as well as the relationship between autoantibodies with pathophysiology and prognostication, along with a discussion regarding novel and other related disease autoantibodies.
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Affiliation(s)
- Kristel K Leung
- Department of Medicine, Division of Gastroenterology & Hepatology, University Health Network, University of Toronto, 200 Elizabeth Street, Eaton Building, 9th Floor, Toronto, Ontario M5G 2C4, Canada
| | - Gideon M Hirschfield
- Department of Medicine, Division of Gastroenterology & Hepatology, University Health Network, University of Toronto, 200 Elizabeth Street, Eaton Building, 9th Floor, Toronto, Ontario M5G 2C4, Canada.
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7
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Cançado GGL, Braga MH, Ferraz MLG, Villela-Nogueira CA, Terrabuio DRB, Cançado ELR, Nardelli MJ, Faria LC, de Faria Gomes NM, Oliveira EMG, Rotman V, Oliveira MB, da Cunha SMCF, Cunha-Silva M, Mendes LSC, Ivantes CAP, Codes L, de Almeida E Borges VF, de Lima Pace FH, Pessoa MG, Signorelli IV, Coral GP, Bittencourt PL, Levy C, Couto CA. Anti-mitochondrial Antibody-Negative Primary Biliary Cholangitis Is Part of the Same Spectrum of Classical Primary Biliary Cholangitis. Dig Dis Sci 2022; 67:3305-3312. [PMID: 34181166 DOI: 10.1007/s10620-021-07122-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 06/16/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease in which anti-mitochondrial antibodies (AMA) are the diagnostic hallmark. Whether AMA-negative PBC patients represent a different phenotype of disease is highly debated. AIMS The purpose of our study was to compare AMA-positive and AMA-negative PBC patients in a large non-white admixed Brazilian cohort. METHODS The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian PBC patients, stratifying data according to AMA status. RESULTS A total of 464 subjects (95.4% females, mean age 56 ± 5 years) with PBC were included. Three hundred and eighty-four (83%) subjects were AMA-positive, whereas 80 (17%) had AMA-negative PBC. Subjects with AMA-negative PBC were significantly younger (52.2 ± 14 vs. 59.6 ± 11 years, p = 0.001) and had their first symptom at an earlier age (43.2 ± 13 vs. 49.5 ± 12 years, p = 0.005). Frequency of type 2 diabetes was significantly increased in subjects with AMA-negative PBC (22.5% vs. 12.2%, p = 0.03). Lower IgM (272.2 ± 183 vs. 383.2 ± 378 mg/dL, p = 0.01) and triglycerides (107.6 ± 59.8 vs.129.3 ± 75.7 mg/dL, p = 0.025) and higher bilirubin (3.8 ± 13.5 vs. 1.8 ± 3.4 mg/dL, p = 0.02) levels were also observed in this subgroup. Response to ursodeoxycholic acid varied from 40.5 to 63.3% in AMA-positive and 34 to 62.3% in AMA-negative individuals, according to different response criteria. Outcomes such as development of liver-related complications, death and requirement for liver transplantation were similar in both groups. CONCLUSIONS AMA-negative PBC patients are similar to their AMA-positive counterparts with subtle differences observed in clinical and laboratory features.
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Affiliation(s)
- Guilherme Grossi Lopes Cançado
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas, Universidade Federal de Minas Gerais, Av. Professor Alfredo Balena 110, Belo Horizonte, Minas Gerais, 30130-100, Brazil.
- Hospital da Polícia Militar de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
| | - Michelle Harriz Braga
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Maria Lucia Gomes Ferraz
- Disciplina de Gastroenterologia, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil
| | - Cristiane Alves Villela-Nogueira
- Hospital Universitário Clementino Fraga Filho e Departamento de Clínica Médica da Faculdade de Medicina, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Eduardo Luiz Rachid Cançado
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Mateus Jorge Nardelli
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas, Universidade Federal de Minas Gerais, Av. Professor Alfredo Balena 110, Belo Horizonte, Minas Gerais, 30130-100, Brazil
| | - Luciana Costa Faria
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas, Universidade Federal de Minas Gerais, Av. Professor Alfredo Balena 110, Belo Horizonte, Minas Gerais, 30130-100, Brazil
| | | | | | - Vivian Rotman
- Hospital Universitário Clementino Fraga Filho e Departamento de Clínica Médica da Faculdade de Medicina, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Maria Beatriz Oliveira
- Ambulatório Municipal de Hepatites Virais de São José Dos Campos, São José dos Campos, São Paulo, Brazil
| | | | - Marlone Cunha-Silva
- Divisão de Gastroenterologia (Gastrocentro), Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil
| | | | | | - Liana Codes
- Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Bahia, Brazil
- Hospital Português, Salvador, Bahia, Brazil
| | - Valéria Ferreira de Almeida E Borges
- Instituto de Gastroenterologia, Endoscopia e Proctologia, Uberlândia, Minas Gerais, Brazil
- Universidade Federal de Uberlândia, Uberlândia, Minas Gerais, Brazil
| | - Fabio Heleno de Lima Pace
- Serviço de Gastroenterologia e Hepatologia, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil
| | - Mario Guimarães Pessoa
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | - Izabelle Venturini Signorelli
- Hospital Universitário Cassiano Antônio Moraes, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Gabriela Perdomo Coral
- Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Paulo Lisboa Bittencourt
- Hospital Português, Salvador, Bahia, Brazil
- Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Cláudia Alves Couto
- Instituto Alfa de Gastroenterologia, Hospital das Clínicas, Universidade Federal de Minas Gerais, Av. Professor Alfredo Balena 110, Belo Horizonte, Minas Gerais, 30130-100, Brazil
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Ding D, Xuan G, Hu Y, Yu J, Liu Y, Guo G, Ma S, Yang F, Tian S, Ma G, Chen L, Zhou X, Shang Y, Han Y. Immunoglobulin M: A Neglected Serum Biomarker in Treatment-Naive Primary Biliary Cholangitis With Normal Alkaline Phosphatase. Hepatol Commun 2022; 6:1403-1412. [PMID: 35182047 PMCID: PMC9134806 DOI: 10.1002/hep4.1907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 12/09/2021] [Accepted: 01/18/2022] [Indexed: 11/22/2022] Open
Abstract
The diagnosis of primary biliary cholangitis (PBC) in patients with seropositive anti-mitochondrial antibody (AMA) but normal alkaline phosphatase (ALP) depends on a liver biopsy. We aimed to reveal potential serum biomarkers that could suggest the necessity of a liver biopsy in such patients. Retrospective analysis was performed. Subjects who were treatment naive with seropositive AMA but normal ALP and who underwent at least one liver biopsy between 2008 and 2020 were included in this study. Histologic biopsies were evaluated by two experienced pathologists blinded to the serum tests. A total of 115 patients who were treatment naive were included in this study. Of these, 77 patients (67%) exhibited histologic PBC features and nonspecific histologic features were found in the remaining 38 (33%) patients. Multivariate analysis suggested that baseline serum immunoglobulin M (IgM) >0.773 × upper limit of normal (ULN) (P < 0.001) and age >42 years (P = 0.002) were associated with the diagnosis of PBC through liver biopsies. A significant decrease in the median levels of gamma-glutamyl transpeptidase (GGT) and IgM was found in 54 patients with PBC who received ursodeoxycholic acid (UDCA). Conclusion: For patients who were treatment naive with seropositive AMA but normal ALP, baseline serum IgM >0.773 × ULN and age >42 years were the factors that strongly suggested a diagnosis of PBC. In these patients receiving UDCA, a dynamic monitoring of GGT and IgM might be helpful in evaluating therapeutic responses.
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Affiliation(s)
- Dawei Ding
- State Key Laboratory of Cancer BiologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Guoyun Xuan
- State Key Laboratory of Cancer BiologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Yinan Hu
- State Key Laboratory of Cancer BiologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Jiahao Yu
- State Key Laboratory of Cancer BiologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Yansheng Liu
- State Key Laboratory of Cancer BiologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Guanya Guo
- State Key Laboratory of Cancer BiologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Shuoyi Ma
- State Key Laboratory of Cancer BiologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Fangfang Yang
- State Key Laboratory of Cancer BiologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Siyuan Tian
- State Key Laboratory of Cancer BiologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Gang Ma
- State Key Laboratory of Cancer BiologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Ling Chen
- Division of PathologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Xinmin Zhou
- State Key Laboratory of Cancer BiologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Yulong Shang
- State Key Laboratory of Cancer BiologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Ying Han
- State Key Laboratory of Cancer BiologyXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
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Ceribelli A, Isailovic N, Gorlino C, Assandri R, Vecellio M, De Santis M, Satoh M, Selmi C. Antigen Reactivity and Clinical Significance of Autoantibodies Directed Against the Pyruvate Dehydrogenase Antigen Complex in Patients With Connective Tissue Disease. Front Immunol 2022; 13:822996. [PMID: 35296099 PMCID: PMC8918651 DOI: 10.3389/fimmu.2022.822996] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 02/04/2022] [Indexed: 11/17/2022] Open
Abstract
Introduction Antimitochondrial antibodies (AMAs) are the hallmark of primary biliary cholangitis (PBC) but can be identified also in patients with connective tissue disease, namely, systemic sclerosis (SSc). Protein immunoprecipitation (IP) and IP-Western blot (WB) can be used to confirm AMA positivity directed at the pyruvate dehydrogenase complex (PDC) subunits E1α, E1β, E2/E3, and E3BP in patients showing a cytoplasmic reticular pattern at indirect immunofluorescence when performed in a screening setting before the onset of overt cholestasis in rheumatic patients. Patients and Methods We studied sera from 285 patients affected by connective tissue disease [SSc, n = 144; dermato/polymyositis (DM/PM), n = 56; and undifferentiated connective tissue disease (UCTD), n = 85] by indirect immunofluorescence (IIF), protein-IP, and IP-WB to identify specific PDC subunits recognized by AMA. Results Twenty percent (57/285) of sera from patients with connective tissue disease had a cytoplasmic reticular pattern at IIF, and in 77% (44/57, including 20 SSc, 12 PM/DM, and 12 UCTD) of these, we detected different titers of autoantibodies against the PDC subunits, specifically against PDC-E2. Among these sera, 4 (9%) tested positive for anti-E1α, 15 (34%) for anti-E1β, and 16 (36%) for anti-E3BP. Four of the 20 AMA-positive SSc cases (20%) had been already diagnosed with PBC, and all were positive for autoantibodies against the subunits PDC-E2, E3, and E3BP. Conclusions Using IIF and IP, we confirm that autoantibodies against the PDC components are detected in rheumatic patients with PBC or without liver dysfunction. In view of the strong predictive value of AMA for PBC, a strict follow-up of these latter patients is warranted for an early diagnosis of the disease.
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Affiliation(s)
- Angela Ceribelli
- Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Natasa Isailovic
- Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Carolina Gorlino
- Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
| | | | - Matteo Vecellio
- Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Maria De Santis
- Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Minoru Satoh
- Department of Clinical Nursing, School of Health Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Carlo Selmi
- Department of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- *Correspondence: Carlo Selmi,
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10
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Parés A. Practical management of primary biliary cholangitis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 114:410-417. [PMID: 34663072 DOI: 10.17235/reed.2021.8219/2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease of autoimmune pathogenesis that mainly affects middle-aged women. Patients show elevated alkaline phosphatase and bilirubin levels as the disease progresses. The main symptoms of the disease are pruritus and fatigue, which interfere with the quality of life of patients. Progressive damage leading to end stage liver disease could require liver transplantation. Despite the efficacy of ursodeoxycholic acid (UDCA), the current standard of care for PBC, up to 40% of patients have an inadequate response to the treatment, requiring a second-line therapy. Obeticholic acid is the only second-line treatment approved for PBC in combination with UDCA in adults with an inadequate response to UDCA, or as monotherapy in patients intolerant to UDCA. Although different clinical guidelines for the diagnosis and management of PBC have been published, PBC is still challenging for many physicians. In this article we briefly review the main characteristics of the disease and include a practical user-friendly algorithm for the diagnosis and management of PBC developed by Spanish PBC experts and based on the European Association for the Study of the Liver recommendations.
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11
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Terziroli Beretta-Piccoli B, Stirnimann G, Mertens J, Semela D, Zen Y, Mazzucchelli L, Voreck A, Kolbus N, Merlo E, Di Bartolomeo C, Messina P, Cerny A, Costantini S, Vergani D, Mieli-Vergani G. Primary biliary cholangitis with normal alkaline phosphatase: A neglected clinical entity challenging current guidelines. J Autoimmun 2020; 116:102578. [PMID: 33229138 DOI: 10.1016/j.jaut.2020.102578] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 11/11/2020] [Accepted: 11/13/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIM The diagnosis of primary biliary cholangitis (PBC), an uncommon immune-mediated cholestatic liver disease, is based on positive circulating anti-mitochondrial (AMA) and/or PBC-specific anti-nuclear autoantibodies (ANA), coupled with elevated serum alkaline phopsphatase (ALP) levels. Timely initiation of treatment with ursodeoxycholic acid prevents progression to cirrhosis and liver failure. We aimed at investigating liver histology in patients with normal ALP level and positive AMA and/or PBC-specific ANA. METHODS We searched the Swiss PBC Cohort Study database, which includes subjects with positive PBC autoimmune serology and normal ALP levels, for patients who underwent a liver biopsy. Histological slides were centrally reviewed by an expert liver pathologist, and sera were centrally re-tested for AMA and ANA. RESULTS 30 patients were included; 90% females, median age 53 (range 27-72) years. Twenty-four (80%) had liver histology typical for (n = 2), consistent with (n = 16) or suggestive of (n = 6) PBC, including three of four AMA-negative ANA-positive patients. Among 22 ursodeoxycholic acid treated patients, 14 had elevated GGT levels before treatment; a significant decrease of the median GGT level between pre- (1.46 x ULN) and post- (0.43 x ULN) treatment (p = 0.0018) was observed. CONCLUSIONS In our series, a high proportion of AMA positive patients with normal ALP levels have PBC. For the first time we show histological diagnosis of PBC in AMA-negative/PBC-specific ANA-positive subjects and the potential role of GGT as a biomarker in PBC patients with normal baseline ALP levels. Current guidelines for the diagnosis of PBC do not cover the whole extent of PBC presentation, with important clinical implications in terms of timely treatment initiation.
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Affiliation(s)
| | - Guido Stirnimann
- Department of Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Joachim Mertens
- Gastroenterology and Hepatology Department, University Hospital Zurich, Zurich, Switzerland
| | - David Semela
- Gastroenterology and Hepatology Department, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Yoh Zen
- Institute of Liver Studies, MowatLabs, King's College London Faculty of Life Sciences & Medicine at King's College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom
| | | | | | | | | | | | | | - Andreas Cerny
- Epatocentro Ticino, Via Soldino 5, 6900, Lugano, Switzerland
| | - Silvia Costantini
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King's College London Faculty of Life Sciences & Medicine at King's College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College London Faculty of Life Sciences & Medicine at King's College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom
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12
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Alvaro D, Carpino G, Craxi A, Floreani A, Moschetta A, Invernizzi P. Primary biliary cholangitis management: controversies, perspectives and daily practice implications from an expert panel. Liver Int 2020; 40:2590-2601. [PMID: 32757367 DOI: 10.1111/liv.14627] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 07/24/2020] [Accepted: 07/26/2020] [Indexed: 02/13/2023]
Abstract
Primary biliary cholangitis (PBC) is a rare progressive immune-mediated liver disease that, if not adequately treated, may culminate in end-stage disease and need for transplantation. According to current guidelines, PBC is diagnosed in the presence of antimitochondrial antibodies (AMA) or specific antinuclear antibodies, and of a cholestatic biochemical profile, while biopsy is recommended only in selected cases. All patients receive ursodeoxycholic acid (UDCA) in first line; the only registered second-line therapy is obeticholic acid (OCA) for UDCA-inadequate responders. Despite the recent advances in understanding PBC pathogenesis and developing new treatments, many grey areas remain. Six Italian experts selected the following topics as the most urgent to address in PBC management: diagnosis and natural history of PBC: as a portion of the subjects with isolated AMA, normal alkaline phosphatase (ALP) levels and no symptoms of liver disease could have PBC by histology, defining how to manage and follow this population is crucial; role of liver biopsy: recent evidence suggests that biopsy may provide relevant information for risk stratification and prediction of UDCA response, possibly facilitating personalized approaches; risk stratification: the tools for risk stratification are well established, but some issues (eg bile acid dosage in routine practice) remain controversial; and therapy: those in more advanced stages of development are nuclear receptor modulators and fibrates, but more data are needed to plan personalized strategies. In this manuscript, for each topic, current evidence, controversies and future perspectives are summarized with the possible implications for clinical practice.
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Affiliation(s)
- Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Division of Health Sciences, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Antonio Craxi
- Gastroenterology and Liver Unit, PROMISE, University of Palermo, Palermo, Italy
| | - Annarosa Floreani
- Studioso Senior University of Padova and, Scientific Consultant IRCCS Negrar, Verona, Italy.,Scientific Consultant IRCCS Negrar, Verona, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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13
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Zandanell S, Strasser M, Feldman A, Tevini J, Strebinger G, Niederseer D, Pohla-Gubo G, Huber-Schönauer U, Ruhaltinger S, Paulweber B, Datz C, Felder TK, Aigner E. Low rate of new-onset primary biliary cholangitis in a cohort of anti-mitochondrial antibody-positive subjects over six years of follow-up. J Intern Med 2020; 287:395-404. [PMID: 31802567 PMCID: PMC7154539 DOI: 10.1111/joim.13005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Anti-mitochondrial antibodies (AMA) are closely linked to primary biliary cholangitis (PBC). The prevalence of AMA in the general population is low, and AMA positivity may precede PBC. We aimed to determine the natural history of subjects with positive AMA. METHODS In total, 302 patients were tested AMA-positive over a ten-year period. Of these, immunoblotting confirmed specific AMA in 184 (29 male, 155 female, age 59.6 ± 14.1 years). These subjects were invited to our liver outpatient clinic for clinical and biochemical re-evaluation. Detailed clinical history data were additionally collected from the hospital computer system and by telephone. The subsequent course with regard to mortality, liver-related morbidity, extrahepatic co-morbidities and effectiveness of PBC treatment was determined in 150 subjects (81.5%). RESULTS After 5.8 ± 5.6 years of follow-up (FU), of 184 AMA-positive subjects, 28 subjects (15.2%; liver-related mortality n = 5) were deceased, and 122 subjects (66.3%) completed FU while 34 subjects (18.5%) were not available for FU. The 122 patients who completed FU were 63 patients with established PBC, six de novo cases of PBC (10.2% of 59 initially at risk), 42 (34.4%) subjects were still AMA-positive without PBC, and 11 (9.0%) subjects were AMA-negative at FU. CONCLUSIONS Anti-mitochondrial antibodies-positive patients without PBC at baseline infrequently developed PBC over six years of FU. AMA positivity represented a transient serological autoimmune phenomenon in a significant proportion of subjects.
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Affiliation(s)
- S Zandanell
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - M Strasser
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - A Feldman
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - J Tevini
- Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria
| | - G Strebinger
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - D Niederseer
- Department of Internal Medicine, Oberndorf Hospital, Oberndorf, Austria.,Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - G Pohla-Gubo
- Laboratory for Immunology, Allergology & Molecular Diagnostics, Department of Dermatology, Paracelsus Medical University, Salzburg, Austria
| | - U Huber-Schönauer
- Department of Internal Medicine, Oberndorf Hospital, Oberndorf, Austria
| | - S Ruhaltinger
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - B Paulweber
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - C Datz
- Department of Internal Medicine, Oberndorf Hospital, Oberndorf, Austria
| | - T K Felder
- Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria
| | - E Aigner
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
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14
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Florin L, Rubben K, Vanhaecke A, Devreese K, De Keyser F, Smith V, Bonroy C. Evaluation of the primary biliary cholangitis-related serologic profile in a large cohort of Belgian systemic sclerosis patients. ACTA ACUST UNITED AC 2019; 58:416-423. [DOI: 10.1515/cclm-2019-0655] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 09/21/2019] [Indexed: 01/27/2023]
Abstract
Abstract
Background
Systemic sclerosis (SSc) and primary biliary cholangitis (PBC) are autoimmune diseases that may occur concomitantly and are both strongly associated with disease-specific autoantibodies. This study investigated the prevalence and fine specificity of PBC-specific serology (PBC-Ab) and associations with the SSc-subtypes and SSc-specific antibodies as well as the association with cholestatic liver enzymes. Furthermore, three different techniques for the detection of PBC-Ab were compared.
Methods
Serum of 184 Belgian SSc patients with a known SSc-antibody profile, was analyzed for PBC-Ab (antimitochondrial antibodies [AMA], anti-Gp210, anti-Sp100 and anti-PML) using indirect immunofluorescence (IIF) analysis on human epithelioma-2000 (HEp-2000) cells (ANA-IIF, Immunoconcepts) and liver-kidney-stomach tissue sections (IIF-LKS) (Menarini), and a line immunoblot (LB) (EuroImmun). Alkaline phosphatase/γ-glutamyl transferase (ALP/GGT) were evaluated at time of first sampling (t0) and after 3 years of follow-up (t3).
Results
PBC-Ab were present in 13% of patients and significantly correlated with centromere antibodies (anti-CENP-B), but not correlated with the limited cutaneous SSc subgroup (lcSSc). The most frequent reactivities were AMA (11%, with 9% AMA-M2) and Sp-100 antibodies (5%), showing a major overlap. There was no relevant association between the presence of PBC-Ab and ALP or GGT elevation at t0 nor at t3. Detection of AMA with IIF-LKS is comparable to LB. ANA-IIF screening was less sensitive compared to LB.
Conclusions
A wide range of PBC-Ab is detectable in SSc in the absence of cholestatic liver enzyme elevations, even after 3 years of follow-up. However, as these antibodies may precede PBC-disease up to 10 years further prospective follow-up of our cohort will be necessary.
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Affiliation(s)
- Lisa Florin
- Department of Laboratory Medicine , Ghent University Hospital , Ghent , Belgium
| | - Kaat Rubben
- Department of Laboratory Medicine , Ghent University Hospital , Ghent , Belgium
| | - Amber Vanhaecke
- Department of Rheumatology , Ghent University Hospital , Ghent , Belgium
- Department of Internal Medicine , Ghent University , Ghent , Belgium
| | - Katrien Devreese
- Department of Laboratory Medicine , Ghent University Hospital , Ghent , Belgium
- Department of Diagnostic Sciences , Ghent University , Ghent , Belgium
| | - Filip De Keyser
- Department of Rheumatology , Ghent University Hospital , Ghent , Belgium
- Praktijk 10A , Maldegem , Belgium
| | - Vanessa Smith
- Department of Rheumatology , Ghent University Hospital , Ghent , Belgium
- Department of Internal Medicine , Ghent University , Ghent , Belgium
- Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center (IRC) , Ghent , Belgium
| | - Carolien Bonroy
- Department of Diagnostic Sciences , Ghent University , Ghent , Belgium
- Department of Laboratory Medicine , Ghent University Hospital , Corneel Heymanslaan 10 , 9000 Ghent , Belgium
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15
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Baldo DC, Dellavance A, Ferraz MLG, Andrade LEC. Evolving liver inflammation in biochemically normal individuals with anti-mitochondria antibodies. AUTOIMMUNITY HIGHLIGHTS 2019; 10:10. [PMID: 32257066 PMCID: PMC7065335 DOI: 10.1186/s13317-019-0120-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 09/24/2019] [Indexed: 01/20/2023]
Abstract
Background Anti-mitochondria autoantibodies (AMA) occur in > 95% primary biliary cholangitis (PBC) patients. Biochemically normal AMA-positive (BN/AMA+) individuals, occasionally noticed by indirect immunofluorescence (IIF) on HEp-2 cells and confirmed in AMA-specific assays, may represent early stages of PBC. The Enhanced Liver Fibrosis (ELF) score is a surrogate marker for liver fibrosis. This prospective study investigated the ELF score in BN/AMA+ individuals and PBC patients, considering autoantibody avidity and serum levels along the years. Methods 327 samples from 35 PBC and 59 BN/AMA+ were prospectively obtained in average 3.83 (range 0.50-7.40) years apart. Samples were tested by IIF on rat-kidney (IIF-AMA), western-blot for AMA (WB-AMA), and ELISA for antibodies against pyruvate-dehydrogenase (PDC-E2), gp210, sp100 and CENP-A/B. Anti-PDC-E2 avidity was determined by 6 M urea-elution ELISA. Alkaline phosphatase (ALP), gamma glutamyl transferase (ɣGT) and ELF score were measured by automated methods. Results Along the follow-up period BN/AMA+ subjects and PBC patients presented significant increase in serum anti-PDC-E2 (mean 10.45% and 8.86% per year; respectively), anti-PDC-E2 avidity (3.02% and 4.94%/year) and ELF score (3.24% and 2.71%/year). IIF-AMA and ɣGT increased in BN/AMA+ (6.59% and 2.36%) and decreased in PBC (- 4.89%/year and - 3.88%/year). In BN/AMA+ individuals there was positive correlation of ELF with IIF-AMA titer (r = 0.465; p < 0.001) and with anti-PDC-E2 levels (r = 0.239; p < 0.001). Expansion of autoantibody targets along time occurred in 39% BN/AMA+ and 49% PBC patients. The frequency of BN/AMA+ with high probability of having established PBC increased from 7 to 14%. Conclusions BN/AMA+ individuals present an orchestrated increase in ELF score and humoral autoimmune response over time, indicating an opportunity for early therapeutic intervention and prevention in autoimmunity.
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Affiliation(s)
- Danielle Cristiane Baldo
- 1Rheumatology Division, Universidade Federal de São Paulo, UNIFESP, Rua Botucatu 740, São Paulo, SP 04023-900 Brazil.,Research and Development Division, Fleury Medicine and Health Laboratories, São Paulo, Brazil
| | - Alessandra Dellavance
- Research and Development Division, Fleury Medicine and Health Laboratories, São Paulo, Brazil
| | | | - Luis Eduardo C Andrade
- 1Rheumatology Division, Universidade Federal de São Paulo, UNIFESP, Rua Botucatu 740, São Paulo, SP 04023-900 Brazil
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16
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D, Vierling JM, Adams D, Alpini G, Banales JM, Beuers U, Björnsson E, Bowlus C, Carbone M, Chazouillères O, Dalekos G, De Gottardi A, Harada K, Hirschfield G, Invernizzi P, Jones D, Krawitt E, Lanzavecchia A, Lian ZX, Ma X, Manns M, Mavilio D, Quigley EM, Sallusto F, Shimoda S, Strazzabosco M, Swain M, Tanaka A, Trauner M, Tsuneyama K, Zigmond E, Gershwin ME. The challenges of primary biliary cholangitis: What is new and what needs to be done. J Autoimmun 2019; 105:102328. [PMID: 31548157 DOI: 10.1016/j.jaut.2019.102328] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 08/18/2019] [Accepted: 08/20/2019] [Indexed: 02/06/2023]
Abstract
Primary Biliary Cholangitis (PBC) is an uncommon, chronic, cholangiopathy of autoimmune origin and unknown etiology characterized by positive anti-mitochondrial autoantibodies (AMA), female preponderance and progression to cirrhosis if left untreated. The diagnosis is based on AMA- or PBC-specific anti-nuclear antibody (ANA)-positivity in the presence of a cholestatic biochemical profile, histologic confirmation being mandatory only in seronegative cases. First-line treatment is ursodeoxycholic acid (UDCA), which is effective in preventing disease progression in about two thirds of the patients. The only approved second-line treatment is obeticholic acid. This article summarizes the most relevant conclusions of a meeting held in Lugano, Switzerland, from September 23rd-25th 2018, gathering basic and clinical scientists with various background from around the world to discuss the latest advances in PBC research. The meeting was dedicated to Ian Mackay, pioneer in the field of autoimmune liver diseases. The role of liver histology needs to be reconsidered: liver pathology consistent with PBC in AMA-positive individuals without biochemical cholestasis is increasingly reported, raising the question as to whether biochemical cholestasis is a reliable disease marker for both clinical practice and trials. The urgent need for new biomarkers, including more accurate markers of cholestasis, was also widely discussed during the meeting. Moreover, new insights in interactions of bile acids with biliary epithelia in PBC provide solid evidence of a role for impaired epithelial protection against potentially toxic hydrophobic bile acids, raising the fundamental question as to whether this bile acid-induced epithelial damage is the cause or the consequence of the autoimmune attack to the biliary epithelium. Strategies are needed to identify difficult-to-treat patients at an early disease stage, when new therapeutic approaches targeting immunologic pathways, in addition to bile acid-based therapies, may be effective. In conclusion, using interdisciplinary approaches, groundbreaking advances can be expected before long in respect to our understanding of the etiopathogenesis of PBC, with the ultimate aim of improving its treatment.
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Affiliation(s)
- Benedetta Terziroli Beretta-Piccoli
- Epatocentro Ticino, Lugano, Switzerland; Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; European Reference Network ERN RARE-LIVER.
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK
| | - John M Vierling
- Division of Abdominal Transplantation and Section of Gastroenterology and Hepatology, Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - David Adams
- Birmingham NIHR Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental SciencesMedical School, University of Birmingham, Birmingham, UK
| | - Gianfranco Alpini
- Indiana Center for Liver Research, Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN, USA
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastián, Spain
| | - Ulrich Beuers
- European Reference Network ERN RARE-LIVER; Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Einar Björnsson
- Division of Gastroenterology and Hepatology, Landspitali the National University Hospital of Iceland, Reykjavík, Iceland
| | - Christopher Bowlus
- Division of Gastroenterology and Hepatology, University of California at Davis School of Medicine, Davis, CA, USA
| | - Marco Carbone
- Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan-Bicocca School of Medicine, Monza, Italy
| | - Olivier Chazouillères
- European Reference Network ERN RARE-LIVER; Service d'Hépatologie, Hôpital Saint-Antoine, Paris, France
| | - George Dalekos
- Institute of Internal Medicine and Hepatology, Department of Medicine and Research, Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece
| | - Andrea De Gottardi
- European Reference Network ERN RARE-LIVER; Epatocentro Ticino & Division of Gastroenterology and Hepatology Ente Ospedaliero Cantonale and Università della Svizzera Italiana, Lugano, Switzerland
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Gideon Hirschfield
- Toronto Centre for Liver Disease, University Health Network and University of Toronto, Toronto, Canada
| | - Pietro Invernizzi
- European Reference Network ERN RARE-LIVER; Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan-Bicocca School of Medicine, Monza, Italy
| | - David Jones
- Institute of Cellular Medicine and NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK
| | - Edward Krawitt
- Department of Medicine, University of Vermont, Burlington, VT, USA
| | | | - Zhe-Xiong Lian
- Institutes for Life Sciences, South China University of Technology, Higher Education Mega Center, Guangzhou, China
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, Jiao Tong University School of Medicine, Shanghai, China
| | - Michael Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Domenico Mavilio
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Italy
| | - Eamon Mm Quigley
- Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA
| | - Federica Sallusto
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
| | - Shinji Shimoda
- Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Mario Strazzabosco
- Liver Center, Department of Medicine, Yale University, New Haven, CT, USA
| | - Mark Swain
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Ehud Zigmond
- Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, California, USA.
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17
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Sultan K, Petkar M, Derbala M. Florid biliary duct lesions in an AMA -positive patient in absence of cholestatic liver biochemistry. J Autoimmun 2019; 101:153-155. [DOI: 10.1016/j.jaut.2019.04.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 03/31/2019] [Accepted: 04/04/2019] [Indexed: 02/08/2023]
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18
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Dalekos GN, Gatselis NK. Variant and Specific Forms of Autoimmune Cholestatic Liver Diseases. Arch Immunol Ther Exp (Warsz) 2019; 67:197-211. [PMID: 31165900 DOI: 10.1007/s00005-019-00550-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Accepted: 05/31/2019] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the main autoimmune cholestatic liver diseases. IgG4-associated sclerosing cholangitis is another distinct immune-mediated cholestatic disorder of unknown aetiology that is frequently associated with autoimmune pancreatitis or other IgG4-related diseases. Although the majority of PBC and PSC patients have a typical presentation, there are common and uncommon important variants or specific subgroups that observed in everyday routine clinical practice. In this updated review, we summarize the published data giving also our own experience on the variants and specific groups of autoimmune cholestatic liver diseases. Actually, we give in detail the underlining difficulties and the rising dilemmas concerning the diagnosis and management of these special conditions in the clinical spectrum of autoimmune cholestatic liver diseases including the IgG4-associated sclerosing cholangitis highlighting also the uncertainties and the potential new eras of the research agenda.
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Affiliation(s)
- George N Dalekos
- Institute of Internal Medicine and Hepatology, Larissa, Greece.
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, 41110, Larissa, Greece.
| | - Nikolaos K Gatselis
- Institute of Internal Medicine and Hepatology, Larissa, Greece
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, 41110, Larissa, Greece
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19
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Sun C, Xiao X, Yan L, Sheng L, Wang Q, Jiang P, Lian M, Li Y, Wei Y, Zhang J, Chen Y, Li B, Li Y, Huang B, Li Y, Peng Y, Chen X, Fang J, Qiu D, Hua J, Tang R, Leung P, Gershwin ME, Miao Q, Ma X. Histologically proven AMA positive primary biliary cholangitis but normal serum alkaline phosphatase: Is alkaline phosphatase truly a surrogate marker? J Autoimmun 2019; 99:33-38. [DOI: 10.1016/j.jaut.2019.01.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 01/17/2019] [Accepted: 01/18/2019] [Indexed: 12/12/2022]
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Abstract
Primary biliary cholangitis (PBC) is a chronic, cholestatic, autoimmune disease with a variable progressive course. PBC can cause debilitating symptoms including fatigue and pruritus and, if left untreated, is associated with a high risk of cirrhosis and related complications, liver failure, and death. Recent changes to the PBC landscape include a name change, updated guidelines for diagnosis and treatment as well as new treatment options that have recently become available. Practicing clinicians face many unanswered questions when managing PBC. To assist these healthcare providers in managing patients with PBC, the American College of Gastroenterology (ACG) Institute for Clinical Research & Education, in collaboration with the Chronic Liver Disease Foundation (CLDF), organized a panel of experts to evaluate and summarize the most current and relevant peer-reviewed literature regarding PBC. This, combined with the extensive experience and clinical expertise of this expert panel, led to the formation of this clinical guidance on the diagnosis and management of PBC.
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. The clinical usage and definition of autoantibodies in immune-mediated liver disease: A comprehensive overview. J Autoimmun 2018; 95:144-158. [DOI: 10.1016/j.jaut.2018.10.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 10/09/2018] [Accepted: 10/11/2018] [Indexed: 02/06/2023]
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22
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Hirschfield GM, Dyson JK, Alexander GJM, Chapman MH, Collier J, Hübscher S, Patanwala I, Pereira SP, Thain C, Thorburn D, Tiniakos D, Walmsley M, Webster G, Jones DEJ. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut 2018; 67:1568-1594. [PMID: 29593060 PMCID: PMC6109281 DOI: 10.1136/gutjnl-2017-315259] [Citation(s) in RCA: 213] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 01/22/2018] [Accepted: 01/23/2018] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.
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Affiliation(s)
- Gideon M Hirschfield
- NIHR Birmingham Biomedical Research Centre, Birmingham, UK
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Jessica K Dyson
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom
| | - Graeme J M Alexander
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
| | - Michael H Chapman
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Jane Collier
- Translational Gastroenterology Unit, Oxford University Hospitals, University of Oxford, Oxford, UK
| | - Stefan Hübscher
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Imran Patanwala
- Department of Gastroenterology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
- University of Liverpool, Liverpool, UK
| | - Stephen P Pereira
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | | | - Douglas Thorburn
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
| | - Dina Tiniakos
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | | | - George Webster
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | - David E J Jones
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom
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Magnetic resonance imaging evidence of hippocampal structural changes in patients with primary biliary cholangitis. Clin Transl Gastroenterol 2018; 9:169. [PMID: 29977030 PMCID: PMC6033882 DOI: 10.1038/s41424-018-0038-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 05/11/2018] [Accepted: 06/07/2018] [Indexed: 12/13/2022] Open
Abstract
Introduction Behavioral symptoms are commonly reported by patients with primary biliary cholangitis (PBC). In other patient populations, symptoms are commonly associated with hippocampal volume reduction linked to neuroinflammation (inferred from regional iron deposition), as demonstrated by magnetic resonance imaging (MRI). We hypothesized that PBC patients would exhibit reduced volume and increased iron deposition of the hippocampus. Methods Seventeen female non-cirrhotic PBC patients and 17 age/gender-matched controls underwent 3-Tesla T1-weighted MRI and quantitative susceptibility mapping (QSM; an indicator of iron deposition). The hippocampus and its subfields were segmented from T1 images using Freesurfer, and susceptibility of the whole hippocampus was calculated from QSM images. Volume and susceptibility were compared between groups, and associations with PBC-40 score and disease indicators (years since diagnosis, Fibroscan value, alkaline phosphatase level, clinical response to ursodeoxycholic acid (UDCA)) were investigated. Results PBC patients exhibited significantly reduced hippocampal volume (p = 0.023) and increased susceptibility (p = 0.048). Subfield volumes were reduced for the subiculum, molecular layer, granule cell layer of the dentate gyrus and CA4 (p < 0.05). Fibroscan value was significantly correlated with PBC-40 (Spearman’s rho = 0.499; p = 0.041) and disease duration (Spearman’s rho = 0.568; p = 0.017). Discussion Our findings suggest hippocampal changes occur early in the disease course of PBC, similar in magnitude to those observed in major depressive disorder and neurodegenerative diseases. Translational impact Clinical management of PBC could include early interventional strategies that promote hippocampal neurogenesis that may beneficially impact behavioral symptoms and improve quality of life.
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Diagnostic accuracy of two tests for determination of anti-m2 in the diagnosis of primary biliary cirrhosis: Is it possible to predict the course of the disease? Immunol Res 2018; 65:299-306. [PMID: 27475095 DOI: 10.1007/s12026-016-8838-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
To evaluate the analytical agreement between results obtained from the indirect immunofluorescence methods and from the multiplexed line-blot assay and EliA-M2, to analyze the diagnostic accuracy in a cohort of primary biliary cirrhosis (PBC) patients and in control patients of two different types of tests for anti-M2 and assess whether, with the advent of a quantitative test, the possibility exists to correlate disease activity with the value of AMA. Serum analysis of 67 patients with fluorescence patterns detected on Hep-2 cells suggestive of PBC-related antibodies and three groups of patients (15 PBC, 16 PBC suspect and 48 disease controls) was carried out. All samples were tested by both a qualitative test multiplexed line-blot Autoimmune Liver Disease Profile Euroline and by a quantitative test EliA-M2 IgG. In order to evaluate a possible correlation between the quantitative M2 and disease activity, we divided patients mixed in a further three groups based on the value EliA-M2. For each of these groups were calculated the average values of the main indices of cholestasis. A perfect agreement was shown between the EliA-M2 and the multiplexed line-blot method for AMA detection. All sera of patients with PBC were positive with both tests, with a 100 % sensitivity. Forty-seven of the 48 sera of the control group were negative for both tests with a 100 % next specificity, and only 70 % for the AMA-IIF. We had also observed in the other three groups of patients that the average of the values of γ-glutamyl transpeptidase and alkaline phosphatase increases with the increase of the value EliA-M2. The difference between the mean values of the most significant parameter which the alkaline phosphatase of the three groups is significant, with a statistically significant difference between the first and the third group (p value 0.023). Both the qualitative method Profile Euroline and the quantitative EliA-M2 have a high diagnostic accuracy for PBC, with a specificity higher than the immunofluorescence method. These preliminary data might suggest the possibility of using the dosage EliA-M2 not only in the diagnosis phase but also in the monitoring of disease activity.
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26
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Parés A. Advances in treatment options for patients with primary biliary cholangitis. Expert Opin Orphan Drugs 2017. [DOI: 10.1080/21678707.2017.1394840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Albert Parés
- Liver Unit, University of Barcelona, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
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Tan S, Ayutyanont N, Bhattarai B, Movahedi Z, Jayaram L, Gish R, Nadir A. Clinical characteristics of antimitochondrial antibody-positive patients at a safety net health care system in Arizona. BMJ Open Gastroenterol 2017; 4:e000158. [PMID: 29018539 PMCID: PMC5623267 DOI: 10.1136/bmjgast-2017-000158] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 08/03/2017] [Accepted: 08/08/2017] [Indexed: 12/13/2022] Open
Abstract
Background and aims To assess whether aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (AP) levels can predict the diagnosis of primary biliary cholangitis (PBC) or any other diagnoses and whether PBC occurs either simultaneously or independently of other liver diseases among antimitochondrial antibody (AMA)-positive patients. Methods Demographic and clinical variables were assessed in 90 AMA-positive patients with and without liver biopsies. These patients were further categorised as having a diagnosis of PBC, overlap syndrome or ‘not established with a diagnosis of PBC’. Receiver operating characteristic curves were constructed to determine the thresholds of liver enzymes that predict these three diagnoses. Results The 48 patients with liver biopsies were more frequently female and had significantly higher AP levels compared with the non-liver biopsy group. Based on liver biopsy findings, 12, 12 and 22 patients were assigned a diagnosis of PBC, overlap syndrome with autoimmune hepatitis and PBC and ‘not established diagnosis of PBC’, respectively. Seven of 12 patients classified as PBC had AP level of ˂200 IU. AST, ALT and AP levels were significant predictors of a diagnosis of overlap syndrome compared with the rest of the patients; however, these tests were not discriminatory between diagnoses of PBC and ‘not established with PBC’. Findings of fatty liver and bile duct injury on liver biopsies were not significantly associated with any liver test pattern. Conclusions As the liver test pattern did not correlate with the liver biopsy findings of PBC or other non-PBC diagnoses in AMA-positive patients at risk for other disease, a liver biopsy and/or non-invasive liver assessment along with serum liver tests should be interpreted to complete liver evaluation.
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Affiliation(s)
- Susanna Tan
- Maricopa Medical Center, Phoenix, Arizona, USA.,University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA
| | - Napatkamon Ayutyanont
- Maricopa Medical Center, Phoenix, Arizona, USA.,University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA
| | - Bikash Bhattarai
- Maricopa Medical Center, Phoenix, Arizona, USA.,University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA
| | - Zohreh Movahedi
- Maricopa Medical Center, Phoenix, Arizona, USA.,University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA
| | - Lakshmi Jayaram
- Maricopa Medical Center, Phoenix, Arizona, USA.,University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA
| | - Robert Gish
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Stanford, California, USA
| | - Abdul Nadir
- Maricopa Medical Center, Phoenix, Arizona, USA.,University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA
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Invernizzi P, Floreani A, Carbone M, Marzioni M, Craxi A, Muratori L, Vespasiani Gentilucci U, Gardini I, Gasbarrini A, Kruger P, Mennini FS, Ronco V, Lanati E, Canonico PL, Alvaro D. Primary Biliary Cholangitis: advances in management and treatment of the disease. Dig Liver Dis 2017; 49:841-846. [PMID: 28546061 DOI: 10.1016/j.dld.2017.05.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 04/28/2017] [Accepted: 05/02/2017] [Indexed: 12/11/2022]
Abstract
Primary Biliary Cholangitis, previously known as Primary Biliary Cirrhosis, is a rare disease, which mainly affects women in their fifth to seventh decades of life. It is a chronic autoimmune disease characterized by a progressive damage of interlobular bile ducts leading to ductopenia, chronic cholestasis and bile acids retention. Even if the disease usually presents a long asymptomatic phase and a slow progression, in many patients it may progress faster toward cirrhosis and its complications. The 10year mortality is greater than in diseases such as human immunodeficiency virus/Hepatitis C Virus coinfection and breast cancer. Ursodeoxycholic acid is the only treatment available today, but even if effective in counteracting the disease progression for the majority of patients, in approximately 40% is not able to decrease effectively the alkaline phosphatase, a surrogate marker of disease activity. Recently, obeticholic acid received the European Medicines Agency conditional approval, as add on treatment in patients non responders or intolerant to ursodeoxycholic acid. The present paper illustrates the opinion of a working group, composed by clinical pharmacologists, gastroenterologists/hepatologists with specific expertise on Primary Biliary Cholangitis and patient associations, on the state of the art and future perspectives of the disease management. The agreement on the document was reached through an Expert Meeting.
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Affiliation(s)
- Pietro Invernizzi
- Department of Medicine and Surgery University of Milan Bicocca, Monza, Italy
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Marco Carbone
- Department of Medicine and Surgery University of Milan Bicocca, Monza, Italy
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology "Università Politecnica delle Marche", Ospedali Riuniti University Hospital, Ancona, Italy
| | | | - Luigi Muratori
- Department of Medical and Surgical Sciences "Alma Mater Studiorum", University of Bologna Policlinico di Sant'Orsola, Bologna, Italy
| | | | | | | | - Paola Kruger
- Patient Expert, EUPATI Fellow (European Patients Academy for Therapeutic Innovation) Italy, Rome, Italy
| | | | | | - Elena Lanati
- Pharm., Sole Administrator 3P Solution Srl, Milan, Italy
| | - Pier Luigi Canonico
- Department of Scienze del Farmaco, University of Piemonte Orientale, Novara, Italy
| | - Domenico Alvaro
- Division of Gastroenterology, University "Sapienza", Rome, Italy.
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29
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Muratori P, Lenzi M, Migliori M, Muratori L. Antimitochondrial antibodies positive autoimmune hepatitis with acute onset. Scand J Gastroenterol 2017; 52:920-921. [PMID: 28388847 DOI: 10.1080/00365521.2017.1311937] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Accepted: 03/22/2017] [Indexed: 02/04/2023]
Affiliation(s)
- Paolo Muratori
- a Department of Medical and Surgical Sciences (DIMEC) , University of Bologna, S.Orsola Malpighi Hospital , Bologna , Italy
| | - Marco Lenzi
- a Department of Medical and Surgical Sciences (DIMEC) , University of Bologna, S.Orsola Malpighi Hospital , Bologna , Italy
| | | | - Luigi Muratori
- a Department of Medical and Surgical Sciences (DIMEC) , University of Bologna, S.Orsola Malpighi Hospital , Bologna , Italy
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30
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Muratori P, Lenzi M, Cassani F, Lalanne C, Muratori L. Diagnostic approach to autoimmune hepatitis. Expert Rev Clin Immunol 2017; 13:769-779. [PMID: 28480763 DOI: 10.1080/1744666x.2017.1327355] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if left without treatment, can evolve into cirrhosis and possibly liver failure. The diagnosis of AIH is hampered by the lack of specific and reliable markers of the disease and a number of clinical, biochemical, immunological, histological and genetic factors should be considered to reach a confident diagnosis Areas covered: Clinical expression of AIH, histological features, serological and genetic profiles, differential diagnosis, overlap with other autoimmune liver diseases, assessed on the basis of personal experience and review of published literature in the last 10 years through a systematic Medline search (keywords: autoimmune hepatitis, diagnosis) Expert commentary: Notwithstanding numerous efforts to identify simple and reliable markers of the disease, the diagnosis of AIH is still based on the combination of histological, immunological and biochemical features and often can represent a real challenge for the hepatologist.
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Affiliation(s)
- Paolo Muratori
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Marco Lenzi
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Fabio Cassani
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Claudine Lalanne
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Luigi Muratori
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
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31
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Ma WT, Chang C, Gershwin ME, Lian ZX. Development of autoantibodies precedes clinical manifestations of autoimmune diseases: A comprehensive review. J Autoimmun 2017; 83:95-112. [PMID: 28739356 DOI: 10.1016/j.jaut.2017.07.003] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 06/30/2017] [Accepted: 07/01/2017] [Indexed: 12/21/2022]
Abstract
The etiology of autoimmune diseases is due to a combination of genetic predisposition and environmental factors that alter the expression of immune regulatory genes through various mechanisms including epigenetics. Both humoral and cellular elements of the adaptive immune system play a role in the pathogenesis of autoimmune diseases and the presence of autoantibodies have been detected in most but not all autoimmune diseases before the appearance of clinical symptoms. In some cases, the presence or levels of these autoantibodies portends not only the risk of developing a corresponding autoimmune disease, but occasionally the severity as well. This observation is intriguing because it suggests that we can, to some degree, predict who may or may not develop autoimmune diseases. However, the role of autoantibodies in the pathogenesis of autoimmune diseases, whether they actually affect disease progression or are merely an epiphenomenon is still not completely clear in many autoimmune diseases. Because of these gaps in our knowledge, the ability to accurately predict a future autoimmune disease can only be considered a relative risk factor. Importantly, it raises the critical question of defining other events that may drive a patient from a preclinical to a clinical phase of disease.
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Affiliation(s)
- Wen-Tao Ma
- Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou 510006, China; Liver Immunology Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China; College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling 712100, China
| | - Christopher Chang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.
| | - Zhe-Xiong Lian
- Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou 510006, China; Liver Immunology Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China; Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China.
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Berdichevski T, Cohen-Ezra O, Pappo O, Ben-Ari Z. Positive antimitochondrial antibody but normal serum alkaline phosphatase levels: Could it be primary biliary cholangitis? Hepatol Res 2017; 47:742-746. [PMID: 27572231 DOI: 10.1111/hepr.12809] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 08/04/2016] [Accepted: 08/23/2016] [Indexed: 01/03/2023]
Abstract
AIM Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease, typically diagnosed by elevated cholestatic liver enzymes and a positive antimitochondrial antibody (AMA) test. The clinical significance of AMA positivity in patients with normal cholestatic liver enzymes is uncertain. METHODS Charts of patients with normal cholestatic liver enzymes and AMA positivity who underwent liver biopsy between 2012 and 2015 were retrospectively analyzed. RESULTS Six AMA-positive patients with normal cholestatic liver enzymes who underwent a liver biopsy were identified. Four (67%) showed florid bile duct lesion compatible with early-stage PBC, whereas the other two showed mild and non-specific histological findings. The patients with histological findings compatible with PBC had higher enzyme-linked immunosorbent assay-determined AMA titers and significantly elevated immunoglobulin M (IgM) level. Patients with non-specific histological findings (33%) had low-titer AMA and a borderline elevated IgM level. CONCLUSIONS Antimitochondrial antibody-positive patients with normal cholestatic liver enzymes should be meticulously evaluated for PBC including a liver biopsy, mainly in patients with high-titer seropositivity for AMA and a significantly elevated IgM level. More studies are required to clarify the role of liver biopsy in these patients and further follow-up may elucidate the relationship of these patients to those with more classical forms of PBC.
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Affiliation(s)
- Tania Berdichevski
- Liver Disease Center, Sheba Medical Center, Ramat Gan, Israel.,The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Oranit Cohen-Ezra
- Liver Disease Center, Sheba Medical Center, Ramat Gan, Israel.,The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Orit Pappo
- Institute of Pathology, Sheba Medical Center, Ramat Gan, Israel
| | - Ziv Ben-Ari
- Liver Disease Center, Sheba Medical Center, Ramat Gan, Israel.,The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Muratori P, Efe C, Muratori L, Ozaslan E, Schiano T, Yoshida EM, Heurgué-Berlot A, Lalanne C, Lenzi M, Wahlin S. Clinical implications of antimitochondrial antibody seropositivity in autoimmune hepatitis: a multicentre study. Eur J Gastroenterol Hepatol 2017; 29:777-780. [PMID: 28328618 DOI: 10.1097/meg.0000000000000870] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIM Antimitochondrial antibody (AMA) positivity is the serological marker of primary biliary cholangitis (PBC), but can also be sporadically detected in autoimmune hepatitis (AIH). Little is known about the clinical significance of AMA in AIH. PATIENTS AND METHODS We recruited 47 AMA-positive AIH cases from several centres and compared them with 264 well-characterized Italian AIH patients. Cases with any features of PBC were excluded. RESULTS In univariate analysis, AMA-positive AIH patients were older (46 vs. 36, P=0.002) and more responsive to immunosuppression (74 vs. 59%, P=0.05), but no differences were observed between the two groups after logistic regression using AMA as a dependent variable. None of the AMA-positive AIH patients showed signs of evolving PBC features after a median follow-up of up 47 months. AMA was detected in combination with all serological AIH markers except antiliver kidney microsome type 1 and antiliver cytosol type 1. AMA was the only marker of autoimmunity in eight cases. CONCLUSION We found no differences between AIH with and without AMA. The groups had similar clinical, biochemical and histological features. AMA-positive AIH patients did not evolve towards PBC. In some cases, AMA was the only autoantibody.
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Affiliation(s)
- Paolo Muratori
- aDepartment of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, Università di Bologna bCenter for the Study and Treatment of the Autoimmune Diseases of the Liver and Biliary System, S. Orsola-Malpighi, Bologna, Italy cDepartment of Gastroenterology, Hacettepe University Ankara dDepartment of Gastroenterology, Numune Education and Research Hospital, Ankara, Turkey eDepartment of Gastroenterology, Division of Liver Diseases, The Mount Sinai Medical Center, New York, New York, USA fDepartment of Gastroenterology, Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada gDepartment of Hepato-Gastroenterology, CHU Reims, Reims, France hDepartment of Gastroenterology and Hepatology, Hepatology Division, Centre for Digestive Disease, Karolinska Institute, Stockholm, Sweden
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Diagnostic autoantibodies for autoimmune liver diseases. Clin Transl Immunology 2017; 6:e139. [PMID: 28690845 PMCID: PMC5493583 DOI: 10.1038/cti.2017.14] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 03/22/2017] [Accepted: 03/22/2017] [Indexed: 12/17/2022] Open
Abstract
Autoimmune liver diseases are conditions of low prevalence that comprise the triad of autoimmune hepatitis, primary biliary cholangitis (cirrhosis) and primary sclerosing cholangitis and their poorly characterised overlapping syndromes. Diagnostic autoantibodies are associated with autoimmune hepatitis and primary biliary cholangitis but not with primary sclerosing cholangitis. Autoantibodies are useful disease markers that facilitate early diagnosis of autoimmune hepatitis and primary biliary cholangitis and allow for therapeutic intervention to prevent progression to liver cirrhosis and associated complications. Adult onset type 1 autoimmune hepatitis is associated with F-actin reactive smooth muscle autoantibody, antinuclear autoantibody in 60% of patients, and autoantibody to SLA/LP in 15–20%. Juvenile onset type 2 autoimmune hepatitis is associated with LKM-1 and LC-1 autoantibodies. Primary biliary cholangitis is associated with a mitochondria-associated autoantibody designated M2 in >90% of patients and with disease-specific antinuclear autoantibodies in 50% that bind to antigens in the nuclear core complex and in multiple nuclear dots. Autoantibodies to the nuclear core complex target gp210, nucleoporin p62 and nuclear lamin B receptor. Autoantibodies to multiple nuclear dots target Sp100 and PML antigens. Liver autoantibodies in asymptomatic patients with normal liver function may precede the subsequent development of overt autoimmune liver disease. For routine diagnostic immunology laboratories, initial screening for liver autoantibodies by immunofluorescence remains the method of choice with confirmation for reactivity with their target antigen by enzyme-linked immunosorbent assay (ELISA) or line blot when required.
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Zhang H, Jin Z, Cui R, Ding S, Huang Y, Zhou L. Autoimmune metaplastic atrophic gastritis in chinese: a study of 320 patients at a large tertiary medical center. Scand J Gastroenterol 2017; 52:150-156. [PMID: 27652682 DOI: 10.1080/00365521.2016.1236397] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Autoimmune metaplastic atrophic gastritis (AMAG) is an uncommon disease worldwide and may predispose to gastric carcinoid tumors or adenocarcinomas. The aims of this study were to outline the clinical characteristics of Chinese AMAG patients, including demographic pattern, hematologic features, and gastroscopic and histopathologic findings. PATIENTS AND METHODS A total of 320 Chinese patients with AMAG, from January 2007 to December 2014, were reviewed in a regional hospital of China. RESULTS Of the 320 AMAG patients, the mean age was 60.6 ± 12.3 years [range 26-86; 206 (64.4%) women]. The coarse annual detection rate was 0.9%. Anemia was present in only 19.3% patients (53/275) and 3.5% (11/315) AMAG patients also had primary biliary cirrhosis. One hundred and thirty-six had endoscopically identifiable lesions. These lesions consisted of 130 polypoid lesions (63 hyperplastic polyps, 2 oxyntic mucosa pseudopolyps, 2 intestinal-type gastric adenomas, 2 fundic gland polyps, 5 concurrent polyps, 14 well-differentiated neuroendocrine neoplasms, 7 submucosal tumors and 35 chronic gastritis), 6 adenocarcinomas. The detection rate of atrophy and intestinal metaplasia in antral mucosa were 47.2 and 37.5%, respectively. CONCLUSIONS AMAG is more frequent than expected in China and display a female predominance, accompanied with other autoimmune disorders. AMAG should be paid more attention by clinicians through a multidisciplinary team approach.
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Affiliation(s)
- Hejun Zhang
- a Pathological Laboratory, Department of Gastroenterology , Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital , Beijing , PR China
| | - Zhu Jin
- a Pathological Laboratory, Department of Gastroenterology , Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital , Beijing , PR China
| | - Rongli Cui
- a Pathological Laboratory, Department of Gastroenterology , Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital , Beijing , PR China
| | - Shigang Ding
- a Pathological Laboratory, Department of Gastroenterology , Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital , Beijing , PR China
| | - Yonghui Huang
- a Pathological Laboratory, Department of Gastroenterology , Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital , Beijing , PR China
| | - Liya Zhou
- a Pathological Laboratory, Department of Gastroenterology , Beijing Key Laboratory for Helicobacter pylori Infection and Upper Gastrointestinal Diseases, Peking University Third Hospital , Beijing , PR China
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Dahlqvist G, Gaouar F, Carrat F, Meurisse S, Chazouillères O, Poupon R, Johanet C, Corpechot C. Large-scale characterization study of patients with antimitochondrial antibodies but nonestablished primary biliary cholangitis. Hepatology 2017; 65:152-163. [PMID: 27688145 DOI: 10.1002/hep.28859] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 08/26/2016] [Accepted: 09/28/2016] [Indexed: 12/07/2022]
Abstract
UNLABELLED The prevalence, clinical characteristics, and outcomes of patients with antimitochondrial antibodies (AMAs), but no clinical evidence of primary biliary cholangitis (PBC), are largely unknown. A prospective study of AMA incidence was conducted through a nation-wide network of 63 French immunology laboratories. Clinical data from 720 of 1,318 AMA-positive patients identified in 1 year were collected. Patients were categorized as either newly diagnosed with PBC (n = 275), previously diagnosed with PBC (n = 216), or with nonestablished diagnosis of PBC (n = 229). The latter group was specifically evaluated. Follow-up data were collected for up to 7 years after detection of AMAs. Prevalence of AMA-positive patients without evidence of PBC was 16.1 per 100,000. These patients had the following characteristics: 78% female; median age 58 years; median AMA titer 1:160; extrahepatic autoimmune disorders 46%; normal serum alkaline phosphatases (ALP) 74%; ALP above 1.5 times the upper limit of normal 13%; and cirrhosis 6%. Compared to those newly diagnosed with PBC, the patients were slightly younger, had lower AMA titers, and lower sex-ratio imbalance. Among the patients with normal ALP and no evidence of cirrhosis, the 5-year incidence rate of PBC was 16%. Whereas no patients died from PBC, the 5-year survival rate was 75%, as compared to 90% in a control, standardized population matched for age and sex (P < 0.05). CONCLUSION Nearly half of the newly detected AMAs in clinical practice does not lead to a diagnosis of PBC. PBC is unrecognized in 13% of those cases. Only 1 in 6 patients with AMAs and normal ALP will develop PBC after 5 years. The mortality of AMA-positive patients without PBC is increased irrespective of the risk of PBC development. (Hepatology 2017;65:152-163).
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Affiliation(s)
- Géraldine Dahlqvist
- Hepatology department, reference center for inflammatory biliary diseases, Health network for rare liver diseases in adults and children (FILFOIE), Saint-Antoine hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.,Hepato-Gastroenterology department, Saint-Luc University Clinics, Brussels, Belgium
| | - Farid Gaouar
- Hepatology department, reference center for inflammatory biliary diseases, Health network for rare liver diseases in adults and children (FILFOIE), Saint-Antoine hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Fabrice Carrat
- Public health department, Saint-Antoine hospital, APHP, PAris, France.,Pierre Louis Institut of Epidemiology and Public Health (IPLESP UMRS 1136), Sorbonne University, Pierre et Marie Curie University (UPMC) Paris 6, Paris, France
| | - Sofia Meurisse
- Public health department, Saint-Antoine hospital, APHP, PAris, France.,Pierre Louis Institut of Epidemiology and Public Health (IPLESP UMRS 1136), Sorbonne University, Pierre et Marie Curie University (UPMC) Paris 6, Paris, France
| | - Olivier Chazouillères
- Hepatology department, reference center for inflammatory biliary diseases, Health network for rare liver diseases in adults and children (FILFOIE), Saint-Antoine hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.,UMR_S938, Pierre and Marie Curie Faculty of Medicine, Saint-Antoine site, UPMC Paris 6, Paris, France
| | - Raoul Poupon
- Hepatology department, reference center for inflammatory biliary diseases, Health network for rare liver diseases in adults and children (FILFOIE), Saint-Antoine hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.,UMR_S938, Pierre and Marie Curie Faculty of Medicine, Saint-Antoine site, UPMC Paris 6, Paris, France
| | | | - Christophe Corpechot
- Hepatology department, reference center for inflammatory biliary diseases, Health network for rare liver diseases in adults and children (FILFOIE), Saint-Antoine hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.,UMR_S938, Pierre and Marie Curie Faculty of Medicine, Saint-Antoine site, UPMC Paris 6, Paris, France
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Vergani D, Mieli-Vergani G. Mouse model of primary biliary cholangitis with a striking female predominance: A new powerful research tool. Hepatology 2016; 64:1024-7. [PMID: 27388433 DOI: 10.1002/hep.28718] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 06/24/2016] [Indexed: 12/07/2022]
Affiliation(s)
- Diego Vergani
- Institute of Liver Studies, King's College Hospital, London, United Kingdom.
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38
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Gulamhusein AF, Juran BD, Atkinson EJ, McCauley B, Schlicht E, Lazaridis KN. Low incidence of primary biliary cirrhosis (PBC) in the first-degree relatives of PBC probands after 8 years of follow-up. Liver Int 2016; 36:1378-82. [PMID: 27062298 PMCID: PMC5014367 DOI: 10.1111/liv.13143] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Accepted: 03/31/2016] [Indexed: 01/06/2023]
Abstract
BACKGROUND & AIMS Primary biliary cirrhosis (PBC) is characterized by chronic cholestasis and disease-specific antimitochondrial antibodies (AMA). A high prevalence of AMAs in first-degree relatives (FDRs) of PBC probands has been reported, although the natural history of such patients has not been described. We aimed to assess the risk of developing PBC in AMA+ FDRs of patients with PBC. METHODS First-degree relatives recruited to the Mayo Clinic PBC Genetic Epidemiology Registry and Biorepository were followed for disease onset after recruitment. Development of PBC was ascertained via self-report during a telephone interview and/or via proband report on a questionnaire. Chi-squared test and t-test were used to assess the differences between categorical and continuous variables respectively. A mixed-effects model was used to assess the change in biochemical profiles over time. RESULTS Forty AMA+ and 423 AMA- subjects were included and followed for a median of 8.9 and 8.4 years respectively. Overall, 3% (n = 15) of FDRs were diagnosed with PBC, and AMA+ FDRs had a higher risk than AMA- FDRs (24% vs. 0.7%, P < 0.01). However, among undiagnosed FDRs, only 4% of AMA+ (n = 1) and 0.4% of AMA- (n = 1) FDRs were diagnosed with PBC (P = 0.17) during the follow-up period. None of the AMA+ FDRs with normal alkaline phosphatase at baseline developed PBC in follow-up. CONCLUSIONS Our results suggest a low risk of developing PBC over time in FDRs of patients with PBC, particularly those without biochemical evidence of cholestasis at baseline. These data are useful in counselling and reassuring relatives of their overall favourable prognosis.
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Affiliation(s)
- Aliya F. Gulamhusein
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Brian D. Juran
- Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - Elizabeth J. Atkinson
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Bryan McCauley
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Erik Schlicht
- Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota, USA
| | - Konstantinos N. Lazaridis
- Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, Minnesota, USA
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Correlation of Anti-mitochondrial Antibodies with Liver Histology and Outcomes. Dig Dis Sci 2016; 61:1770-1. [PMID: 26972083 DOI: 10.1007/s10620-016-4094-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 02/20/2016] [Indexed: 12/09/2022]
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41
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Ghanadan A, Saghazadeh A, Jahanzad I, Rezaei N. Clinical aspects of indirect immunofluorescence for autoimmune diseases. Expert Rev Clin Immunol 2015; 11:597-616. [PMID: 25786676 DOI: 10.1586/1744666x.2015.1027152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Because the most common term used in conversations considering autoimmunity is autoantibodies, it is well-expected that the indirect immunofluorescence assay, which detects antibodies directed against various antigens, is one of our most impressive techniques for investigating autoimmune diseases (AIDs). Roughly speaking, the current literature corroborates that this immunopathologic investigation means that autoantibodies detection makes a considerable contribution to both diagnostic and prognostic aspects of AIDs in the clinical setting. However, it varies between different AIDs, autoantibodies, ethnicities or detection methodologies. Directly focusing on the indirect immunofluorescence assay, we present evidence to support this multidimensional variation regarding the subject via reviewing briefly the best-investigated autoantibodies in the well-documented AIDs, including vasculitis, inflammatory bowel disease, scleroderma, autoimmune hepatitis, primary biliary cirrhosis, systemic lupus erythematosus and Sjögren's syndrome.
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Affiliation(s)
- Alireza Ghanadan
- Department of Pathology, Imam Khomeini Complex Hospital, School of Medicine, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
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Damoiseaux J, Andrade LE, Fritzler MJ, Shoenfeld Y. Autoantibodies 2015: From diagnostic biomarkers toward prediction, prognosis and prevention. Autoimmun Rev 2015; 14:555-63. [PMID: 25661979 DOI: 10.1016/j.autrev.2015.01.017] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Accepted: 01/28/2015] [Indexed: 12/29/2022]
Abstract
At the 12th International Workshop on Autoantibodies and Autoimmunity (IWAA), organized in August 2014 in Sao Paulo, Brazil, more than 300 autoimmunologists gathered to discuss the status of many novel autoantibodies in clinical practice, and to envisage additional value of autoantibodies in terms of prediction, prognosis and prevention of autoimmune diseases. Two separate workshops were dedicated to standardization and harmonization of autoantibody testing and nomenclature: International Autoantibody Standardization (IAS) and International Consensus on ANA Patterns (ICAP). It was apparent to all in attendance that the discovery and elucidation of novel autoantibodies did not slow down, but that multiple challenges lay ahead of us in order to apply these discoveries to effective and efficient clinical practice. Importantly, this requires optimal bidirectional communication between clinicians and laboratory specialists, as well as close collaboration with the diagnostic industry. This paper is a report on the 12th IWAA in combination with a review of the recent developments in the field of autoantibodies.
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Affiliation(s)
- Jan Damoiseaux
- Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands.
| | - Luis E Andrade
- Rheumatology Division, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; Immunology Division, Fleury Medicine and Health Laboratories, Sao Paulo, Brazil
| | - Marvin J Fritzler
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Yehuda Shoenfeld
- The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel
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43
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Affiliation(s)
- Diego Vergani
- Institute of Liver Studies, King's College Hospital, London, UK
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44
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Dahlqvist G, Corpechot C. Les anticorps anti-mitochondries sont-ils toujours le signe d’une cirrhose biliaire primitive ? Presse Med 2014; 43:1311-3. [DOI: 10.1016/j.lpm.2014.07.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Accepted: 07/28/2014] [Indexed: 11/15/2022] Open
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45
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Hu ZD, Deng AM. Autoantibodies in pre-clinical autoimmune disease. Clin Chim Acta 2014; 437:14-8. [PMID: 24972003 DOI: 10.1016/j.cca.2014.06.015] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 06/17/2014] [Accepted: 06/18/2014] [Indexed: 12/22/2022]
Abstract
The presence of autoantibodies is characteristic of autoimmune diseases. It is widely accepted that autoantibodies provide crucial diagnostic and prognostic information for autoimmune diseases. Indeed, numerous studies have demonstrated that the appearance of autoantibodies precedes the clinical onset of autoimmune diseases. We performed a literature review regarding the appearance of autoantibodies that preceded the clinical onset of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, primary biliary cirrhosis, inflammatory bowel disease, and multiple sclerosis. Herein we review and comment on the major findings of these studies.
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Affiliation(s)
- Zhi-De Hu
- Department of Laboratory Medicine, General Hospital of Ji'nan Military Command Region, Ji'nan, PR China
| | - An-Mei Deng
- Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai, PR China.
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Yamagiwa S, Kamimura H, Takamura M, Aoyagi Y. Autoantibodies in primary biliary cirrhosis: recent progress in research on the pathogenetic and clinical significance. World J Gastroenterol 2014; 20:2606-2612. [PMID: 24627596 PMCID: PMC3949269 DOI: 10.3748/wjg.v20.i10.2606] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 11/22/2013] [Accepted: 01/08/2014] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease characterized by immune-mediated destruction of the small- and medium-sized intrahepatic bile ducts and the presence of antimitochondrial antibodies (AMA) in the serum. AMA are detected in over 90% of patients with PBC, whereas their prevalence in the general population is extremely low, varying from 0.16% to 1%. Previous studies have shown that the unique characteristics of biliary epithelial cells undergoing apoptosis may result in a highly direct and very specific immune response to mitochondrial autoantigens. Moreover, recent studies have demonstrated that serum from AMA-positive PBC patients is reactive with a number of xenobiotic modified E2 subunits of the pyruvate dehydrogenase complex, which is not observed in the serum of normal individuals. These findings indicate that chemicals originating from the environment may be associated with a breakdown in the tolerance to mitochondrial autoantigens. While it is currently generally accepted that AMA are the most specific serological markers of PBC, more than 60 autoantibodies have been investigated in patients with PBC, and some have previously been considered specific to other autoimmune diseases. This review covers the recent progress in research on the pathogenetic and clinical significance of important autoantibodies in PBC. Determining the pathogenic role of those autoantibodies in PBC remains a priority of basic and clinical research.
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Guidelines for the management of primary biliary cirrhosis: The Intractable Hepatobiliary Disease Study Group supported by the Ministry of Health, Labour and Welfare of Japan. Hepatol Res 2014; 44 Suppl S1:71-90. [PMID: 24397841 DOI: 10.1111/hepr.12270] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Liberal R, Grant CR, Sakkas L, Bizzaro N, Bogdanos DP. Diagnostic and clinical significance of anti-centromere antibodies in primary biliary cirrhosis. Clin Res Hepatol Gastroenterol 2013; 37:572-85. [PMID: 23876351 DOI: 10.1016/j.clinre.2013.04.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 03/31/2013] [Accepted: 04/23/2013] [Indexed: 02/04/2023]
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver characterised by biochemical evidence of cholestasis, elevated alkaline phosphatase levels and the presence of the highly disease specific anti-mitochondrial autoantibodies. Extra-hepatic autoimmune manifestations are common, including rheumatic disorders, such as systemic sclerosis (SSc). Notably, PBC is the most frequent autoimmune liver disease in SSc patients. Based on skin lesion extension, two major SSc disease subgroups are recognised: limited cutaneous SSc (lSSc) and diffuse cutaneous SSc. Anti-centromere antibody (ACA) positivity is highly characteristic of SSc, with up to 90% prevalence in lSSc patients. ACA has also been found in up to 30% of PBC patients and 80% of patients with a PBC/SSc overlap syndrome. The diagnostic and clinical significance of ACA positivity in patients with PBC without SSc has recently been under investigation, with several studies highlighting links to severe bile duct injury and portal hypertension. This review discusses the diagnostic and clinical relevance of ACA in patients with PBC, with or without SSc.
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Affiliation(s)
- Rodrigo Liberal
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill Campus, London SE5 9RS, UK; Faculty of Medicine, University of Porto, Porto, Portugal.
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Achenza MIS, Meda F, Brunetta E, Selmi C. Serum autoantibodies for the diagnosis and management of autoimmune liver diseases. Expert Rev Gastroenterol Hepatol 2012; 6:717-29. [PMID: 23237257 DOI: 10.1586/egh.12.58] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The spectrum of autoimmune liver diseases (AILD) includes primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. The immunological mechanisms triggering the initiation and perpetuation of AILD remains unknown, while autoantigens are now recognized in most cases, and are generally nontraditional in their widespread distribution. Sensitive and specific methods for the detection of serum autoantibodies in patients affected by AILD represent a challenge for researchers and clinicians who desire to obtain an early and certain diagnosis as well as markers of disease control. To this regard, the use and interpretation of serum autoantibodies in AILD may be seen as paradigmatic for the large gaps in our knowledge based on the lack of true population-based studies. The present review article will critically discuss the available evidence on the use of autoantibody findings in the diagnosis or management of autoimmune liver disease.
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Affiliation(s)
- Maria I S Achenza
- Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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Bianchi I, Lleo A, Bernuzzi F, Caliari L, Smyk DS, Invernizzi P. The X-factor in primary biliary cirrhosis: monosomy X and xenobiotics. AUTO- IMMUNITY HIGHLIGHTS 2012; 3:127-132. [PMID: 26000136 PMCID: PMC4389075 DOI: 10.1007/s13317-012-0043-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Accepted: 10/24/2012] [Indexed: 12/12/2022]
Abstract
Primary biliary cirrhosis (PBC) is a chronic, cholestatic, autoimmune liver disease characterised by the destruction of small- and medium-sized bile ducts. The serological hallmark of PBC includes antimitochondrial antibodies (AMA). The disease has a striking female predominance, and primarily affects women of middle-age. First-degree relatives, and in particular female relatives, are known to have an increased risk of developing the disease. Several studies have attempted to explain the female predominance of PBC, and autoimmune diseases in general. Two components that are of interest in PBC include monosomy X and xenobiotics. Monosomy X has been noted to be prevalent in the peripheral blood mononuclear cells of PBC patients. Xenobiotics, which are exogenous chemicals not normally found within the body, have been implicated in the modification of, and loss of, tolerance to AMA. Several cosmetics are known to contain these xenobiotics, which is of interest given the information provided in regards to known risk factors for PBC development. This review will focus on X monosomy and xenobiotics, which appear to constitute the X-factor of PBC.
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Affiliation(s)
- Ilaria Bianchi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (MI), Italy
| | - Ana Lleo
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (MI), Italy
| | - Francesca Bernuzzi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (MI), Italy
| | - Lisa Caliari
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (MI), Italy
| | - Dan S. Smyk
- Institute of Liver Transplantation, Division of Transplantation Immunology and Mucosal Biology, King’s College London School of Medicine at King’s College Hospital, London, SE5 9RJ UK
| | - Pietro Invernizzi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano (MI), Italy
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, USA
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