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Kumar NN, Ahmad Dit Al Hakim S, Grygiel-Górniak B. Antinuclear Antibodies in Non-Rheumatic Diseases. Arch Immunol Ther Exp (Warsz) 2025; 73:aite-2025-0004. [PMID: 39827475 DOI: 10.2478/aite-2025-0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 11/04/2024] [Indexed: 01/22/2025]
Abstract
Antinuclear antibodies (ANAs) are critical immunological markers commonly associated with various connective tissue diseases (CTDs). However, these autoantibodies are also detectable in healthy individuals, patients with non-rheumatic autoimmune diseases, those with viral infections, and subjects using specific medications (such as procainamide, hydralazine, and minocycline) that can lead to drug-induced ANA elevation. The standard method for ANA detection is indirect immunofluorescence, a process that requires precision and thoroughness as it assesses both titer and fluorescence patterns. Additionally, immunoblotting and enzyme-linked immunosorbent assay (ELISA) are recommended to identify specific ANAs precisely, highlighting the importance of precision in ANA detection. This review explores the advantages and limitations of current ANA detection methods. It also describes the clinical implications of ANA presence in non-rheumatic diseases, including autoimmune disorders, infectious conditions, non-autoimmune and non-infectious diseases, and autoimmune cutaneous diseases. The presence of elevated ANA titers in these contexts can complicate clinical decision-making, as the diagnostic value of ANA testing alone is limited in non-rheumatic conditions. However, despite these limitations, ANA remains a key component in diagnosing and prognosis systemic CTDs, as it can indicate disease activity, severity, and response to treatment, which is of utmost importance in rheumatology and internal medicine. This paper provides a comprehensive review of the role of ANA in non-rheumatic diseases. It focuses on ANA diagnostic and prognostic significance and offers valuable insights for clinical practice.
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Affiliation(s)
- Nikita Niranjan Kumar
- Department of Rheumatology, Rehabilitation and Internal Diseases, Poznañ University of Medical Sciences, Poznañ, Poland
| | - Samir Ahmad Dit Al Hakim
- Department of Rheumatology, Rehabilitation and Internal Diseases, Poznañ University of Medical Sciences, Poznañ, Poland
| | - Bogna Grygiel-Górniak
- Department of Rheumatology, Rehabilitation and Internal Diseases, Poznañ University of Medical Sciences, Poznañ, Poland
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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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Li Y, Wu Y, Huang J, Cao X, An Q, Peng Y, Zhao Y, Luo Y. A variety of death modes of neutrophils and their role in the etiology of autoimmune diseases. Immunol Rev 2024; 321:280-299. [PMID: 37850797 DOI: 10.1111/imr.13284] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2023]
Abstract
Neutrophils are important in the context of innate immunity and actively contribute to the progression of diverse autoimmune disorders. Distinct death mechanisms of neutrophils may exhibit specific and pivotal roles in autoimmune diseases and disease pathogenesis through the orchestration of immune homeostasis, the facilitation of autoantibody production, the induction of tissue and organ damage, and the incitement of pathological alterations. In recent years, more studies have provided in-depth examination of various neutrophil death modes, revealing nuances that challenge conventional understanding and underscoring their potential clinical utility in diagnosis and treatment. This review explores the multifaceted processes and characteristics of neutrophil death, with a focus on tailored investigations within various autoimmune diseases. It also highlights the potential interplay between neutrophil death and the landscape of autoimmune disorders. The review encapsulates the pertinent pathways implicated in various neutrophil death mechanisms across diverse autoimmune diseases while also charts possible avenues for future research.
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Affiliation(s)
- Yanhong Li
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yinlan Wu
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jingang Huang
- Medical Research Center, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xue Cao
- Department of Rheumatology and Immunology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, Henan, China
| | - Qiyuan An
- School of Inspection and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yun Peng
- Department of Rheumatology and Clinical Immunology, School of Medicine, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Yi Zhao
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yubin Luo
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Dias B, Aguiar A, Morais CI, Nery FG. Correlation between individual autoantibodies and clinical features in primary biliary cholangitis: results of a retrospective longitudinal study. Eur J Gastroenterol Hepatol 2023; 35:682-689. [PMID: 37116005 DOI: 10.1097/meg.0000000000002565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/30/2023]
Abstract
BACKGROUND AND AIMS Primary biliary cholangitis (PBC) is an immune-mediated liver disease. The immunological profile seems to relate to clinical prognosis. This study aims to determine the role of autoantibodies in the course of liver disease and in the response to ursodeoxycholic acid. METHODS Between January 2016 and December 2020, 143 patients with PBC who underwent immunological liver profile evaluation were enrolled. All data were extracted retrospectively from electronic clinical records. Chi-square test, Fisher's exact test and Mann-Whitney test were used to evaluate the relationship between autoantibodies and biochemical parameters, clinical outcomes and therapeutic response scores. A significance level of 0.05 was used. RESULTS Antimitochondrial antibodies were present in 91.6%, antiglycoprotein-210 antibody (anti-gp210) in 18.2% and anti-Sp100 in 19.6% of patients. The incidence of liver-related death was higher in patients with autoimmune hepatitis variants. The occurrence of cirrhosis or portal hypertension was not linked to the presence of any of the autoantibodies tested. No relationship was found with the probability of dying or being transplanted. Patients with anti-Sp100 antibodies had higher baseline levels of aspartate aminotransferase and alanine aminotransferase and lower immunoglobulin M levels. Patients with anti-gp210 were more likely to have a lower median transplant-free survival rate and higher median risk of liver transplant or liver-related death using the GLOBE and UK-PBC scores. CONCLUSION Our findings confirm a strong association between anti-gp210 antibodies and a worse outcome. The association between anti-Sp100 and hepatic lesions requires further elucidation.
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Affiliation(s)
- Beatriz Dias
- Instituto de Ciências Biomédicas de Abel Salazar
| | - Ana Aguiar
- Instituto de Ciências Biomédicas de Abel Salazar
- EPIUnit - Instituto De Saúde Pública, Universidade do Porto
- Laboratório para a Investigação Integrativa e Translacional em Saúde Populacional (ITR)
| | - Cátia Iracema Morais
- Instituto de Ciências Biomédicas de Abel Salazar
- Serviço de Imunologia, Departamento de Patologia, Centro Hospitalar e Universitário de Santo António
| | - Filipe Gaio Nery
- Instituto de Ciências Biomédicas de Abel Salazar
- EPIUnit - Instituto De Saúde Pública, Universidade do Porto
- Laboratório para a Investigação Integrativa e Translacional em Saúde Populacional (ITR)
- Unidade de Cuidados Intermédios Médicos, Serviço de Cuidados Intensivos, Centro Hospitalar e Universitário de Santo António, Porto, Portugal
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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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Dalekos GN, Gatselis NK. Autoimmune serology testing in clinical practice: An updated roadmap for the diagnosis of autoimmune hepatitis. Eur J Intern Med 2023; 108:9-17. [PMID: 36400668 DOI: 10.1016/j.ejim.2022.11.013] [Citation(s) in RCA: 4] [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: 08/20/2022] [Revised: 11/04/2022] [Accepted: 11/06/2022] [Indexed: 11/18/2022]
Abstract
Diagnosis of autoimmune hepatitis (AIH) is in most cases challenging for clinicians as there is not a single specific laboratory or histological marker to diagnose or exclude the presence of the disease. The clinical spectrum of AIH varies from completely asymptomatic to acute-severe or even rarely fulminant hepatic failure, while everybody can be affected irrespective of age, gender, and ethnicity. The old revised and the newer simplified diagnostic scores have been established by the International Autoimmune Hepatitis Group (IAIHG) in 1999 and 2008, respectively, which are based on several clinical, laboratory and histological parameters. Additionally, a thorough differential diagnosis from other diseases mimicking AIH is absolutely indicated. In this context, autoantibodies detection in patients with suspected AIH is mandatory -even though not pathognomonic- not only for AIH diagnosis but furthermore, for AIH classification (AIH-type 1 and AIH-type 2). Although autoimmune serology can be supportive of AIH diagnosis in ≥95% of cases if testing has been performed according to the IAIHG guidelines, this is not the case under real-life circumstances in routine clinical laboratories. Clinicians should be careful both for the importance of the required testing and how to interpret the results and therefore, they should communicate and discuss with the laboratory personnel to achieve the maximum benefit for the patient. Herein, a detailed and updated review of the diagnostic work-up for AIH diagnosis under real-life conditions is given to minimize the underestimation and misdiagnosis of AIH which can result in progression of the disease and unfavourable outcomes.
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Affiliation(s)
- George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece.
| | - Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
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The prognostic value of antibodies to gp210 among patients with primary biliary cholangitis in Northeast China. Dig Liver Dis 2022; 54:1094-1100. [PMID: 34789400 DOI: 10.1016/j.dld.2021.10.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 10/26/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Whether the anti-gp210 antibody can be used as a biomarker in patients with primary biliary cholangitis (PBC) remains controversial. AIMS We aimed to investigate the association between anti-gp210 antibodies and prognosis in ursodeoxycholic acid (UDCA)-treated PBC patients. METHODS We conducted a retrospective cohort study of 180 UDCA-treated PBC patients to assess the prognostic value of anti-gp210 antibodies using the Kaplan-Meier method and Cox proportional hazard regression analysis. RESULTS Of the patients included in our analysis, 50 (27.8%) were anti-gp210 positive, and 130 (72.2%) were anti-gp210 negative. The incidence of liver-related death or transplantation was more common in the anti-gp210 + group (22.0 vs. 9.2%, P=0.022). The five-year transplant-free survival rates of anti-gp210-positive patients vs. anti-gp210-negative patients were 77.0% and 90.3%, respectively. We found that the probability of transplant-free survival was significantly lower in the anti-gp210-positive patients than in the anti-gp210-negative patients (log-rank P=0.004). After adjusting for potential confounders using multivariable Cox regression model, positivity for anti-gp210 antibody (hazard ratio: 4.619, 95% confidence interval: 1.895-11.261, P=0.001) was found to be independently associated with an increase in liver-related mortality or transplantation. CONCLUSION In this cohort of UDCA-treated PBC patients, positivity for anti-gp210 antibody was independently associated with a higher risk of liver-related death or transplantation.
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Nguyen HH, Fritzler MJ, Swain MG. A Review on Biomarkers for the Evaluation of Autoimmune Cholestatic Liver Diseases and Their Overlap Syndromes. FRONTIERS IN MOLECULAR MEDICINE 2022; 2:914505. [PMID: 39086971 PMCID: PMC11285550 DOI: 10.3389/fmmed.2022.914505] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 05/30/2022] [Indexed: 08/02/2024]
Abstract
Autoimmune cholestatic liver disease includes both Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC). Both conditions result in impairment of hepatic bile flow ultimately leading to chronic liver injury, liver fibrosis and eventually end stage cirrhosis. Early and accurate diagnosis are important for the risk stratification, follow up and management of these patients. The underlying pathogenesis of these conditions have not been completely resolved and poses a barrier for the development of new diagnostic and prognostics tools. Current research work suggests that the pathogenesis of autoimmune cholestatic liver disease results from environmental, genetic, and a large component of underlying immune dysfunction. While the current available serum biomarkers and imaging modalities showcases progression in precision medicine for the management of autoimmune cholestatic liver disease, development of new biomarkers are still an area of need in this field. In this review, we will discuss the current and emerging biomarkers in patients with PBC, PSC, and a special population that exhibit overlap syndrome with autoimmune hepatitis (AIH). The use of these biomarkers for diagnosis and prognosis of these patients will be reviewed through the lens of the current understanding of the complex immune pathophysiology of these conditions.
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Affiliation(s)
- Henry H. Nguyen
- University of Calgary Liver Unit, Department of Medicine & Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Marvin J. Fritzler
- Department of Medicine, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Mark G. Swain
- University of Calgary Liver Unit, Department of Medicine, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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Early histopathologic changes in primary biliary cholangitis: does 'minimal change' primary biliary cholangitis exist? A pathologist's view. Eur J Gastroenterol Hepatol 2021; 33:e7-e12. [PMID: 32804848 DOI: 10.1097/meg.0000000000001876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an autoimmune, slowly progressive, cholestatic liver disease characterized by nonsuppurative destructive cholangitis, and interlobular bile duct destruction. Necroinflammatory activities of the hepatic parenchyma and limiting plates of milder form along with late liver fibrosis may develop. Serum liver tests include elevated serum alkaline phosphatase along with a positive antimitochondrial antibody (AMA) in nearly 95% of patients. Liver biopsies are an important confirmatory and staging tool and are additionally very helpful when AMA is negative. More specifically, the earliest changes in liver biopsy suspicious for PBC can be detected, namely loss of the canals of Hering (CoH), as proposed by various authors recently. CoH loss has been described as an early feature of PBC. We focus on early histologic features of PBC, investigating through the literature the possible role of 'minimal change' supporting the clinical diagnosis of PBC, even in the absence of characteristic granulomatous duct destructive lesions.
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Abid H, Akoch I, Lahlali M, Lahmidani N, El Yousfi M, Benajah D, El Abkari M, Ibrahimi A. Primary Biliary Cholangitis: Predictors of Poor Response to Ursodeoxycholic Acid after 1 Year of Treatment in Moroccan Patients. JOURNAL OF MEDICAL AND SURGICAL RESEARCH 2021. [DOI: 10.46327/msrjg.1.000000000000202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Introduction: Primary biliary cholangitis (PBC), the new dominance of primary biliary cirrhosis, is a cholestatic disease of autoimmune etiology and represents the leading cause of intra-hepatic cholestasis. Treatment is mainly based on ursodeoxycholic acid. The biological response to treatment is the main predictor of survival without liver transplantation. The Globe-score has been recently validated as the main prognostic factor. Materials and methods: This is a retrospective study carried out in our department collating all cases of PBC followed in consultation. The aim of our work is to research the predictors of poor response to UDCA. Results: 46 patients were collected. The mean age of the patients was 58.82 years, with a predominance of women (n = 43, 93.5%). 34.78% of patients were in the stage of cirrhosis. Anti-M2 mitochondria antibodies were positive in 44 patients (95.65%). An overlap syndrome was found in 11 patients (23.9%). Treatment was based on UDCA combined with corticosteroid therapy and immunosuppressant for overlap syndrome. A biochemical response at 1 year of treatment according to the Paris II criteria was found in 47.8%. The average value of the globe score was 1.35. A score greater than 0.30 was objectified in 20 cases (43.47%). Nineteen cirrhotic patients (41.30%) had a globe score> 0.30. Factors associated with poor response to therapy were: stage of decompensated cirrhosis, elevated pre-therapy total bilirubin greater than 30 g / l and hypoalbunemia less than 35 g / l. The study of the correlation between Globe score and Paris II showed a strong and significant association with a correlation coefficient estimated at 67%. The Paris II score was significantly correlated with the response to treatment (p = 0.001). Conclusion: In accordance with the data in the literature, the globe-score and Paris II are two similar predictive means for evaluating the response at 1 year of treatment in Moroccan context.
Keywords: Morocco, Predictors of response, Primary biliary cholangitis, Ursodeoxycholic acid
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Gijbels E, Pieters A, De Muynck K, Vinken M, Devisscher L. Rodent models of cholestatic liver disease: A practical guide for translational research. Liver Int 2021; 41:656-682. [PMID: 33486884 PMCID: PMC8048655 DOI: 10.1111/liv.14800] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 01/08/2021] [Accepted: 01/15/2021] [Indexed: 12/12/2022]
Abstract
Cholestatic liver disease denotes any situation associated with impaired bile flow concomitant with a noxious bile acid accumulation in the liver and/or systemic circulation. Cholestatic liver disease can be subdivided into different types according to its clinical phenotype, such as biliary atresia, drug-induced cholestasis, gallstone liver disease, intrahepatic cholestasis of pregnancy, primary biliary cholangitis and primary sclerosing cholangitis. Considerable effort has been devoted to elucidating underlying mechanisms of cholestatic liver injuries and explore novel therapeutic and diagnostic strategies using animal models. Animal models employed according to their appropriate applicability domain herein play a crucial role. This review provides an overview of currently available in vivo animal models, fit-for-purpose in modelling different types of cholestatic liver diseases. Moreover, a practical guide and workflow is provided which can be used for translational research purposes, including all advantages and disadvantages of currently available in vivo animal models.
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Affiliation(s)
- Eva Gijbels
- Department of In Vitro Toxicology and Dermato‐CosmetologyVrije Universiteit BrusselBrusselsBelgium,Gut‐Liver Immunopharmacology Unit, Basic and Applied Medical SciencesLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium
| | - Alanah Pieters
- Department of In Vitro Toxicology and Dermato‐CosmetologyVrije Universiteit BrusselBrusselsBelgium
| | - Kevin De Muynck
- Gut‐Liver Immunopharmacology Unit, Basic and Applied Medical SciencesLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium,Hepatology Research UnitInternal Medicine and PaediatricsLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato‐CosmetologyVrije Universiteit BrusselBrusselsBelgium
| | - Lindsey Devisscher
- Gut‐Liver Immunopharmacology Unit, Basic and Applied Medical SciencesLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium
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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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Ronca V, Mancuso C, Milani C, Carbone M, Oo YH, Invernizzi P. Immune system and cholangiocytes: A puzzling affair in primary biliary cholangitis. J Leukoc Biol 2020; 108:659-671. [PMID: 32349179 DOI: 10.1002/jlb.5mr0320-200r] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 03/09/2020] [Accepted: 03/19/2020] [Indexed: 12/13/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by the destruction of the small and medium bile ducts. Its pathogenesis is still unknown. Despite the genome wide association study findings, the therapies targeting the cytokines pathway, tested so far, have failed. The concept of the biliary epithelium as a key player of the PBC pathogenesis has emerged over the last few years. It is now well accepted that the biliary epithelial cells (BECs) actively participate to the genesis of the damage. The chronic stimulation of BECs via microbes and bile changes the cell phenotype toward an active state, which, across the production of proinflammatory mediators, can recruit, retain, and activate immune cells. The consequent immune system activation can in turn damage BECs. Thus, the crosstalk between both innate and adaptive immune cells and the biliary epithelium creates a paracrine loop responsible for the disease progression. In this review, we summarize the evidence provided in literature about the role of BECs and the immune system in the pathogenesis of PBC. We also dissect the relationship between the immune system and the BECs, focusing on the unanswered questions and the future potential directions of the translational research and the cellular therapy in this area.
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Affiliation(s)
- Vincenzo Ronca
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- National Institute of Health Research Liver Biomedical Research Centre Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Clara Mancuso
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Chiara Milani
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Ye Htun Oo
- National Institute of Health Research Liver Biomedical Research Centre Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Pietro Invernizzi
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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14
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Villalta D, Seaman A, Tiongson M, Warren C, Bentow C, Bizzaro N, Alessio MG, Porcelli B, Norman GL, Mahler M. Evaluation of a novel extended automated particle-based multi-analyte assay for the detection of autoantibodies in the diagnosis of primary biliary cholangitis. Clin Chem Lab Med 2020; 58:1499-1507. [PMID: 32286240 DOI: 10.1515/cclm-2020-0122] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 03/10/2020] [Indexed: 02/07/2023]
Abstract
Background Anti-mitochondrial autoantibodies (AMA) detected by indirect immunofluorescence (IIF) on rodent tissues are the diagnostic marker of primary biliary cholangitis (PBC). However, up to 15% of patients with PBC are AMA-negative by IIF. In the effort to close the serological gap and improve the diagnostic sensitivity of PBC testing, recently, novel autoantibodies specific for PBC, such as kelch-like 12 (KLHL12, KLp epitope) and hexokinase 1 (HK1) have been described. In this study, we evaluated the autoantibody profile in a large cohort of PBC patients and in patients with other liver disease, including anti-HK1 and anti-KLp autoantibodies. Methods Sera of 194 PBC patients (126 AMA-IIF-positive and 68 AMA-IIF-negative) and 138 disease controls were tested for a panel of PBC-specific antibodies (MIT3, sp100, gp210, HK1, KLp) using a new automated particle-based multi-analyte technology (PMAT) assay on the Aptiva instrument (Inova). Results Selecting a cutoff yielding a specificity of >95% for all the markers, the sensitivity for anti-MIT3, anti-sp100, anti-gp210, anti-HK1 and anti-KLp in the PBC AMA-IIF-negative cohort was 20.6%, 16.2%, 23.5%, 22.0%, 17.6 and 13.2%, respectively. Six out of the 68 (8.8%) AMA-IIF negative sera were positive for anti-HK1 or anti-KLp alone. Using these new markers in addition to anti-MIT3, anti-sp100 and anti-gp210, the overall sensitivity in this cohort of AMA-IIF-negative patients increased from 53% to 61.8%, reducing the serological gap in AMA-negative PBC patients. Conclusions PBC antibody profiling, made possible by the new Aptiva-PMAT technology, allows recognition of a higher number of AMA-negative PBC patients than conventional immunoassays and may represent a useful tool to evaluate the prognostic significance of autoantibody association in PBC patients.
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Affiliation(s)
- Danilo Villalta
- Immunologia e Allergologia, Ospedale S. Maria degli Angeli, Pordenone, Italy
| | - Andrea Seaman
- Research and Development, Inova Diagnostics, San Diego, CA, USA
| | | | - Charles Warren
- Research and Development, Inova Diagnostics, San Diego, CA, USA
| | - Chelsea Bentow
- Research and Development, Inova Diagnostics, San Diego, CA, USA
| | - Nicola Bizzaro
- Laboratorio di Patologia Clinica, Ospedale S. Antonio, Tolmezzo (UD), via M.L. King 25, 30027 San Donà di Piave (Venice), Italy
| | - Maria Grazia Alessio
- Dipartimento di Patologia Clinica, Laboratorio Analisi, AO Papa Giovanni XXIII, Bergamo, Italy
| | - Brunetta Porcelli
- Dipartimento di Biotecnologie Mediche, Università di Siena, Policlinico Le Scotte, Siena, Italy
| | - Gary L Norman
- Research and Development, Inova Diagnostics, San Diego, CA, USA
| | - Michael Mahler
- Research and Development, Inova Diagnostics, San Diego, CA, USA
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15
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Zian Z, Bennani Mechita M, Hamdouch K, Maamar M, Barakat A, Ghailani Nourouti N, El Aouad R, Valdivia MM, Arji N. Proteomics characterization of CENP-B epitope in Moroccan scleroderma patients with anti-centromere autoantibodies. Immunol Lett 2020; 221:1-5. [PMID: 32057908 DOI: 10.1016/j.imlet.2020.02.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/17/2019] [Accepted: 02/10/2020] [Indexed: 11/25/2022]
Abstract
BACKGROUND Anti-centromere auto-antibodies (ACA) have been described as a marker in Systemic sclerosis (SSc) disease. CENP-B is the major centromere auto-antigen recognized by SSc patients with positive ACA. Our aim was to characterize the major epitope involved in the anti-CENP-B immune response of Moroccan SSc patients. PATIENTS AND METHOD For identification of SSc biomarkers, 80 sera from patients with SSc and systemic lupus erythematosus (SLE) were screened by indirect immunofluorescence test (IIF) to assess the presence of ANA reactivity. Immunoblotting analysis was performed for 11 sera with positive ACA using the N-terminal and C-terminal region of CENP-B protein as antigens. RESULTS 29 out of 30 (96, 66 %) patients with SSc had positive ANA. 11 out of 30 (36, 67 %) patients were ACA positive and 6 of them produced auto-antibodies against Nt-CENPB antigen. Two of these 6 Nt-CENPB positive sera produced also other auto-antibodies associated to primary biliary cirrhosis. None of all sera tested showed reactivity against Ct-CENPB. CONCLUSION Our data showed, for the first time in Morocco, that the Nt-CENPB contains a major epitope for Moroccan SSc patients. These findings could provide additional information that would contribute to improving the diagnosis and management of these patients.
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Affiliation(s)
- Zeineb Zian
- Biomedical Genomics and Oncogenetics Research Laboratory, Department of Biology, Faculty of Sciences and Techniques of Tangier, Abdelmalek Essaadi University, Morocco.
| | - Mohcine Bennani Mechita
- Biomedical Genomics and Oncogenetics Research Laboratory, Department of Biology, Faculty of Sciences and Techniques of Tangier, Abdelmalek Essaadi University, Morocco.
| | - Khaoula Hamdouch
- Biomedical Genomics and Oncogenetics Research Laboratory, Department of Biology, Faculty of Sciences and Techniques of Tangier, Abdelmalek Essaadi University, Morocco; Department of Biomedicine, Biotechnology and Public Health, Faculty of Sciences, University of Cadiz, Cadiz, Spain.
| | - Mouna Maamar
- Internal Medicine Department, Hospital Ibn Sina, Rabat, Morocco.
| | - Amina Barakat
- Biomedical Genomics and Oncogenetics Research Laboratory, Department of Biology, Faculty of Sciences and Techniques of Tangier, Abdelmalek Essaadi University, Morocco.
| | - Naima Ghailani Nourouti
- Biomedical Genomics and Oncogenetics Research Laboratory, Department of Biology, Faculty of Sciences and Techniques of Tangier, Abdelmalek Essaadi University, Morocco.
| | - Rajae El Aouad
- Autoimmunity Laboratory, National Institute of Hygiene, Rabat, Morocco.
| | - Manuel M Valdivia
- Department of Biomedicine, Biotechnology and Public Health, Faculty of Sciences, University of Cadiz, Cadiz, Spain.
| | - Naima Arji
- Autoimmunity Laboratory, National Institute of Hygiene, Rabat, Morocco.
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16
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Cristoferi L, Invernizzi P. Comment on "Early Prognostic Utility of Gp210 Antibody-Positive Rate in Primary Biliary Cholangitis: A Meta-Analysis". DISEASE MARKERS 2020; 2020:2453908. [PMID: 32076457 PMCID: PMC6996691 DOI: 10.1155/2020/2453908] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 12/12/2019] [Indexed: 01/10/2023]
Affiliation(s)
- Laura Cristoferi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy
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17
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Bombaci M, Pesce E, Torri A, Carpi D, Crosti M, Lanzafame M, Cordiglieri C, Sinisi A, Moro M, Bernuzzi F, Gerussi A, Geginat J, Muratori L, Terracciano LM, Invernizzi P, Abrignani S, Grifantini R. Novel biomarkers for primary biliary cholangitis to improve diagnosis and understand underlying regulatory mechanisms. Liver Int 2019; 39:2124-2135. [PMID: 31033124 DOI: 10.1111/liv.14128] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 03/15/2019] [Accepted: 04/19/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Primary biliary cholangitis is an autoimmune biliary disease characterized by injury of bile ducts, eventually leading to cirrhosis and death. In most cases, anti-mitochondrial antibodies and persistently elevated serum alkaline phosphatase are the basis for the serological diagnosis. Anti-nuclear antibodies are also useful and may indicate a more aggressive diseases course. In patients in which anti-mitochondrial antibodies are not detected, an accurate diagnosis requires liver histology. This study aims at identifying specific biomarkers for the serological diagnosis of primary biliary cholangitis. METHODS Sera from patients affected by primary biliary cholangitis, primary sclerosing cholangitis, hepatitis C virus (with and without cryoglobulinemia), hepatocarcinoma and healthy donors were tested on a protein array representing 1658 human proteins. The most reactive autoantigens were confirmed by DELFIA analysis on expanded cohorts of the same mentioned serum classes, and on autoimmune hepatitis sera, using anti-PDC-E2 as reference biomarker. RESULTS Two autoantigens, SPATA31A3 and GARP, showed high reactivity with primary biliary cholangitis sera, containing or not anti-mitochondrial antibodies. Their combination with PDC-E2 allowed to discriminate primary biliary cholangitis from all tested control classes with high sensitivity and specificity. We found that GARP expression is upregulated upon exposure to biliary salts in human cholangiocytes, an event involving EGFR and insulin pathways. GARP expression was also detected in biliary duct cells of PBC patients. CONCLUSIONS This study highlighted SPATA31A3 and GARP as new biomarkers for primary biliary cholangitis and unravelled molecular stimuli underlying GARP expression in human cholangiocytes.
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Affiliation(s)
- Mauro Bombaci
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Elisa Pesce
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Anna Torri
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Donatella Carpi
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Mariacristina Crosti
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Manuela Lanzafame
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Chiara Cordiglieri
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Antonia Sinisi
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Monica Moro
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesca Bernuzzi
- Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan, Bicocca School of Medicine, Monza, Italy
| | - Alessio Gerussi
- Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan, Bicocca School of Medicine, Monza, Italy
| | - Jens Geginat
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
| | - Luigi Muratori
- Department of Medical and Surgical Sciences, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | | | - Pietro Invernizzi
- Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan, Bicocca School of Medicine, Monza, Italy
| | - Sergio Abrignani
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.,Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy
| | - Renata Grifantini
- Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
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18
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Bauer A, Habior A. Detection of Autoantibodies Against Nucleoporin p62 in Sera of Patients With Primary Biliary Cholangitis. Ann Lab Med 2019; 39:291-298. [PMID: 30623621 PMCID: PMC6340841 DOI: 10.3343/alm.2019.39.3.291] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 06/07/2018] [Accepted: 11/07/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by specific autoantibodies. We evaluated the prevalence of autoantibodies against nucleoporin p62 (anti-p62) in PBC patients' sera to determine whether it can be a marker for PBC, in comparison with other immunological and biochemical parameters. We validated the performance of our in-house ELISA technique. METHODS Serum samples were collected from 135 PBC patients. Thirty patients with primary sclerosing cholangitis (PSC) and 30 with autoimmune hepatitis (AIH) were included as pathological controls, and 40 healthy blood donors served as healthy controls. The presence of anti-p62 was determined by an in-house ELISA using a recombinant protein. We calculated the sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratio (LR+ and LR-) of our in-house ELISA for diagnosing PBC based on anti-p62. Findings were correlated with biochemical data and survival. RESULTS Anti-p62 was detected in 32 PBC patients (23.7%). Specificity and PPV of anti-p62 for PBC were 99% and 97%, respectively. The difference between proportions of anti-p62-positive patients and controls was 0.23 (95% confidence interval [CI]: 0.03-0.40; P<0.0001); LR+ and LR- were 23.7 and 0.77, respectively. The presence of anti-p62 was associated with higher levels of bilirubin and alkaline phosphatase (P<0.001). The odds ratio for survival was 2.44 (95% CI: 0.87-6.87; P=0.091). CONCLUSIONS Anti-p62 may be regarded as a significant serological marker of PBC.
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Affiliation(s)
- Alicja Bauer
- Department of Biochemistry and Molecular Biology, Hepatology and Clinical Oncology, Centre of Postgraduate Medical Education, Warsaw, Poland.
| | - Andrzej Habior
- Department of Gastroenterology, Hepatology and Clinical Oncology, Centre of Postgraduate Medical Education, Warsaw, Poland
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19
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Norman GL, Reig A, Viñas O, Mahler M, Wunsch E, Milkiewicz P, Swain MG, Mason A, Stinton LM, Aparicio MB, Aldegunde MJ, Fritzler MJ, Parés A. The Prevalence of Anti-Hexokinase-1 and Anti-Kelch-Like 12 Peptide Antibodies in Patients With Primary Biliary Cholangitis Is Similar in Europe and North America: A Large International, Multi-Center Study. Front Immunol 2019; 10:662. [PMID: 31001269 PMCID: PMC6456688 DOI: 10.3389/fimmu.2019.00662] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 03/11/2019] [Indexed: 12/12/2022] Open
Abstract
Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is present worldwide. Autoantibodies, in particular anti-mitochondrial antibodies (AMA) detected by indirect immunofluorescence assays or newer solid phase immunoassays can detect most, but not all individuals with PBC. Detection of antibodies to the anti-nuclear antigens sp100 and gp210 can identify additional PBC patients, but some seronegative patients remain, often resulting in delayed diagnosis and treatment. Antibodies to kelch-like 12 (KLHL12) and hexokinase 1 (HK-1) were recently identified as new biomarkers for PBC and notably identify patients who are negative for conventional autoantibodies. To become globally adopted, it is important to validate these new biomarkers in different geographic areas. In the present study we evaluated the prevalence of anti-KLHL12 (measured by a KLHL12-derived peptide referred to as KL-p) and anti-HK-1 antibodies by ELISA at five sites within Europe and North America and demonstrated the presence of these antibodies in patients with PBC in all geographies.
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Affiliation(s)
- Gary L Norman
- Department of Research and Development, Inova Diagnostics, San Diego, CA, United States
| | - Anna Reig
- Liver Unit, Hospital Clínic, Institut D'Investigacions Biomèdiques August Pi i Sunyer, CIBERehd, University of Barcelona, Barcelona, Spain
| | - Odette Viñas
- Immunology Department, Hospital Clínic, Centre Diagnòstic Biomèdic, Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Michael Mahler
- Department of Research and Development, Inova Diagnostics, San Diego, CA, United States
| | - Ewa Wunsch
- Translational Medicine Group, Pomeranian Medicine University, Szczecin, Poland
| | - Piotr Milkiewicz
- Translational Medicine Group, Pomeranian Medicine University, Szczecin, Poland.,Liver and Internal Medicine Unit, Department General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Mark G Swain
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Andrew Mason
- Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, AB, Canada
| | - Laura M Stinton
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Maria Belen Aparicio
- Laboratorio Autoimmunidad, Hospital Universitario de Salamanca, Salamanca, Spain
| | - Maria Jose Aldegunde
- Laboratorio Autoimmunidad, Hospital Universitario de Salamanca, Salamanca, Spain
| | - Marvin J Fritzler
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Albert Parés
- Liver Unit, Hospital Clínic, Institut D'Investigacions Biomèdiques August Pi i Sunyer, CIBERehd, University of Barcelona, Barcelona, Spain
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20
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Inflammatory Hepatobiliary Diseases. Clin Immunol 2019. [DOI: 10.1016/b978-0-7020-6896-6.00076-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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21
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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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Terziroli Beretta-Piccoli B, Stirnimann G, Cerny A, Semela D, Hessler R, Helbling B, Stickel F, Kalid-de Bakker C, Bihl F, Giostra E, Filipowicz Sinnreich M, Oneta C, Baserga A, Invernizzi P, Carbone M, Mertens J. Geoepidemiology of Primary Biliary Cholangitis: Lessons from Switzerland. Clin Rev Allergy Immunol 2018; 54:295-306. [PMID: 29181702 DOI: 10.1007/s12016-017-8656-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
No data on primary biliary cholangitis (PBC) are available in Switzerland. We established a national patient cohort to obtain information on PBC phenotypes and disease course in Switzerland. Local databases in all university hospitals and in two large secondary centers were searched for case finding. In addition, all primary care physicians, gastroenterologists, rheumatologists, and dermatologists were invited to contribute patients from their own medical records. PBC diagnosis was centrally reviewed. Five hundred one PBC patients were identified, 474 were included in data analysis, and 449 of them were enrolled by tertiary centers. The catchment area accounts for approximately one third of the Swiss population or approximately 2.8 million inhabitants. The median age at diagnosis was 53 years, 84% were women, and 86% were anti-mitochondrial antibody positive. The median follow-up was 5.4 years, 12.6% experienced a liver-related endpoint. Splenomegaly was present at diagnosis in one quarter of patients and in half of male patients. Approximately one third were non-responders to ursodeoxycholic acid (UDCA). The median transplant-free survival at 10 years was 85%. The following variables were independently associated with poor outcome: low platelet count at baseline (HR = 0.99, p < 0.0001), elevated alkaline phosphatase at baseline (HR = 1.36, p < 0.0001), elevated bilirubin at baseline (HR = 1.11, p = 0.001), and elevated alanine aminotransaminase (HR = 1.35, p = 0.04) after 12 months of UDCA therapy. The AUROC for the UK-PBC risk score at 5, 10, and 15 years was 0.82. The AUROC for the Globe score at 5, 10, and 15 years was 0.77. Patients included in this study are currently being enrolled in a prospective nationwide registry with biobank, taking advantage of the collaboration network generated by this study. Our study provides the first snapshot of PBC in Switzerland, describing a diagnostic delay with one quarter of patients diagnosed when already in the cirrhotic stage. We were also able to externally validate the UK-PBC risk score and the Globe score. The ongoing nationwide prospective registry will be fundamental to improve disease awareness and interdisciplinary collaborations and will serve as a platform for clinical and translational research. TRIAL REGISTRATION NUMBER clinicaltrials.gov : NCT02846896; SNCTP000001870.
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Affiliation(s)
| | - Guido Stirnimann
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Andreas Cerny
- Epatocentro Ticino, via Soldino 5, 6900, Lugano, Switzerland
| | - David Semela
- Hepatologie, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Roxane Hessler
- Department of Gastroenterology and Hepatology, Centre Hôpitalier Universitaire Vaudois, Lausanne, Switzerland
| | | | - Felix Stickel
- Hepatologie Hirslanden Bern, Bern, Switzerland.,Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | | | - Florian Bihl
- Servizio Epatologia EOC, Bellinzona, Switzerland
| | | | | | - Carl Oneta
- Medical office for Gastroenterology and Hepatology, Winterthur, Switzerland
| | - Adriana Baserga
- Epatocentro Ticino, via Soldino 5, 6900, Lugano, Switzerland
| | - Pietro Invernizzi
- Center for Autoimmune Liver Diseases, Division of Gastroenterology, University of Milan Bicocca, Milan, Italy
| | - Marco Carbone
- Center for Autoimmune Liver Diseases, Division of Gastroenterology, University of Milan Bicocca, Milan, Italy
| | - Joachim Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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23
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Gulamhusein AF, Hirschfield GM. Pathophysiology of primary biliary cholangitis. Best Pract Res Clin Gastroenterol 2018; 34-35:17-25. [PMID: 30343706 DOI: 10.1016/j.bpg.2018.05.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/22/2018] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis is a prototypical autoimmune disease characterized by an overwhelming female predominance, a distinct clinical phenotype, and disease specific anti-mitochondrial antibodies targeted against a well-defined auto-antigen. In a genetically susceptible host, multi-lineage loss of tolerance to the E2 component of the 2-oxo-dehydrogenase pathway and dysregulated immune pathways directed at biliary epithelial cells leads to cholestasis, progressive biliary fibrosis, and cirrhosis in a subset of patients. Several key insights have shed light on the complex pathogenesis of disease. First, characteristic anti-mitochondrial antibodies (AMAs) target lipoic acid containing immunodominant epitopes, particularly pyruvate dehydrogenase complex (PDC-E2), on the inner mitochondrial membrane of BECs. Next, breakdown of the protective apical bicarbonate rich umbrella may sensitize BECs to aberrant apoptotic pathways leaving the antigenic PDC-E2 epitope immunologically tact within an apoptotic bleb. A multi-lineage immune response ensues characterized by an imbalance between effector and regulatory activity resulting in progressive and self-perpetuating biliary injury. Genome wide studies shed light on important pathways involved in disease, key among them being IL-12. Epigenetic mechanisms and microRNAs may play help shed light on the missing heritability and female preponderance of disease. Taken together, these findings have dramatically advanced our understanding of disease and may lead to important therapeutic advances.
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Affiliation(s)
- Aliya F Gulamhusein
- Toronto Centre for Liver Disease, 200 Elizabeth Street, Toronto, ON, Canada.
| | - Gideon M Hirschfield
- Centre for Liver Research and NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK.
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24
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Preuß BE, Berg CP, Werner C, Plankenhorn S, Malek NP, Klein R. Sulphite oxidase (SO) - a mitochondrial autoantigen as target for humoral and cellular immune reactions in primary sclerosing cholangitis. BMC Gastroenterol 2018; 18:58. [PMID: 29720090 PMCID: PMC5932765 DOI: 10.1186/s12876-018-0787-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 04/24/2018] [Indexed: 12/22/2022] Open
Abstract
Background In a recent study we had evidence that sulphite oxidase (SO) may be a relevant autoantigen in primary sclerosing cholangitis (PSC). Aim of the present study was, therefore, to analyse humoral and cellular immune-reactivity towards SO in these patients in more detail. Methods Sera from 53 patients with PSC (30 untreated and 23 treated with ursodeoxycholic acid [UDCA] at time of analysis), from 422 patients with different hepatic and non-hepatic disorders, and from 50 healthy individuals were tested by ELISA for antibodies against full-length-SO (SO-fl) and its three major domains expressed in E.coli (SO-I, SO-II, SO-III). For epitope-mapping, 29 overlapping peptides were used. Peripheral blood mononuclear cells (PBMC) were obtained from 33 PSC-patients and analysed for SO-induced proliferation, production of cytokines, and expression of the activation marker cluster of differentiation (CD) 69. Results 43% of the 30 untreated and 26% of the 23 treated PSC-patients had IgG anti-SO-antibodies predominantly reacting with SO-fl, SO-I and SO-II. Antibody-reactivity decreased after UDCA-treatment. Prevalence and reactivity of anti-SO-antibodies were significantly higher in PSC than in patients with other hepatic and non-hepatic disorders. Epitope mapping revealed no distinct immuno-dominant regions within SO. Incubation of PBMC from PSC-patients (but not from controls) with SO-antigens revealed an activation of B-cells and a T-helper cell type-2 reaction pattern (production of interleukin [IL]-13, IL-10). Conclusions PSC-patients show humoral and cellular immune response towards SO. Antibodies may be predominantly directed against conformational epitopes. SO enhances in vitro especially T-helper cell type-2 immune-reactions, which may be pro-fibrotic. SO is a detoxifying enzyme present also in bacteria; further studies analysing its role in the aetiology and pathogenesis in PSC may, therefore, be important. Electronic supplementary material The online version of this article (10.1186/s12876-018-0787-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Beate E Preuß
- Department of Internal Medicine II, University of Tuebingen, Otfried-Mueller Str. 11, 72076, Tuebingen, Germany
| | - Christoph P Berg
- Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany
| | - Christoph Werner
- Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany
| | - Sandra Plankenhorn
- Department of Internal Medicine II, University of Tuebingen, Otfried-Mueller Str. 11, 72076, Tuebingen, Germany
| | - Nisar P Malek
- Department of Internal Medicine I, University of Tuebingen, Tuebingen, Germany
| | - Reinhild Klein
- Department of Internal Medicine II, University of Tuebingen, Otfried-Mueller Str. 11, 72076, Tuebingen, Germany.
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Sebode M, Weiler-Normann C, Liwinski T, Schramm C. Autoantibodies in Autoimmune Liver Disease-Clinical and Diagnostic Relevance. Front Immunol 2018; 9:609. [PMID: 29636752 PMCID: PMC5880919 DOI: 10.3389/fimmu.2018.00609] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 03/12/2018] [Indexed: 12/12/2022] Open
Abstract
Testing for liver-related autoantibodies should be included in the workup of patients with hepatitis or cholestasis of unknown origin. Although most of these autoantibodies are not disease specific, their determination is a prerequisite to diagnose autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), and they are components of the diagnostic scoring system in these diseases. In primary sclerosing cholangitis (PSC), on the other hand, autoantibodies are frequently present but play a minor role in establishing the diagnosis. In PSC, however, data on antibodies suggest a link between disease pathogenesis and the intestinal microbiota. This review will focus on practical aspects of antibody testing in the three major autoimmune liver diseases AIH, PBC, and PSC.
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Affiliation(s)
- Marcial Sebode
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Christina Weiler-Normann
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Timur Liwinski
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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26
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Terziroli Beretta-Piccoli B, Invernizzi P, Gershwin ME, Mainetti C. Skin Manifestations Associated with Autoimmune Liver Diseases: a Systematic Review. Clin Rev Allergy Immunol 2017; 53:394-412. [DOI: 10.1007/s12016-017-8649-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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27
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Di Sabatino A, Biagi F, Lenzi M, Frulloni L, Lenti MV, Giuffrida P, Corazza GR. Clinical usefulness of serum antibodies as biomarkers of gastrointestinal and liver diseases. Dig Liver Dis 2017; 49:947-956. [PMID: 28733178 DOI: 10.1016/j.dld.2017.06.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2017] [Revised: 06/05/2017] [Accepted: 06/07/2017] [Indexed: 12/11/2022]
Abstract
The progressively growing knowledge of the pathophysiology of a number of immune-mediated gastrointestinal and liver disorders, including autoimmune atrophic gastritis, coeliac disease, autoimmune enteropathy, inflammatory bowel disease, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis and autoimmune pancreatitis, together with the improvement of their detection methods have increased the diagnostic power of serum antibodies. In some cases - coeliac disease and autoimmune atrophic gastritis - they have radically changed gastroenterologists' diagnostic ability, while in others - autoimmune hepatitis, inflammatory bowel disease and autoimmune pancreatitis - their diagnostic performance is still inadequate. Of note, serum antibody misuse in clinical practice has raised a number of controversies, which may generate confusion in the diagnostic management of the aforementioned disorders. In this review, we critically re-evaluate the usefulness of serum antibodies as biomarkers of immune-mediated gastrointestinal and liver disorders, and discuss their pitfalls and merits.
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Affiliation(s)
- Antonio Di Sabatino
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.
| | - Federico Biagi
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Marco Lenzi
- Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy
| | - Luca Frulloni
- Department of Medicine, Pancreas Center, University of Verona, Verona, Italy
| | - Marco Vincenzo Lenti
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Paolo Giuffrida
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Gino Roberto Corazza
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
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28
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Chronic Autoimmune Epithelitis in Sjögren's Syndrome and Primary Biliary Cholangitis: A Comprehensive Review. Rheumatol Ther 2017; 4:263-279. [PMID: 28791611 PMCID: PMC5696286 DOI: 10.1007/s40744-017-0074-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Indexed: 12/12/2022] Open
Abstract
Within the spectrum of autoimmune diseases, Sjögren's syndrome and primary biliary cholangitis are exemplary and can be coined as chronic epithelitis based on their frequent coexistence in clinical practice and the highly specific immune-mediated injury of the small bile ducts and the exocrine glands. The pathogenic mechanisms underlying the diseases are similar, with apoptosis being the key element leading to organ-specific immune-mediated injury directed against the small bile ducts and salivary gland epithelia, respectively along with similar epidemiological features, such as female predominance and the age of onset in the fifth decade of life. Indeed, novel insights into the pathogenesis of the diseases have been obtained in recent years, including a better definition of the role of B and T cells, particularly Th17 cells, and the mechanisms of autoantibody-mediated tissue injury, with anti-mitochondrial antibodies and SS-A/SS-B being identified as specific for primary biliary cholangitis and Sjögren's syndrome, respectively. These findings have opened the possibility to new targeted therapies, but most clinical needs remain unmet, particularly from a therapeutic standpoint where options diverge, with bile acids being the predominant treatment strategy in primary biliary cholangitis and immunomodulators being used to treat Sjögren's syndrome. Here we provide a comprehensive review of the most recent findings on the pathogenesis, clinical manifestations and therapeutic options for Sjögren's syndrome and primary biliary cholangitis, respectively, while stressing the common traits between these conditions. Our cumulative hypothesis is that similarities outnumber differences and that this may prove advantageous towards a better management of patients.
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29
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Kanth R, Shrestha RB, Rai I, VanWormer JJ, Roy PK. Incidence of Primary Biliary Cholangitis in a Rural Midwestern Population. Clin Med Res 2017; 15:13-18. [PMID: 28487448 PMCID: PMC5573520 DOI: 10.3121/cmr.2017.1351] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 04/03/2017] [Accepted: 04/24/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a rare disease with incidence that varies with time and geography. Only two studies have assessed PBC incidence in the United States, with the most recent appearing over a decade ago. The objective of the present study was to assess PBC incidence in the United States in a more recent era. METHODS The incidence of PBC was assessed in a population-based cohort in rural, Midwestern Wisconsin over two decades spanning from June 1992 through June 2011. Cases were initially identified in the electronic medical record and then manually verified for inclusion according to the American Association for the Study of Liver Disease criteria for PBC. Additional data were abstracted for verified cases. RESULTS A total of 79 cases of PBC were identified over the 20-year period for an overall age- and sex-standardized incidence of 4.9 cases per 100,000 person-years. Incidence was higher in females, but changes over time were not significant. After a mean 7.3 years follow-up, all-cause mortality of those with PBC was 29%, and estimated 10-year survival was 76%. CONCLUSIONS The overall incidence of PBC in a Midwestern population of the United States has remained relatively stable over the last two decades. Patients have better prognosis, and the survival of PBC cases has improved.
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Affiliation(s)
- Rajan Kanth
- At the time the study was conducted, Dr. Kanth was a hospitalist at the Marshfield Clinic, Marshfield, Wisconsin USA. Current affiliation: Carilion Clinic, Department of Gastroenterology, Roanoke, Virginia USA
| | - Ram Babu Shrestha
- Integrated Research and Development Laboratory, Marshfield Clinic Research Institute, Marshfield, Wisconsin USA
| | - Indira Rai
- Department of Internal Medicine, Marshfield Clinic, Marshfield, Wisconsin USA
| | - Jeffrey J VanWormer
- Center for Clinical Epidemiology & Population Health, Marshfield Clinic Research Institute, Marshfield, Wisconsin USA
| | - Praveen K Roy
- Department of Gastroenterology, Presbyterian Healthcare Services, Albuquerque, New Mexico USA
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30
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Larson L, James M, Gossard A. Cholestatic Liver Injury: Care of Patients With Primary Biliary Cholangitis or Primary Sclerosing Cholangitis. AACN Adv Crit Care 2017; 27:441-452. [PMID: 27959300 DOI: 10.4037/aacnacc2016202] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
The most common causes of chronic cholestatic liver disease are primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Both disease processes are characterized by a destruction of intrahepatic and/or extrahepatic biliary ducts. The etiology is not entirely clear; however, there is an underlying autoimmune component contributing to both disease processes. Although PBC and PSC are often diagnosed and managed in the outpatient setting, in some instances, a patient may have jaundice, fatigue, and pruritus requiring evaluation and determination of the cholestatic cause. Patients with PSC should be monitored for evidence of cholangiocarcinoma, colon cancer, and gallbladder polyps as they are at an increased risk of malignant neoplasms. Liver transplant has the potential for improving quality of life, although disease recurrence is a risk.
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Affiliation(s)
- Laurie Larson
- Laurie Larson is Nurse Practitioner, Hepatology, 406 Harvard St SE, MMC 36, University of Minnesota, Minneapolis, MN 55455 . Michelle James is Clinical Director of Transplant Services, University of Minnesota, Minneapolis, Minnesota. Andrea Gossard is Nurse Practitioner, Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Michelle James
- Laurie Larson is Nurse Practitioner, Hepatology, 406 Harvard St SE, MMC 36, University of Minnesota, Minneapolis, MN 55455 . Michelle James is Clinical Director of Transplant Services, University of Minnesota, Minneapolis, Minnesota. Andrea Gossard is Nurse Practitioner, Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Andrea Gossard
- Laurie Larson is Nurse Practitioner, Hepatology, 406 Harvard St SE, MMC 36, University of Minnesota, Minneapolis, MN 55455 . Michelle James is Clinical Director of Transplant Services, University of Minnesota, Minneapolis, Minnesota. Andrea Gossard is Nurse Practitioner, Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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31
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Terziroli Beretta-Piccoli B, Guillod C, Marsteller I, Blum R, Mazzucchelli L, Mondino C, Invernizzi P, Gershwin ME, Mainetti C. Primary Biliary Cholangitis Associated with Skin Disorders: A Case Report and Review of the Literature. Arch Immunol Ther Exp (Warsz) 2017; 65:299-309. [DOI: 10.1007/s00005-016-0448-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 12/07/2016] [Indexed: 01/12/2023]
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32
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Ozaslan E, Efe C, Gokbulut Ozaslan N. The diagnosis of antimitochondrial antibody-negative primary biliary cholangitis. Clin Res Hepatol Gastroenterol 2016; 40:553-561. [PMID: 27567165 DOI: 10.1016/j.clinre.2016.06.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 06/12/2016] [Accepted: 06/23/2016] [Indexed: 02/04/2023]
Abstract
Autoimmune liver diseases are heterogenous disorders that share largely non-specific clinical, serological and pathological features. The correct diagnosis requires discriminative features which are highly specific, for example high-titer antimitochondrial antibodies (AMA) and florid duct lesion in primary biliary cholangitis (PBC). However, the imperfect sensitivities of these characteristic features and abuse of scoring systems led to many artificial diagnoses such as overlap syndromes and outliers for example "autoimmune cholangitis" which is now called as "AMA-negative PBC". Patients lacking detectable AMA (up to 20% in indirect immunofluorescence - IF), but otherwise presenting signs and symptoms of PBC should be regarded as affected by "AMA-negative PBC" because they seem to follow a natural history similar to that of their AMA positive counterparts. The complementary use of IF, ELISA and immunoblotting have disclosed that the majority of patients initially considered AMA-negative are in fact AMA positive. Moreover, the use of PBC-specific ANA's like Gp210 and sp100 have diminished the AMA-negative cases (if truly exists!) to less than 5%. The histological spectrum of PBC includes typical florid duct lesions and/or compatible features such as non-specific hepatitic and biliary findings. In the absence of florid duct lesion and AMA positivity, histology alone cannot differentiate PBC from other biliary disorders. However, the analysis of compatible histological features with the clinical, serological and imaging findings usually points to a specific diagnosis. In this review, we present serological, clinical and pathological pitfalls regarding AMA-negative PBC including illustrative cases and a diagnostic algorithm.
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Affiliation(s)
- Ersan Ozaslan
- Numune Education and Research Hospital, Department of Gastroenterology, Ankara, Turkey.
| | - Cumali Efe
- Batman State Hospital, Department of Gastroenterology, Batman, Turkey
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33
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Lin P, Jiang CM. Latest advances in diagnosis of autoimmune liver disease. Shijie Huaren Xiaohua Zazhi 2016; 24:4085-4091. [DOI: 10.11569/wcjd.v24.i29.4085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Autoimmune liver disease (AILD) includes autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and overlap syndromes. AILD is the main inducing factor for late chronic liver failure, and in Western countries it is also one of the major liver diseases for which orthotopic liver transplantation is performed. In recent years, with the increasing incidence of AILD in both China and other countries, clinicians have paid more and more attention to AILD. Further standardization of diagnostic criteria for AILD has become a new hot research topic, and experts and scholars have put forward some corresponding opinions. This article describes the latest advances in the diagnosis of AILD.
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34
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Gatselis NK, Dalekos GN. Molecular diagnostic testing for primary biliary cholangitis. Expert Rev Mol Diagn 2016; 16:1001-10. [DOI: 10.1080/14737159.2016.1217159] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Nikolaos K. Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
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35
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Mitra S, Minz RW. Autoantibodies in Autoimmune Liver Diseases-Methods of Detection and Interpretation: An Update for the Reporting Pathologist. Int J Surg Pathol 2016; 24:576-85. [PMID: 27388199 DOI: 10.1177/1066896916657643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Autoimmune liver disease (AILD) is a type of chronic liver disease with autoimmune etiology. The diagnosis of the disease is multipronged and detection of autoantibodies in AILDs is an important diagnostic tool and it also helps in the classification of the disease. There are multiple autoantibodies that are detected in AILDs but none is diagnostic. Moreover, these autoantibodies are detected in many other pathological and nonpathological conditions. So the significance of seropositivity for these autoantibodies should be known by both the pathologists as well as the clinicians. In addition, there is prognostic significance associated with some of the antibodies and they also sometimes help in the disease monitoring. The whole array of antibodies detected in AILDs is discussed in detail in this review along with their clinical significance and interpretation.
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Affiliation(s)
- Suvradeep Mitra
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Ranjana Walker Minz
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
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36
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Abstract
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the most common chronic cholestatic liver diseases (CLD) in adults and are associated with immune mechanisms. PBC is considered a model autoimmune disease, and more than 90% of patients present very specific autoantibodies against mitochondrial antigens. Whether PSC should be considered an autoimmune or merely immune-mediated disease is still under debate. This review addresses the clinical relevance of autoantibodies in CLD and their pathogenic mechanisms and illustrates the technology available for appropriate autoantibody detection.
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Affiliation(s)
- Simona Marzorati
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via A. Manzoni 113, Rozzano, Milan 20089, Italy; Department of Electronics, Information and Bioengineering, Politecnico di Milano, via Ponzio 34/5, Milan 20133, Italy
| | - Pietro Invernizzi
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via A. Manzoni 113, Rozzano, Milan 20089, Italy; Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, GBSF, 451 Health Science Drive, Davis, CA 95616, USA
| | - Ana Lleo
- Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Via A. Manzoni 113, Rozzano, Milan 20089, Italy.
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37
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The coexistence of Sjögren's syndrome and primary biliary cirrhosis: a comprehensive review. Clin Rev Allergy Immunol 2016; 48:301-15. [PMID: 25682089 DOI: 10.1007/s12016-015-8471-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Organ-specific and systemic autoimmune diseases share numerous features and often coexist in the same patient. Autoimmune cholangitis/primary biliary cirrhosis and Sjogren syndrome represent paradigmatic examples of the common grounds of different autoimmunity phenotypes based on similarities in clinical manifestations and immunopathogenesis. In fact, primary biliary cirrhosis and Sjogren's syndrome have both been coined as an autoimmune epithelitis in which apoptosis may be in both cases the key element to explain the organ-specific immune-mediated injury against the biliary and exocrine gland epithelia, respectively. Further, growing evidence supports in both diseases the view that B cells, T cytotoxic cells, and T helper cells are involved in chronic inflammation, likely via the altered expression of pro-inflammatory cytokines. The presence of estrogen receptors on the biliary and exocrine gland epithelia has been advocated as a key to the female predominance encountered in primary biliary cirrhosis and Sjogren's syndrome. Sadly, despite available data, therapeutic approaches remain largely unsatisfactory and recent studies with mechanistic approaches (as in the case of B cell depletion with rituximab) have been of partial benefit only. Future studies should focus on new molecular tools (single-cell transcriptomics, microRNA, epigenetics) to provide unique insights into common mechanisms.
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38
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Floreani A, Franceschet I, Perini L, Cazzagon N, Gershwin ME, Bowlus CL. New therapies for primary biliary cirrhosis. Clin Rev Allergy Immunol 2016; 48:263-72. [PMID: 25331740 DOI: 10.1007/s12016-014-8456-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Primary biliary cirrhosis (PBC) is a rare inflammatory liver disease for which ursodeoxycholic acid (UDCA) is the only therapy approved by the U.S. Food and Drug Administration. Patients with a biochemical response to UDCA therapy have a similar survival rate compared to the general population. However, up to 40% of PBC patients do not achieve a complete response to UDCA, have an increased risk of liver-related death and liver transplantation, and represent a persistent medical need for new therapies. Several novel drugs have recently been studied and show potential efficacy in PBC. Obeticholic acid, a farnesoid X receptor agonist, has been tested in phase II trials and initial results after 1 year in a phase III international trial suggest that it may be effective in achieving a biochemical response in approximately 40% of patients who do not completely respond to UDCA. Several small studies on fibrates have suggested that they may have efficacy, but larger studies are needed. Surprisingly, results of immunomodulators and biologics have not yet been able to demonstrate efficacy, but new approaches have shown promise in animal models and their translation to human clinical trials are awaited.
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Affiliation(s)
- Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy,
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39
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Agmon-Levin N, Kopilov R, Selmi C, Nussinovitch U, Sánchez-Castañón M, López-Hoyos M, Amital H, Kivity S, Gershwin EM, Shoenfeld Y. Vitamin D in primary biliary cirrhosis, a plausible marker of advanced disease. Immunol Res 2015; 61:141-6. [PMID: 25424577 DOI: 10.1007/s12026-014-8594-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Vitamin D immune-modulating effects were extensively studied, and low levels have been linked with autoimmune diseases. The associations of vitamin D with autoimmune diseases of the liver, and particularly primary biliary cirrhosis (PBC), are yet to be defined. Hence, in this study, serum levels of vitamin D were determined in 79 patients with PBC and 70 age- and sex-matched controls by the LIAISON chemiluminescent immunoassays (DiaSorin-Italy). Clinical and serological parameters of patients were analyzed with respect to vitamin D status. Mean levels of vitamin D were significantly lower among patients with PBC compared with controls (16.8 ± 9 vs. 22.1 ± 9 ng/ml; p = 0.029), and vitamin D deficiency (≤10 ng/ml) was documented in 33% of patients with PBC versus 7% of controls (p < 0.0001). Vitamin D levels inversely correlated with advanced liver damage and the presence of concomitant autoimmune diseases. In contrast, higher levels of vitamin D were observed among patients with PBC treated with ursodeoxycholic acid (UDCA). In conclusion, low vitamin D levels are common among patients with PBC and correlate with advanced disease, lack of UDCA therapy and autoimmune comorbidity. This alludes to the plausible roles of vitamin D as a prognostic marker of PBC severity, and as a potential player in this disease pathogenesis. While further studies are awaited, monitoring vitamin D in patients with PBC and use of supplements may be advisable.
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Affiliation(s)
- Nancy Agmon-Levin
- The Zabludowicz Center for Autoimmune Diseases, Chaim Sheba Medical Center, 52621, Tel Hashomer, Israel
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40
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Kouroumalis E, Notas G. Primary biliary cirrhosis: From bench to bedside. World J Gastrointest Pharmacol Ther 2015; 6:32-58. [PMID: 26261733 PMCID: PMC4526840 DOI: 10.4292/wjgpt.v6.i3.32] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 11/19/2014] [Accepted: 05/18/2015] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic non-suppurative destructive intrahepatic cholangitis leading to cirrhosis after a protractive non cirrhotic stage. The etiology and pathogenesis are largely unknown and autoimmne mechanisms have been implicated to explain the pathological lesions. Many epitopes and autoantigens have been reported as crucial in the pathophysiology of the disease and T and B cells abnormalities have been described, the exact pathways leading to the destruction of small intrahepatic ductules are mostly speculative. In this review we examined the various epidemiologal and geoepidemiological data as well as the complex pathogenetic aspects of this disease, focusing on recent in vivo and in vitro studies in this field. Initiation and progression of PBC is believed to be a multifactorial process with strong infuences from the patient’s genetic background and by various environmental factors. The role of innate and adaptive immunity, including cytokines, chemokines, macrophages and the involvement of apoptosis and reactive oxygen species are outlined in detailed. The current pathogenetic aspects are presented and a novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated. A review of clinical manifestations and immunological and pathological diagnosis was presented. Treatment modalities, including the multiple mechanisms of action of ursodeoxycholate were finally discussed.
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41
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Reshetnyak VI. Primary biliary cirrhosis: Clinical and laboratory criteria for its diagnosis. World J Gastroenterol 2015; 21:7683-7708. [PMID: 26167070 PMCID: PMC4491957 DOI: 10.3748/wjg.v21.i25.7683] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 04/07/2015] [Accepted: 06/10/2015] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic granulomatous, and destructive inflammatory lesion of small intralobular and septal bile ducts, which is likely to be caused by an autoimmune mechanism with a the presence of serum antimitochondrial antibodies and a potential tendency to progress to cirrhosis. Despite the fact that the etiology of this disease has been unknown so far, there has been a considerable body of scientific evidence that can reveal the clinical and laboratory signs of PBC and the individual components of its pathogenesis and elaborate diagnostic criteria for the disease and its symptomatic therapy. Deficiencies in autoimmune tolerance are critical factors for the initiation and perpetuation of the disease. The purpose of this review is to summarize the data available in the literature and the author's findings on clinical and laboratory criteria for the diagnosis of PBC. This review describes the major clinical manifestations of the disease and the mechanisms of its development. It presents the immunological, biochemical, and morphological signs of PBC and their significance for its diagnosis. A great deal of novel scientific evidence for the problem of PBC has been accumulated. However, the inadequate efficiency of therapy for the disease lends impetus to the quest for its etiological factors and to further investigations of its pathogenetic mechanisms and, on this basis, to searches for new methods for its early diagnosis.
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Hu S, Zhao F, Wang Q, Chen WX. The accuracy of the anti-mitochondrial antibody and the M2 subtype test for diagnosis of primary biliary cirrhosis: a meta-analysis. Clin Chem Lab Med 2015; 52:1533-42. [PMID: 24501161 DOI: 10.1515/cclm-2013-0926] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 01/07/2014] [Indexed: 12/14/2022]
Abstract
The aim of this study was to evaluate the diagnostic value of anti-mitochondrial antibodies (AMAs) and/or the M2 subtype (AMA-M2) in patients with primary biliary cirrhosis (PBC). AMA/AMA-M2 data were obtained by searching electronic databases. Studies showing AMA/AMA-M2 results in patients with PBC and control groups with other liver diseases or healthy livers were included. The quality of the involved studies was assessed using the QUADAS tool. The pooled sensitivity and specificity were calculated, and stratified analysis was performed according to possible heterogeneity sources. The pooled AMA (all methods) sensitivity and specificity were 84.5% (95% confidence interval (CI) 83.3%-85.6%) and 97.8% (95% CI 97.6%-98.0%), respectively. The positive and negative likelihood ratios were 25.201 (95% CI 17.583-36.118) and 0.162 (95% CI 0.131-0.199), respectively. The current evidence suggests that AMA and AMA-M2 show favorable accuracy for the diagnosis of PBC with high specificity and sensitivity. AMA is a better and more comprehensive marker than AMA-M2. The accuracy established in this meta-analysis is based on clinical studies using patient cohorts from different ethnicities.
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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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Monoe K, Takahashi A, Abe K, Kanno Y, Watanabe H, Ohira H. Evaluation of nail fold capillaroscopy findings in patients with primary biliary cirrhosis. Hepatol Res 2014; 44:E129-36. [PMID: 24119054 DOI: 10.1111/hepr.12255] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Revised: 09/26/2013] [Accepted: 09/30/2013] [Indexed: 02/08/2023]
Abstract
AIM Some patients with primary biliary cirrhosis (PBC) experience Raynaud's phenomenon. The objective of this study was to clarify the relationships between nail fold capillaroscopy findings and clinical presentations of PBC. METHODS A total of 70 patients with PBC and 57 patients with non-PBC liver diseases, including 44 patients with chronic viral hepatic disease, eight with autoimmune hepatitis and five with non-alcoholic fatty liver disease, were included in this study. Nail fold capillaroscopy findings were classified as normal or abnormal and were further graded as mild, moderate or severe, and the relationships between frequency of abnormal blood vessel and their clinical presentations were examined. RESULTS The frequency of abnormal nail fold capillaroscopy findings was significantly higher in PBC patients (54.3%) than in patients with non-PBC liver disease (13.8%) (P < 0.01). These abnormal findings observed in PBC patients were graded as mild in 15 patients, moderate in 18 patients and severe in five patients. Significantly more PBC patients with abnormal capillaroscopy findings (19/38, 50%) were positive for anticentromere antibody than were those with normal capillaroscopy findings (3/32, 9.4%) (P < 0.01). CONCLUSION PBC patients had significantly higher frequency of abnormal nail fold capillaroscopy findings than did patients with non-PBC liver disease.
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Affiliation(s)
- Kyoko Monoe
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
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Abstract
Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease characterised by a breakdown of immune tolerance to mitochondrial and nuclear antigens, causing injury to the biliary epithelial cells (BEC) lining the small intrahepatic bile ducts. This leads to bile duct injury and the retention of hydrophobic bile acids which cause further BEC injury leading to a self-sustaining cycle of bile duct injury. Initially the BEC respond to injury via a homeostatic response including through proliferation. Ultimately they become senescent; an active process with accompanying release of inflammatory cytokines ('the senescent secretome') which contributes to the process of interface hepatitis which is a feature of high-risk and treatment-unresponsive disease. This model for pathogenesis of PBC has implications for potential therapy approaches in targeting both the 'upstream' immune injury and 'downstream' BEC response to the immune injury. Fatigue is the commonest reported symptom in PBC and has a negative impact on patients' perceived quality of life, often through social isolation. It is unrelated to the severity of liver disease and appears unresponsive to current therapies, including ursodeoxycholic acid and transplantation. Fatigue in PBC is complex, with numerous associated peripheral and CNS features. Initially, cholestasis causes degenerative CNS change affecting areas of the brain regulating autonomic dysfunction and sleep, and these changes lead directly to some manifestations of fatigue and the associated cognitive impairment. In addition to this, the anti-mitochondrial antibody has direct muscle level metabolic effects leading to over-utilisation of anaerobic metabolism. Autonomic dysfunction contributes to the impact of this metabolic change by limiting the capacity of the muscle to respond through increased proton/lactate efflux from cells and outflow from tissues. The model has a number of implications for potential therapy approaches.
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Affiliation(s)
- Laura Griffiths
- Institute of Cellular Medicine, Newcastle University and Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK
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Hu SL, Zhao FR, Hu Q, Chen WX. Meta-analysis assessment of GP210 and SP100 for the diagnosis of primary biliary cirrhosis. PLoS One 2014; 9:e101916. [PMID: 25010534 PMCID: PMC4092088 DOI: 10.1371/journal.pone.0101916] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 06/10/2014] [Indexed: 01/26/2023] Open
Abstract
PURPOSE To conduct a systematic review of included studies assessing the association of GP210 and SP100 with the risk of primary biliary cirrhosis (PBC) using meta-analysis. METHODS Five databases, the Cochrane Library, MEDLINE, VIP, CNKI, WANFANG were used to detect the role of GP210 and SP100 in diagnosis of PBC. Approximately 13,000 participants from several countries were included in this analysis. Meta-DiSc statistical software was used for analysis. RESULTS 25 studies on GP210 and 21 studies on SP100 were included in the meta-analysis. The DOR, sensitivity, specificity of GP210 in diagnosis of PBC were 24.854 (11.957-51.660), 0.272 (0.257-0.288), 0.985 (0.982-0.988), respectively, and they were 9.133 (4.739-17.600), 0.231 (0.213-0.249), 0.977 (0.973-0.981) for SP100. CONCLUSION Our meta-analysis indicated both GP210 and SP100 had high specificity but low sensitivity in diagnosis of PBC.
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Affiliation(s)
- Shi-Ling Hu
- The Department of Laboratory Medicine, the Second Hospital Affiliated to Chongqing Medical University, Chongqing, China
| | - Feng-Rong Zhao
- The Department of Gynecology and obstetrics, Youyang People’s Hospital, Chongqing, China
| | - Qin Hu
- The Department of Laboratory Medicine, the Second Hospital Affiliated to Chongqing Medical University, Chongqing, China
| | - Wei-Xian Chen
- The Department of Laboratory Medicine, the Second Hospital Affiliated to Chongqing Medical University, Chongqing, China
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Tsuneyama K, Baba H, Kikuchi K, Nishida T, Nomoto K, Hayashi S, Miwa S, Nakajima T, Nakanishi Y, Masuda S, Terada M, Imura J, Selmi C. Autoimmune features in metabolic liver disease: a single-center experience and review of the literature. Clin Rev Allergy Immunol 2014; 45:143-8. [PMID: 23842720 DOI: 10.1007/s12016-013-8383-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is the progressive phenotype of non-alcoholic fatty liver disease associated with the metabolic syndrome. The existence of autoimmune features in NASH has been reported, but its significance remains unclear. We herein report the autoantibody profile of 54 patients with histologically proven NASH and further determined the development of autoimmunity in three different murine NASH models (monosodium glutamate, CDAA (choline-deficient L-amino acid-defined), and TSOD (Tsumura Suzuki, Obese Diabetes)) at 48 weeks of age. Forty-eight percent (26/54) of NASH cases were positive for antinuclear (ANA) or antimitochondrial antibody and manifested histological signs of overlap with autoimmune hepatitis and primary biliary cirrhosis, respectively. These patients were significantly older (60 ± 10 versus 50 ± 16 years), more frequently women (81 % versus 43 %), and with more severe portal inflammatory infiltrate compared with patients without autoimmunity. In one third of mice, regardless of the model, we observed a marked lymphoid infiltrate with non-suppurative cholangitis, and several cases were ANA-positive, but none AMA-positive. Our data suggest that autoimmunity may share some pathogenetic traits with the chronic inflammation of NASH, possibly related to advanced age.
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Affiliation(s)
- Koichi Tsuneyama
- Department of Diagnostic Pathology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan.
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Zhao DT, Liao HY, Zhang X, Liu YM, Zhao Y, Zhang HP, Sun LM, Ma YX, Yan HP. Human leucocyte antigen alleles and haplotypes and their associations with antinuclear antibodies features in Chinese patients with primary biliary cirrhosis. Liver Int 2014; 34:220-6. [PMID: 23809616 DOI: 10.1111/liv.12236] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 05/28/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Primary biliary cirrhosis (PBC) is an autoimmune liver disease. Genetic factors are critical in determining susceptibility to PBC. Among human leuocyte antigen (HLA) genes, an association between the DRB1*08 allele and PBC has been reported in many populations, but not in Chinese patients. METHODS We investigated HLA-A, B, DRB1, and DQB1 alleles and haplotypes in 145 PBC patients and 500 healthy subjects. Patients were also stratified according to autoantibody features, and associations between these and HLA alleles were analyzed. RESULTS Significant associations existed between HLA-DRB1*08:03 (22.1% vs. 9.0%, Pc < 0.0001, OR = 2.86), DQ2 (41.4% vs. 25.4%, Pc < 0.0001, OR = 2.07) and DQB1*06:01 (31.0% vs. 17.8%, Pc = 0.014, OR = 2.08) alleles and PBC. DRB1*08:03-DQB1*06:01 (22.1% vs. 8.2%, P < 0.0001, OR = 3.17) and DRB1*07:01-DQB1*02:02 haplotypes (28.3% vs. 17.6%, P = 0.005, OR = 1.85) were also associated with PBC susceptibility. In contrast, the DQB1*03:01 allele (21.4% vs. 39.2%, Pc < 0.0001, OR = 0.42) and DRB1*12:02-DQB1*03:01 haplotype (6.9% vs. 14.6%, P = 0.015, OR = 0.43) were significantly decreased in PBC patients compared with controls. DRB1*14:54 and DQ5(1) protected against antinuclear antibody (ANA) (OR = 0.25) and anti-gp210 antibody (OR = 0.39) production, respectively, while HLA-B*44:03 predisposed patients to anti-gp210 antibody (OR = 5.70) production. CONCLUSION These results suggest that Chinese patients with PBC have a distinct genetic background in eastern Asia, and we confirmed the role of HLA genes in determining PBC susceptibility and autoantibody features in the Chinese population.
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Affiliation(s)
- Dan-Tong Zhao
- Clinical Research Center for Autoimmune Liver Disease, Beijing You'an Hospital, Capital Medical University, Beijing, China
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Abstract
Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by the immune mediated destruction of small intrahepatic bile duct epithelial cells leading to cholestasis and cirrhosis. The autoimmune basis of PBC is supported by the highly specific anti-mitochondrial antibodies (AMAs) and autoreactive T cells, the former being the basis for diagnosis in the vast majority of cases. Although a rare disease, the incidence rates of PBC have been increasing, possibly due to increased testing and diagnosis as opposed to a true increase in disease incidence. Presently, most cases are asymptomatic and only suspected based upon routine liver tests. Those with symptoms typically complain of pruritus and fatigue. The diagnosis of PBC is based on the presence of at least 2 of 3 key criteria including a persistently elevated serum alkaline phosphatase, the presence of serum AMAs, and liver histology consistent with PBC. Anti-nuclear antibodies specific to PBC are useful in cases in which AMAs are not detected and may indicate a more aggressive course. Ursodeoxycholic acid is the only proven therapy for PBC and in most cases can delay or prevent disease progression. However, a subgroup of patients does not adequately respond to ursodeoxycholic acid and for whom new therapies are needed.
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Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis, United States; Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, United States.
| | - M Eric Gershwin
- Division of Gastroenterology and Hepatology, University of California Davis, United States; Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, United States
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