|
1
|
Xu Q, Zhu W, Yin Y. Diagnostic value of anti-mitochondrial antibody in patients with primary biliary cholangitis: A systemic review and meta-analysis. Medicine (Baltimore) 2023; 102:e36039. [PMID: 37960792 PMCID: PMC10637435 DOI: 10.1097/md.0000000000036039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 10/19/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Anti-mitochondrial antibodies (AMA) and the M2 subtype are considered serological hallmarks in the diagnosis of primary biliary cholangitis (PBC). However, these autoantibodies may be undetectable in some patients. This meta-analysis aimed to evaluate the diagnostic accuracy of serum AMA and M2 for PBC. METHODS We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library for relevant studies. Pooled sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), and diagnostic odds ratio (DOR) were calculated using a random-effects model. We also constructed hierarchical summary receiver operating characteristic curves and calculated the area under the curve values. RESULTS Our meta-analysis included 28 studies, of which 24 examined the diagnostic accuracy of AMA for PBC. Pooled sensitivity and specificity of AMA were 84% (95% confidence intervals [CI] 77-90%) and 98% (96-99%), respectively. Pooled LR+, LR-, and DOR were 42.2 (22.1-80.5), 0.16 (0.11-0.24), and 262 (114-601), respectively. Sixteen studies explored the diagnostic value of the M2 subtype, demonstrating pooled sensitivity and specificity of 89% (81-94%) and 96% (93-98%), respectively. Pooled LR+, LR-, and DOR were 20.3 (8.0-51.1), 0.12 (0.05-0.26), and 169 (41-706), respectively. The hierarchical summary receiver operating characteristic curves for both of serum AMA and M2 subtype lie closer to the upper left corner of the plot with area under the curve values of 0.98 (95% CI = 0.96-0.99) and 0.98 (95% CI = 0.96-0.99) respectively. CONCLUSION This meta-analysis provides evidence affirming the utility of AMA and M2 as sensitive and specific serological hallmarks that can facilitate early screening and diagnosis of PBC.
Collapse
Affiliation(s)
- Qingling Xu
- Department of Gastroenterology, Wuxi Xinwu District Xinrui Hospital, Jiangsu Wuxi, China
| | - Weijia Zhu
- Department of Gastroenterology, Wuxi Xinwu District Xinrui Hospital, Jiangsu Wuxi, China
| | - Yufeng Yin
- Department of Rheumatology, The First Affiliated Hospital of Soochow University, Jiangsu Suzhou, China
| |
Collapse
|
|
2
|
Gatselis NK, Zachou K, Loza AJM, Cançado ELR, Arinaga-Hino T, Muratori P, Efe C, Floreani A, Invernizzi P, Takahashi A, Takaki A, Beretta-Piccoli BT, van Hoek B, Lytvyak E, Guedes LV, Purnak T, Cazzagon N, Lygoura V, Arvaniti P, Rigopoulou EI, Muratori L, Dalekos GN. Prevalence and significance of antimitochondrial antibodies in autoimmune hepatitis (AIH): Results from a large multicentre study of the International AIH Group. Eur J Intern Med 2023; 116:43-50. [PMID: 37302951 DOI: 10.1016/j.ejim.2023.06.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/21/2023] [Accepted: 06/06/2023] [Indexed: 06/13/2023]
Abstract
BACKGROUND & AIMS Antimitochondrial antibodies (AMA) are specific markers for the diagnosis of primary biliary cholangitis (PBC) but can also be found occasionally in patients with autoimmune hepatitis (AIH). The present large multicentre cohort study assessed the prevalence and significance of AMA in AIH-patients. METHODS 123 AMA-positive AIH-patients were investigated and compared with 711 age-matched AMA-negative AIH-patients and 69 patients with AIH/PBC variant. RESULTS AMA prevalence in AIH-patients was 5.1% (range: 1.2%-11.8%). AMA-positivity was associated with female sex (p = 0.031) in AMA-positive AIH-patients but not with liver biochemistry, bile duct injury on liver biopsy, disease severity at baseline and response to treatment compared to AMA-negative AIH-patients. Comparing AMA-positive AIH-patients to those with AIH/PBC variant, there was no difference in disease severity. Regarding liver histology, AIH/PBC variant patients were characterized by the presence of at least one feature of bile duct damage (p<0.001). Response to immunosuppressive treatment was similar among groups. From AMA-positive AIH patients only those with evidence of non-specific bile duct injury had higher risk to progress to cirrhosis (HR=4.314, 95%CI: 2.348-7.928; p<0.001). During follow-up, AMA-positive AIH-patients had higher risk to develop histological bile duct injury (HR 4.654, 95%CI 1.829-11.840; p = 0.001). CONCLUSIONS AMA presence is relatively common among AIH-patients, but their clinical significance seems important only when they co-exist with non-specific bile duct injury at the histological level. Therefore, a careful evaluation of liver biopsy seems of utmost importance in these patients.
Collapse
Affiliation(s)
- 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
| | - Kalliopi Zachou
- 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
| | - Aldo J Montano Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Canada
| | | | - Teruko Arinaga-Hino
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Paolo Muratori
- Division of Internal Medicine, Morgagni-Pierantoni Hospital, Forlì 47100, Department of Science for the Quality of Life, University of Bologna, Bologna, Italy
| | - Cumali Efe
- Department of Gastroenterology, Gazi Yaşargil Education and Research Hospital, Diyarbakir, Turkey
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; Scientific Institute for Research, Hospitalization and Healthcare, Negrar, Verona, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Centre 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
| | - Athushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine Fukushima, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | | | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Ellina Lytvyak
- Division of Preventive Medicine, University of Alberta, Edmonton, Canada
| | - Laura Vilar Guedes
- University of Sao Paulo, School of Medicine, Department of Gastroenterology, Sao Paulo, Brazil
| | - Tugrul Purnak
- Department of Gastroenterology, Hacettepe University, Ankara, Turkey
| | - Nora Cazzagon
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Vasiliki Lygoura
- 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
| | - Pinelopi Arvaniti
- 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
| | - 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, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Luigi Muratori
- Division of Internal Medicine, Morgagni-Pierantoni Hospital, Forlì 47100, Department of Science for the Quality of Life, University of Bologna, Bologna, Italy
| | - 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.
| |
Collapse
|
|
3
|
Guadalupi G, Contini C, Iavarone F, Castagnola M, Messana I, Faa G, Onali S, Chessa L, Vitorino R, Amado F, Diaz G, Manconi B, Cabras T, Olianas A. Combined Salivary Proteome Profiling and Machine Learning Analysis Provides Insight into Molecular Signature for Autoimmune Liver Diseases Classification. Int J Mol Sci 2023; 24:12207. [PMID: 37569584 PMCID: PMC10418803 DOI: 10.3390/ijms241512207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are autoimmune liver diseases that target the liver and have a wide spectrum of presentation. A global overview of quantitative variations on the salivary proteome in presence of these two pathologies is investigated in this study. The acid-insoluble salivary fraction of AIH and PBC patients, and healthy controls (HCs), was analyzed using a gel-based bottom-up proteomic approach combined with a robust machine learning statistical analysis of the dataset. The abundance of Arginase, Junction plakoglobin, Desmoplakin, Hexokinase-3 and Desmocollin-1 decreased, while that of BPI fold-containing family A member 2 increased in AIHp compared to HCs; the abundance of Gelsolin, CD14, Tumor-associated calcium signal transducer 2, Clusterin, Heterogeneous nuclear ribonucleoproteins A2/B1, Cofilin-1 and BPI fold-containing family B member 2 increased in PBCp compared to HCs. The abundance of Hornerin decreased in both AIHp and PBCp with respect to HCs and provided an area under the ROC curve of 0.939. Machine learning analysis confirmed the feasibility of the salivary proteome to discriminate groups of subjects based on AIH or PBC occurrence as previously suggested by our group. The topology-based functional enrichment analysis performed on these potential salivary biomarkers highlights an enrichment of terms mostly related to the immune system, but also with a strong involvement in liver fibrosis process and with antimicrobial activity.
Collapse
Affiliation(s)
- Giulia Guadalupi
- Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09124 Cagliari, Italy; (G.G.); (C.C.); (T.C.); (A.O.)
| | - Cristina Contini
- Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09124 Cagliari, Italy; (G.G.); (C.C.); (T.C.); (A.O.)
| | - Federica Iavarone
- Fondazione Policlinico Universitario IRCCS “A. Gemelli”, 00168 Rome, Italy;
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Massimo Castagnola
- Laboratorio di Proteomica, Centro Europeo di Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, 00168 Rome, Italy;
| | - Irene Messana
- Istituto di Scienze e Tecnologie Chimiche “Giulio Natta”, Consiglio Nazionale delle Ricerche, 00168 Rome, Italy;
| | - Gavino Faa
- Division of Pathology, Department of Medical Sciences and Public Health, University Hospital, 09124 Cagliari, Italy;
| | - Simona Onali
- Liver Unit, University Hospital of Cagliari, 09124 Cagliari, Italy; (S.O.); (L.C.)
| | - Luchino Chessa
- Liver Unit, University Hospital of Cagliari, 09124 Cagliari, Italy; (S.O.); (L.C.)
| | - Rui Vitorino
- iBiMED, Department of Medical Science, University of Aveiro, 3810-193 Aveiro, Portugal;
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal
| | - Francisco Amado
- LAQV/REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal;
| | - Giacomo Diaz
- Dipartimento di Scienze Biomediche, Università di Cagliari, 09124 Cagliari, Italy;
| | - Barbara Manconi
- Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09124 Cagliari, Italy; (G.G.); (C.C.); (T.C.); (A.O.)
| | - Tiziana Cabras
- Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09124 Cagliari, Italy; (G.G.); (C.C.); (T.C.); (A.O.)
| | - Alessandra Olianas
- Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09124 Cagliari, Italy; (G.G.); (C.C.); (T.C.); (A.O.)
| |
Collapse
|
|
4
|
Savino S, Nicola B, Luigi MP, Dimitrios B, Borghi MO, Xavier B, Grossi C, Tornai D, Papp M, Shoenfeld Y, Ielo D, Fritzler MJ. Autoantibodies testing in autoimmunity: Diagnostic, prognostic and classification value. Autoimmun Rev 2023; 22:103356. [PMID: 37150488 DOI: 10.1016/j.autrev.2023.103356] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 05/04/2023] [Indexed: 05/09/2023]
Abstract
Diagnosis of autoimmune diseases 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 conditions. This review focused on the current knowledge of the role of autoantibodies' testing in various diseases, such as systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome, undifferentiated connective tissues disease, primary biliary cirrhosis and primary sclerosing cholangitis. Similarly, the prognostic and diagnostic values of autoantibodies testing in patients with interstitial lung disease have been reviewed. In-depth research on the molecular action of these autoantibodies on immune regulation and diseases pathogenesis has been explored beyond their correlation with disease phenotypes, highlighting the impact of autoantibodies targeting on disease outcomes and etiopathogenesis.
Collapse
Affiliation(s)
- Sciascia Savino
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) with Nephrology and Dialysis Unit and Center of Immuno-Rheumatology and Rare Diseases, Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hub Hospital, Turin, Italy
| | - Bizzaro Nicola
- Laboratory of Clinical Pathology, Azienda Sanitaria Universitaria Integrata di Udine, Tolmezzo, Italy
| | - Meroni Pier Luigi
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Laboratory of Immuno-Rheumatology, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Italy
| | - Bogdanos Dimitrios
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - M O Borghi
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Laboratory of Immuno-Rheumatology, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Italy
| | - Bossuyt Xavier
- Clinical and diagnostic immunology, Department of Microbiology, Immunology and transplantation, KU Leuven, Leuven, Belgium; Department of laboratory medicine, UZ Leuven, Leuven, Belgium
| | - C Grossi
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Laboratory of Immuno-Rheumatology, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Italy
| | - Dávid Tornai
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, European Reference Network on Hepatological Diseases, ERN RARE-LIVER, Hungary
| | - Maria Papp
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, European Reference Network on Hepatological Diseases, ERN RARE-LIVER, Hungary
| | - Yehuda Shoenfeld
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Zabludowicz Center for Autoimmune Diseases, Chaim Sheba Medical Center, Israel
| | | | - Marvin J Fritzler
- Department of Medicine, Cumming School of Medicine, Calgary, Alberta, Canada
| |
Collapse
|
|
5
|
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.
Collapse
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
| |
Collapse
|
|
6
|
Hayrapetyan H, Tran T, Tellez-Corrales E, Madiraju C. Enzyme-Linked Immunosorbent Assay: Types and Applications. Methods Mol Biol 2023; 2612:1-17. [PMID: 36795355 DOI: 10.1007/978-1-0716-2903-1_1] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
Enzyme-linked immunosorbent assay (ELISA) is an immunological assay widely used in basic science research, clinical application studies, and diagnostics. The ELISA technique relies on the interaction between the antigen (i.e., the target protein) versus the primary antibody against the antigen of interest. The presence of the antigen is confirmed through the enzyme-linked antibody catalysis of the added substrate, the products of which are either qualitatively detected by visual inspection or quantitatively using readouts from either a luminometer or a spectrophotometer. ELISA techniques are broadly classified into direct, indirect, sandwich, and competitive ELISA-all of which vary based on the antigens, antibodies, substrates, and experimental conditions. Direct ELISA relies on the binding of the enzyme-conjugated primary antibodies to the antigen-coated plates. Indirect ELISA introduces enzyme-linked secondary antibodies specific to the primary antibodies bound to the antigen-coated plates. Competitive ELISA involves a competition between the sample antigen and the plate-coated antigen for the primary antibody, followed by the binding of enzyme-linked secondary antibodies. Sandwich ELISA technique includes a sample antigen introduced to the antibody-precoated plate, followed by sequential binding of detection and enzyme-linked secondary antibodies to the recognition sites on the antigen. This review describes ELISA methodology, the types of ELISA, their advantages and disadvantages, and a listing of some multifaceted applications both in clinical and research settings, including screening for drug use, pregnancy testing, diagnosing disease, detecting biomarkers, blood typing, and detecting SARS-CoV-2 that causes coronavirus disease 2019 (COVID-19).
Collapse
Affiliation(s)
- Hovhannes Hayrapetyan
- Marshall B. Ketchum University, Fullerton, CA, USA.,Wayne State University, School of Medicine, Detroit, MI, USA
| | - Thao Tran
- Marshall B. Ketchum University, Fullerton, CA, USA
| | | | | |
Collapse
|
|
7
|
Jaskowski TD, Nandakumar V, Novis CL, Palmer M, Tebo AE. Presence of anti-gp210 or anti-sp100 antibodies in AMA-positive patients may help support a diagnosis of primary biliary cholangitis. Clin Chim Acta 2023; 540:117219. [PMID: 36610465 DOI: 10.1016/j.cca.2023.117219] [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: 09/08/2022] [Revised: 12/08/2022] [Accepted: 01/02/2023] [Indexed: 01/06/2023]
Abstract
BACKGROUND Anti-mitochondrial antibody (AMA) positivity is not always associated with primary biliary cholangitis (PBC). We aimed to determine the additional value of anti-sp100 or anti-gp210 antibody in AMA-positive patients for PBC. METHODS Patients (n = 190) and healthy donors (n = 50) were evaluated for AMA, anti-gp210 and anti-sp100 antibodies by ELISA. Antibody frequencies in cohorts and performance characteristics in some patients categorized as 'definitive-', 'probable-', and 'no PBC' were determined following review of their charts. RESULTS Of the patients (n = 190), 38.4% were AMA-positive (n = 73) and 61.6% AMA-negative (n = 117). Frequency of anti-sp100 or anti-gp210 antibody was 17.8%, 2.6%, and 0% in AMA-positive, AMA-negative and healthy controls, respectively. Clinical data was available for 63 of 73 AMA-positive patients with 28.6%, 22.2%, and 49.2% categorized as definite, probable, and no PBC, respectively. Patients with definite PBC had higher mean levels of AMA and frequencies of sp100 or gp210 antibody compared to other groups. Sensitivities were low (anti-sp100: 18.8% and anti-gp210: 16.7%) with specificities above 98.0% for both. CONCLUSION AMA-positive patients positive for anti-sp100 or anti-gp210 antibody were more likely to have a diagnosis of definite or probable PBC than those with AMA alone. Use of all tests is likely to improve characterization of patients at-risk for PBC.
Collapse
Affiliation(s)
- Troy D Jaskowski
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States
| | - Vijayalakshmi Nandakumar
- Department of Pathology, University of Utah Health, Salt Lake City, UT, United States; ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States
| | - Camille L Novis
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States
| | - Michael Palmer
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States
| | - Anne E Tebo
- Department of Pathology, University of Utah Health, Salt Lake City, UT, United States; ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States.
| |
Collapse
|
|
8
|
Olianas A, Guadalupi G, Cabras T, Contini C, Serrao S, Iavarone F, Castagnola M, Messana I, Onali S, Chessa L, Diaz G, Manconi B. Top-Down Proteomics Detection of Potential Salivary Biomarkers for Autoimmune Liver Diseases Classification. Int J Mol Sci 2023; 24:959. [PMID: 36674470 PMCID: PMC9866740 DOI: 10.3390/ijms24020959] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/23/2022] [Accepted: 12/27/2022] [Indexed: 01/06/2023] Open
Abstract
(1) Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are autoimmune liver diseases characterized by chronic hepatic inflammation and progressive liver fibrosis. The possible use of saliva as a diagnostic tool has been explored in several oral and systemic diseases. The use of proteomics for personalized medicine is a rapidly emerging field. (2) Salivary proteomic data of 36 healthy controls (HCs), 36 AIH and 36 PBC patients, obtained by liquid chromatography/mass spectrometry top-down pipeline, were analyzed by multiple Mann-Whitney test, Kendall correlation, Random Forest (RF) analysis and Linear Discriminant Analysis (LDA); (3) Mann-Whitney tests provided indications on the panel of differentially expressed salivary proteins and peptides, namely cystatin A, statherin, histatin 3, histatin 5 and histatin 6, which were elevated in AIH patients with respect to both HCs and PBC patients, while S100A12, S100A9 short, cystatin S1, S2, SN and C showed varied levels in PBC with respect to HCs and/or AIH patients. RF analysis evidenced a panel of salivary proteins/peptides able to classify with good accuracy PBC vs. HCs (83.3%), AIH vs. HCs (79.9%) and PBC vs. AIH (80.2%); (4) RF appears to be an attractive machine-learning tool suited for classification of AIH and PBC based on their different salivary proteomic profiles.
Collapse
Affiliation(s)
- Alessandra Olianas
- Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09042 Cagliari, Italy
| | - Giulia Guadalupi
- Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09042 Cagliari, Italy
| | - Tiziana Cabras
- Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09042 Cagliari, Italy
| | - Cristina Contini
- Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09042 Cagliari, Italy
| | - Simone Serrao
- Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09042 Cagliari, Italy
| | - Federica Iavarone
- Fondazione Policlinico Universitario “A. Gemelli”—IRCCS, 00168 Rome, Italy
| | - Massimo Castagnola
- Laboratorio di Proteomica, Centro Europeo di Ricerca sul Cervello, IRCCS Fondazione Santa Lucia, 00179 Rome, Italy
| | - Irene Messana
- Istituto di Scienze e Tecnologie Chimiche “Giulio Natta”, Consiglio Nazionale delle Ricerche, 00168 Rome, Italy
| | - Simona Onali
- Liver Unit, University Hospital of Cagliari, 09042 Cagliari, Italy
| | - Luchino Chessa
- Liver Unit, University Hospital of Cagliari, 09042 Cagliari, Italy
- Dipartimento di Scienze Mediche e Sanità Pubblica, Università di Cagliari, 09042 Cagliari, Italy
| | - Giacomo Diaz
- Dipartimento di Scienze Biomediche, Università di Cagliari, 09042 Cagliari, Italy
| | - Barbara Manconi
- Dipartimento di Scienze della Vita e dell’Ambiente, Università di Cagliari, 09042 Cagliari, Italy
| |
Collapse
|
|
9
|
Leung KK, Hirschfield GM. Autoantibodies in Primary Biliary Cholangitis. Clin Liver Dis 2022; 26:613-627. [PMID: 36270719 DOI: 10.1016/j.cld.2022.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is a chronic immune-mediated liver disease characterized by a lymphocytic cholangitis, with subsequent cholestasis, progressive liver fibrosis, and ultimately complications arising from end-stage liver disease. Testing for autoantibodies is important in the diagnosis of PBC, as well as stratifying prognosis. This review focuses on the role of autoantibodies in the diagnosis of PBC, as well as the relationship between autoantibodies with pathophysiology and prognostication, along with a discussion regarding novel and other related disease autoantibodies.
Collapse
Affiliation(s)
- Kristel K Leung
- Department of Medicine, Division of Gastroenterology & Hepatology, University Health Network, University of Toronto, 200 Elizabeth Street, Eaton Building, 9th Floor, Toronto, Ontario M5G 2C4, Canada
| | - Gideon M Hirschfield
- Department of Medicine, Division of Gastroenterology & Hepatology, University Health Network, University of Toronto, 200 Elizabeth Street, Eaton Building, 9th Floor, Toronto, Ontario M5G 2C4, Canada.
| |
Collapse
|
|
10
|
Gaiani F, Minerba R, Picanza A, Russo A, Melegari A, De Santis E, Trenti T, Belloni L, Peveri S, Aloe R, Ferrari C, Laghi L, de’Angelis GL, Bonaguri C. Optimization of Laboratory Diagnostics of Primary Biliary Cholangitis: When Solid-Phase Assays and Immunofluorescence Combine. J Clin Med 2022; 11:5238. [PMID: 36079166 PMCID: PMC9457280 DOI: 10.3390/jcm11175238] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 08/31/2022] [Accepted: 09/02/2022] [Indexed: 11/23/2022] Open
Abstract
The laboratory diagnostics of primary biliary cholangitis (PBC) have substantially improved, thanks to innovative analytical opportunities, such as enzyme-linked immunosorbent assays (ELISA) and multiple immunodot liver profile tests, based on recombinant or purified antigens. This study aimed to identify the best diagnostic test combination to optimize PBC diagnosis. Between January 2014 and March 2017, 164 PBC patients were recruited at the hospitals of Parma, Modena, Reggio-Emilia, and Piacenza. Antinuclear antibodies (ANA) and anti-mitochondrial antibodies (AMA) were assayed by indirect immunofluorescence (IIF), ELISA, and immunodot assays (PBC Screen, MIT3, M2, gp210, and sp100). AMA-IIF resulted in 89.6% positive cases. Using multiple immunodot liver profiles, AMA-M2 sensitivity was 94.5%, while anti-gp210 and anti-sp100 antibodies were positive in 16.5% and 17.7% of patients, respectively. PBC screening yielded positive results in 94.5% of cases; MIT3, sp100, and gp210 were detected by individual ELISA test in 89.0%, 17.1%, and 18.9% of patients, respectively. The association of PBC screening with IIF-AMA improved the diagnostic sensitivity from 89.6% to 98.2% (p < 0.01). When multiple immunodot liver profile testing was integrated with AMA-IIF, the diagnostic sensitivity increased from 89.1% to 98.8% (p < 0.01). The combination of IIF with solid-phase methods significantly improved diagnostic efficacy in PBC patients.
Collapse
Affiliation(s)
- Federica Gaiani
- Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy
- Gastroenterology and Endoscopy Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Roberta Minerba
- Laboratory of Clinical Chemistry and Hematology, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Alessandra Picanza
- Laboratory of Clinical Chemistry and Hematology, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Annalisa Russo
- Laboratory of Clinical Chemistry and Hematology, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Alessandra Melegari
- Autoimmunity Unit, Department of Laboratory Medicine and Pathology, S. Agostino Estense Hospital, Via Giardini 1355, 41126 Baggiovara, Italy
| | - Elena De Santis
- Autoimmunity Unit, Department of Laboratory Medicine and Pathology, S. Agostino Estense Hospital, Via Giardini 1355, 41126 Baggiovara, Italy
| | - Tommaso Trenti
- Department of Laboratory Medicine and Pathology, S. Agostino Estense Hospital, Via Giardini 1355, 41126 Baggiovara, Italy
| | - Lucia Belloni
- Unit of Clinical Immunology, Allergy and Advanced Biotechnologies, Azienda Unità Sanitaria Locale—IRCCS of Reggio-Emilia, Viale Risorgimento 80, 42123 Reggio-Emilia, Italy
| | - Silvia Peveri
- Allergology Unit, Guglielmo da Saliceto Hospital, Via Giuseppe Taverna 49, 29121 Piacenza, Italy
| | - Rosalia Aloe
- Laboratory of Clinical Chemistry and Hematology, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Carlo Ferrari
- Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Luigi Laghi
- Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy
- Gastroenterology and Endoscopy Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Gian Luigi de’Angelis
- Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy
- Gastroenterology and Endoscopy Unit, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Chiara Bonaguri
- Laboratory of Clinical Chemistry and Hematology, University Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| |
Collapse
|
|
11
|
Diagnostic and Clinical Value of Specific Autoantibodies against Kelch-like 12 Peptide and Nuclear Envelope Proteins in Patients with Primary Biliary Cholangitis. Biomedicines 2022; 10:biomedicines10040801. [PMID: 35453551 PMCID: PMC9029829 DOI: 10.3390/biomedicines10040801] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/25/2022] [Accepted: 03/26/2022] [Indexed: 11/19/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by the presence of antimitochondrial and antinuclear antibodies in patients’ serum. Here, we analyzed the reactivity of autoantibodies against a novel autoantigen, kelch-like 12 (KLHL12) protein, in a cohort of 138 PBC and 90 non-PBC patients. Additionally, we compared the reactivity of KLHL12 with antinuclear envelope antibodies: anti-gp210, anti-p62, and anti-LBR. Commercially available kits and an ‘in-house’ ELISA were used in the studies. Antinuclear envelope antibodies were detected in 65% of PBC patients and the presence of these antibodies was observed more frequently in patients diagnosed with later stages (III/IV) of PBC, according to Ludwig’s classification (p < 0.05) and were found to correlate with a higher concentration of bilirubin. Overall, anti-KLHL12 antibodies were found more frequently in PBC patients than in non-PBC controls (p < 0.001). Anti-KLHL12 antibodies were detected in 36% of the tested PBC cohort, including PBC patients negative for antimitochondrial antibodies. Presence of anti-KLHL12 was also associated with a higher concentration of bilirubin and correlated with fibrosis (p < 0.05). Anti-KLHL12 antibodies were detected in 30% of PBC individuals positive for antinuclear envelope antibodies, while anti-KLHL12 and antinuclear envelope antibodies were found in 17% of all PBC cases. Concluding, our data confirm that antibodies against the KLHL12 protein are highly specific for PBC and when used in combination with other markers, may significantly increase the diagnosis of PBC.
Collapse
|
|
12
|
You H, Ma X, Efe C, Wang G, Jeong SH, Abe K, Duan W, Chen S, Kong Y, Zhang D, Wei L, Wang FS, Lin HC, Yang JM, Tanwandee T, Gani RA, Payawal DA, Sharma BC, Hou J, Yokosuka O, Dokmeci AK, Crawford D, Kao JH, Piratvisuth T, Suh DJ, Lesmana LA, Sollano J, Lau G, Sarin SK, Omata M, Tanaka A, Jia J. APASL clinical practice guidance: the diagnosis and management of patients with primary biliary cholangitis. Hepatol Int 2022; 16:1-23. [PMID: 35119627 PMCID: PMC8843914 DOI: 10.1007/s12072-021-10276-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 11/08/2021] [Indexed: 12/14/2022]
Affiliation(s)
- Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Xiong Ma
- Department of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, Mainland, China
| | - Cumali Efe
- Department of Gastroenterology, Gazi Yaşargil Education and Research Hospital, Diyarbakir, Turkey
| | - Guiqiang Wang
- Department of Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, Beijing, Mainland, China
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, South Korea
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Sha Chen
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| | - Yuanyuan Kong
- Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland, China
| | - Dong Zhang
- Experimental and Translational Research Center, Beijing Clinical Research Institute, Beijing, Mainland, China
| | - Lai Wei
- Hepatobiliary Pancreatic Center, Tsinghua Changgung Hospital, Tsinghua University, Beijing, Mainland, China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of PLA General Hospial, Beijing, Mainland, China
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jin Mo Yang
- Division of Hepatology, Department of Internal Medicine, College of Medicine, St. Vincent’s Hospital, The Catholic University of Korea, Suwon, South Korea
| | - Tawesak Tanwandee
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Rino A. Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Diana A. Payawal
- Department of Medicine, Fatima University Medical Center, Manila, Philippines
| | | | - Jinlin Hou
- Department of Infectious Disease and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Mainland, China
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - A. Kadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Darrell Crawford
- School of Medicine, University of Queensland, Brisbane, Australia
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand
| | - Dong Jin Suh
- Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, South Korea
| | | | - Jose Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - George Lau
- Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong SAR, China
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Tokyo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Beijing, Mainland, China
| |
Collapse
|
|
13
|
Cinquanta L, Infantino M, Bizzaro N. Detecting Autoantibodies by Multiparametric Assays: Impact on Prevention, Diagnosis, Monitoring, and Personalized Therapy in Autoimmune Diseases. J Appl Lab Med 2022; 7:137-150. [PMID: 34996071 DOI: 10.1093/jalm/jfab132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 10/07/2021] [Indexed: 11/13/2022]
Abstract
BACKGROUND The introduction of multiparametric autoantibody tests has been proposed to improve the accuracy of the immunological diagnosis of autoimmune diseases (AID) and to accelerate time for completing the diagnostic process. Multiplex tests are capable of detecting many autoantibodies in a single run whereas a traditional immunoassay uses a single antigen to detect only a single specificity of autoantibodies. The reasons why multiplex tests could replace conventional immunoassays lie in the evidence that they allow for more efficient handling of large numbers of samples by the laboratory, while ensuring greater diagnostic sensitivity in AID screening. CONTENT This review aims to highlight the important role that multiparametric tests could assume when designed for defined profiles they are used not only for diagnostic purposes but also to predict the onset of AID to identify clinical phenotypes and to define prognosis. Furthermore, differences in the antibody profile could identify which subjects will be responsive or not to a specific pharmacological treatment. SUMMARY The use of autoantibody profiles, when specifically requested and performed with clinically validated technologies, can represent a significant step toward personalized medicine in autoimmunology.
Collapse
Affiliation(s)
| | - Maria Infantino
- Laboratorio di Immunologia e Allergologia, Ospedale S. Giovanni di Dio, Firenze, Italy
| | - Nicola Bizzaro
- Laboratorio di Patologia Clinica, Ospedale San Antonio, Tolmezzo, Italy.,Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
| |
Collapse
|
|
14
|
Ben Lamine Z, Ben Jazia I, Ben Ahmed M, Ben Slama A, Baccouche A, Slama F, Jemaa A, Ghedira I, Mankaï A. Anti-gp210 and anti-Sp100 antibodies in primary biliary cholangitis. Arab J Gastroenterol 2021; 22:316-320. [PMID: 34090832 DOI: 10.1016/j.ajg.2021.05.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 11/29/2020] [Accepted: 05/06/2021] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND STUDY AIMS To determine the sensitivity and specificity of anti-gp210 and anti-Sp100 autoantibodies in primary biliary cholangitis (PBC) PATIENTS AND METHODS: Sera of 106 PBC patients with positive anti-mitochondrial antibodies and 58 healthy blood donors were analyzed. A line immunoassay was used to evaluate the reactivity of anti-gp210 and anti-Sp100 antibodies. RESULTS The frequency of anti-gp210 and anti-Sp100 autoantibodies was 29.2% and 28.3%, respectively. Eight patients had both anti-gp210 and anti-Sp100 antibodies. Of 106 patients, 23 (21.7%) had anti-gp210 antibody, although not anti-Sp100 antibody, and 22 (20.7%) had anti-Sp100, although not anti-gp210 antibodies. Their combination increased the frequency of anti-gp210 and anti-Sp100 antibodies from 29.2% to 50% (P = 0.002) and 28.3% to 50% (P = 0.0012), respectively. In the control group, two subjects had anti-gp210 antibody and none had anti-Sp100 antibody. Thus, the specificity of anti-gp210 and anti-Sp100 antibodies was 96.5% and 100%, respectively. The positive predictive value (PPV) of anti-gp210 antibody was 94%; its negative predictive value (NPV) was 42.7%. The PPV and NPV of anti-Sp100 antibody were 100% and 43.3%, respectively. CONCLUSION It is important to combine anti-gp210 and anti-Sp100 antibodies in the immunological exploration of PBC.
Collapse
Affiliation(s)
- Zeineb Ben Lamine
- Laboratory of Immunology, Farhat Hached University Hospital, Sousse, Tunisia.
| | - Ilhem Ben Jazia
- Department of Gastroenterology, Farhat Hached University Hospital, Sousse, Tunisia
| | - Mariem Ben Ahmed
- Laboratory of Immunology, Farhat Hached University Hospital, Sousse, Tunisia
| | - Ayda Ben Slama
- Department of Gastroenterology, Sahloul University Hospital, Sousse, Tunisia
| | - Azza Baccouche
- Department of Gastroenterology, Ibn El Jazzar Hospital, Kairouan, Tunisia
| | - Foued Slama
- Laboratory of Immunology, Research Unit UR 807, Faculty of Medicine, Sousse University, Tunisia
| | - Ali Jemaa
- Department of Gastroenterology, Sahloul University Hospital, Sousse, Tunisia
| | - Ibtissem Ghedira
- Laboratory of Immunology, Farhat Hached University Hospital, Sousse, Tunisia; Department of Immunology, Faculty of Pharmacy, Monastir University, Tunisia
| | - Amani Mankaï
- Laboratory of Immunology, Farhat Hached University Hospital, Sousse, Tunisia; High School of Sciences and Techniques of Health, Tunis El Manar University, Tunis, Tunisia.
| |
Collapse
|
|
15
|
Papamichalis PA, Zachou K, Papamichali RA, Ioannou M, Gatselis NK, Dalekos GN, Koukoulis GK. Promyelocytic Leukemia Antigen Expression: a Histological Marker for Primary Biliary Cholangitis Diagnosis? J Transl Int Med 2021; 9:43-51. [PMID: 33850801 PMCID: PMC8016348 DOI: 10.2478/jtim-2021-0008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Distinguishing primary biliary cholangitis (PBC) from other cholestatic diseases at the histological level could be assisted by new methods, such as immunohistochemical staining of specific antigens. METHODS We evaluated whether the detection of promyelocytic leukemia protein (PML) can serve as a specific and sensitive marker for PBC diagnosis. Liver biopsies from 26 PBC patients, 20 primary sclerosing cholangitis (PSC), 37 viral hepatitis, 11 non-alcoholic steatohepatitis (NASH) and 5 normal patients were investigated after immunostaining with the anti-PML monoclonal PG-M3, IgG1 antibody. RESULTS Immunoreactivity in bile ducts was expressed by the PML-score (quotient of positive ducts to the total number of portal tracts multiplied by 2). PML-score was higher in PBC as compared to controls (P < 0.001). Using a cutoff of 0.18, PML-score proved highly sensitive (84.6%) and specific (89.7%) for confirming PBC as compared to only 5% of PSC, 9.1% of NASH and 13.5% of viral hepatitis patients (P < 0.001). Irrespective of the underlying disease, patients with PML-score > 0.18 were older (P = 0.007), more often females (P < 0.001) with higher ALP (P < 0.001), γ-GT (P = 0.001) and IgM (P < 0.001) compared to the patients with PML-score < 0.18. CONCLUSIONS We postulate that a simple PML immunohistochemical test could be sufficient for histopathological discrimination of PBC in problematic cases of undefined cholestatic disorders, including small-duct PSC and AMA-negative PBC cases.
Collapse
Affiliation(s)
- Panagiotis A. Papamichalis
- Department of Pathology, Medical School, University of Thessaly, 41110Larissa, Greece
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110Larissa, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110Larissa, Greece
| | | | - Maria Ioannou
- Department of Pathology, Medical School, University of Thessaly, 41110Larissa, 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, 41110Larissa, Greece
| | - 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, 41110Larissa, Greece
| | - George K. Koukoulis
- Department of Pathology, Medical School, University of Thessaly, 41110Larissa, Greece
| |
Collapse
|
|
16
|
Abstract
Primary biliary cholangitis (PBC) causes chronic and persistent cholestasis in the liver, eventually resulting in cirrhosis and hepatic failure without appropriate treatment. PBC mainly develops in middle-aged women, but it is also common in young women and men. PBC is considered a model of autoimmune disease because of the presence of disease-specific autoantibodies, that is, antimitochondrial antibodies (AMAs), intense infiltration of mononuclear cells into the bile ducts, and a high prevalence of autoimmune diseases such as comorbidities. Histologically, PBC is characterized by degeneration and necrosis of intrahepatic biliary epithelial cells surrounded by a dense infiltration of mononuclear cells, coined as chronic non-suppurative destructive cholangitis, which leads to destructive changes and the disappearance of small- or medium-sized bile ducts. Since 1990, early diagnosis with the detection of AMAs and introduction of ursodeoxycholic acid as first-line treatment has greatly altered the clinical course of PBC, and liver transplantation-free survival of patients with PBC is now comparable to that of the general population.
Collapse
Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
17
|
Terziroli Beretta-Piccoli B, Stirnimann G, Mertens J, Semela D, Zen Y, Mazzucchelli L, Voreck A, Kolbus N, Merlo E, Di Bartolomeo C, Messina P, Cerny A, Costantini S, Vergani D, Mieli-Vergani G. Primary biliary cholangitis with normal alkaline phosphatase: A neglected clinical entity challenging current guidelines. J Autoimmun 2020; 116:102578. [PMID: 33229138 DOI: 10.1016/j.jaut.2020.102578] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 11/11/2020] [Accepted: 11/13/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIM The diagnosis of primary biliary cholangitis (PBC), an uncommon immune-mediated cholestatic liver disease, is based on positive circulating anti-mitochondrial (AMA) and/or PBC-specific anti-nuclear autoantibodies (ANA), coupled with elevated serum alkaline phopsphatase (ALP) levels. Timely initiation of treatment with ursodeoxycholic acid prevents progression to cirrhosis and liver failure. We aimed at investigating liver histology in patients with normal ALP level and positive AMA and/or PBC-specific ANA. METHODS We searched the Swiss PBC Cohort Study database, which includes subjects with positive PBC autoimmune serology and normal ALP levels, for patients who underwent a liver biopsy. Histological slides were centrally reviewed by an expert liver pathologist, and sera were centrally re-tested for AMA and ANA. RESULTS 30 patients were included; 90% females, median age 53 (range 27-72) years. Twenty-four (80%) had liver histology typical for (n = 2), consistent with (n = 16) or suggestive of (n = 6) PBC, including three of four AMA-negative ANA-positive patients. Among 22 ursodeoxycholic acid treated patients, 14 had elevated GGT levels before treatment; a significant decrease of the median GGT level between pre- (1.46 x ULN) and post- (0.43 x ULN) treatment (p = 0.0018) was observed. CONCLUSIONS In our series, a high proportion of AMA positive patients with normal ALP levels have PBC. For the first time we show histological diagnosis of PBC in AMA-negative/PBC-specific ANA-positive subjects and the potential role of GGT as a biomarker in PBC patients with normal baseline ALP levels. Current guidelines for the diagnosis of PBC do not cover the whole extent of PBC presentation, with important clinical implications in terms of timely treatment initiation.
Collapse
Affiliation(s)
| | - Guido Stirnimann
- Department of Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Joachim Mertens
- Gastroenterology and Hepatology Department, University Hospital Zurich, Zurich, Switzerland
| | - David Semela
- Gastroenterology and Hepatology Department, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Yoh Zen
- Institute of Liver Studies, MowatLabs, King's College London Faculty of Life Sciences & Medicine at King's College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom
| | | | | | | | | | | | | | - Andreas Cerny
- Epatocentro Ticino, Via Soldino 5, 6900, Lugano, Switzerland
| | - Silvia Costantini
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King's College London Faculty of Life Sciences & Medicine at King's College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College London Faculty of Life Sciences & Medicine at King's College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom
| | | |
Collapse
|
|
18
|
Zheng B, Mora RA, Fritzler MJ, Satoh M, Bloch DB, Garcia-De La Torre I, Boylan K, Kohl K, Wener MH, Andrade LEC, Chan EKL. Establishment of international autoantibody reference standards for the detection of autoantibodies directed against PML bodies, GW bodies, and NuMA protein. Clin Chem Lab Med 2020; 59:197-207. [PMID: 32776893 PMCID: PMC7855248 DOI: 10.1515/cclm-2020-0981] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 07/21/2020] [Indexed: 12/16/2022]
Abstract
Objectives: Reference materials are important in the standardization of autoantibody testing and only a few are freely available for many known autoantibodies. Our goal was to develop three reference materials for antibodies to PML bodies/multiple nuclear dots (MND), antibodies to GW bodies (GWB), and antibodies to the nuclear mitotic apparatus (NuMA). Methods: Reference materials for identifying autoantibodies to MND (MND-REF), GWB (GWB-REF), and NuMA (NuMA-REF) were obtained from three donors and validated independently by seven laboratories. The sera were characterized using indirect immunofluorescence assay (IFA) on HEp-2 cell substrates including two-color immunofluorescence using antigen-specific markers, western blot (WB), immunoprecipitation (IP), line immunoassay (LIA), addressable laser bead immunoassay (ALBIA), enzyme-linked immunosorbent assay (ELISA), and immunoprecipitation–mass spectrometry (IP-MS). Results: MND-REF stained 6–20 discrete nuclear dots that colocalized with PML bodies. Antibodies to Sp100 and PML were detected by LIA and antibodies to Sp100 were also detected by ELISA. GWB-REF stained discrete cytoplasmic dots in interphase cells, which were confirmed to be GWB using two-color immunofluorescence. Anti-Ge-1 antibodies were identified in GWB-REF by ALBIA, IP, and IP-MS. All reference materials produced patterns at dilutions of 1:160 or greater. NuMA-REF produced fine speckled nuclear staining in interphase cells and staining of spindle fibers and spindle poles. The presence of antibodies to NuMA was verified by IP, WB, ALBIA, and IP-MS. Conclusions: MND-REF, GWB-REF, and NuMA-REF are suitable reference materials for the corresponding antinuclear antibodies staining patterns and will be accessible to qualified laboratories.
Collapse
Affiliation(s)
- Bing Zheng
- Department of Oral Biology,University of Florida, Gainesville, FL, USA.,Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China
| | - Rodrigo A Mora
- Department of Oral Biology,University of Florida, Gainesville, FL, USA
| | - Marvin J Fritzler
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Minoru Satoh
- Department of Clinical Nursing, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Donald B Bloch
- Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ignacio Garcia-De La Torre
- Department of Immunology and Rheumatology, Hospital General de Occidente and University of Guadalajara, Guadalajara, Mexico
| | - Katherine Boylan
- Scientific & Clinical Affairs, Plasma Services Group Inc., Huntingdon Valley, PA, USA
| | - Kathryn Kohl
- Scientific & Clinical Affairs, Plasma Services Group Inc., Huntingdon Valley, PA, USA
| | - Mark H Wener
- Division of Rheumatology and Department of Laboratory Medicine,University of Washington, Seattle, WA, USA
| | - Luis E C Andrade
- Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.,Immunology Division, Fleury Laboratories, São Paulo, Brazil
| | - Edward K L Chan
- Department of Oral Biology,University of Florida, Gainesville, FL, USA
| |
Collapse
|
|
19
|
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.
Collapse
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
| |
Collapse
|
|
20
|
Bonaguri C, Melegari A, Picanza A, Russo A, De Santis E, Trenti T, Parmeggiani M, Belloni L, Savi E, de'Angelis GL, Gaiani F, Ferrari C, Lippi G. Association of solid-phase assays to the indirect immunofluorescence in primary biliary cholangitis diagnosis: Results of an Italian multicenter study. Autoimmun Rev 2019; 18:102389. [PMID: 31520799 DOI: 10.1016/j.autrev.2019.102389] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 06/09/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Chiara Bonaguri
- Laboratory of Clinical Chemistry and Hematology, University Hospital of Parma, Parma, Italy.
| | - Alessandra Melegari
- Department of Laboratory Medicine and Pathology, S.Agostino Estense Hospital, Modena, Italy
| | - Alessandra Picanza
- Laboratory of Clinical Chemistry and Hematology, University Hospital of Parma, Parma, Italy
| | - Annalisa Russo
- Laboratory of Clinical Chemistry and Hematology, University Hospital of Parma, Parma, Italy
| | - Elena De Santis
- Department of Laboratory Medicine and Pathology, S.Agostino Estense Hospital, Modena, Italy
| | - Tommaso Trenti
- Department of Laboratory Medicine and Pathology, S.Agostino Estense Hospital, Modena, Italy
| | - Maria Parmeggiani
- Unit of Clinical Immunology, Allergy and Advanced Biotechnologies, Azienda Unità Sanitaria, Locale, IRCCS of Reggio-Emilia, Reggio-Emilia, Italy
| | - Lucia Belloni
- Unit of Clinical Immunology, Allergy and Advanced Biotechnologies, Azienda Unità Sanitaria, Locale, IRCCS of Reggio-Emilia, Reggio-Emilia, Italy
| | - Eleonora Savi
- Allergy Unit, Guglielmo da Saliceto Hospital, Piacenza, Italy
| | | | - Federica Gaiani
- Gastroenterology and Endoscopy Unit, University Hospital of Parma, Parma, Italy
| | - Carlo Ferrari
- Unit of Infectious Diseases and Hepatology, University Hospital of Parma, Parma, Italy
| | - Giuseppe Lippi
- Section of Clinical Biochemistry, University of Verona, Verona, Italy
| |
Collapse
|
|
21
|
Early Prognostic Utility of Gp210 Antibody-Positive Rate in Primary Biliary Cholangitis: A Meta-Analysis. DISEASE MARKERS 2019; 2019:9121207. [PMID: 31737133 PMCID: PMC6815635 DOI: 10.1155/2019/9121207] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 07/15/2019] [Accepted: 08/12/2019] [Indexed: 12/14/2022]
Abstract
Background The prevalence of primary biliary cholangitis (PBC), which is an autoimmune liver disease, has increased over time. PBC often leads to severe consequences, such as liver failure and death. Stratification tools using biochemical liver tests are needed to assess and predict the progression of this disease at the time of PBC diagnosis. Methods We searched PubMed, Cochrane Library, Web of Science, and Embase for studies focused on the relationship between positive rates of Gp210 antibodies and poor prognosis of PBC. The primary end point was the number of PBC patients with poor outcome in the Gp210 antibody (+) and Gp210 antibody (-) groups. The secondary end point was the basic serum level of alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBIL), and IgM in the two groups. The age and number of female patients were also measured. Results A total of 5 studies, comprising 737 patients, were included in this analysis. A positive rate of Gp210 antibodies was positively correlated with poor outcomes and with many types of progression in PBC, especially liver failure. Mortality was also higher in the Gp210 antibody (+) group. Furthermore, the serum levels of ALP and IgM were associated with the positive rate of Gp210 antibodies, while the serum levels of ALT and TBIL were not. The age and number of female patients were also not associated with the positive rate of Gp210 antibodies. Conclusion PBC-specific Gp120 antibodies are optimal predictors of PBC prognosis at the time of diagnosis. Some other liver function indicators, such as ALP and IgM, can be used as predictors to complement Gp210 antibodies to establish a stratification tool to predict the prognosis of PBC at the time of diagnosis.
Collapse
|
|
22
|
Abstract
For many years the one-size-fits-all approach has been the only one available to manage patients affected by primary biliary cholangitis. The introduction of obeticholic acid in 2016 as a second-line treatment, together with the creation and validation of several biochemically based scores to stratify the risk of progressive disease, has opened up the need to redefine clinical practice by changing the actual paradigm. The precision medicine initiative is a model of patient-centered health care that aims to improve medicine based on genotypic and molecular characteristics that correlate to specific phenotypic, individual characteristics. In summary, the aim of the precision medicine is to define the right treatment for the right person at the right time. The availability of a second-line disease-modifying drug and new molecules in phase 2 or 3 trials makes this an exciting time for the precision medicine initiative in primary biliary cholangitis. In this review we describe the current risk stratification tools and we track a possible path towards the application of precision medicine in clinical daily life.
Collapse
Affiliation(s)
- Vincenzo Ronca
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Alessio Gerussi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Laura Cristoferi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, San Gerardo Hospital, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| |
Collapse
|
|
23
|
Dalekos GN, Gatselis NK. Variant and Specific Forms of Autoimmune Cholestatic Liver Diseases. Arch Immunol Ther Exp (Warsz) 2019; 67:197-211. [PMID: 31165900 DOI: 10.1007/s00005-019-00550-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Accepted: 05/31/2019] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the main autoimmune cholestatic liver diseases. IgG4-associated sclerosing cholangitis is another distinct immune-mediated cholestatic disorder of unknown aetiology that is frequently associated with autoimmune pancreatitis or other IgG4-related diseases. Although the majority of PBC and PSC patients have a typical presentation, there are common and uncommon important variants or specific subgroups that observed in everyday routine clinical practice. In this updated review, we summarize the published data giving also our own experience on the variants and specific groups of autoimmune cholestatic liver diseases. Actually, we give in detail the underlining difficulties and the rising dilemmas concerning the diagnosis and management of these special conditions in the clinical spectrum of autoimmune cholestatic liver diseases including the IgG4-associated sclerosing cholangitis highlighting also the uncertainties and the potential new eras of the research agenda.
Collapse
Affiliation(s)
- George N Dalekos
- Institute of Internal Medicine and Hepatology, Larissa, Greece.
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, 41110, Larissa, Greece.
| | - Nikolaos K Gatselis
- Institute of Internal Medicine and Hepatology, Larissa, Greece
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, 41110, Larissa, Greece
| |
Collapse
|
|
24
|
Zipprich A. Rheumatologie und Hepatologie: Diagnostik und Therapie von
autoimmunen Lebererkrankungen. AKTUEL RHEUMATOL 2019. [DOI: 10.1055/a-0885-9314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
ZusammenfassungUnter autoimmunen Lebererkrankungen werden im klassischen Sinne 3 verschiedene
Entitäten, die Autoimmune Hepatitis (AIH), die Primär biliäre Cholangitis (PBC)
und die Primär sklerosierende Cholangitis (PSC) verstanden. Der nachfolgende
Übersichtartikel fokusiert auf die Diagnostik und die Therapie dieser 3
autoimmunen Lebererkrankungen und gibt eine Übersicht zu möglichen zusätzlich
assoziierten Autoimmunerkrankungen.
Collapse
|
|
25
|
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.
Collapse
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
| |
Collapse
|
|
26
|
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.
Collapse
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
| |
Collapse
|
|
27
|
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]
|
|
28
|
Hirschfield GM, Dyson JK, Alexander GJM, Chapman MH, Collier J, Hübscher S, Patanwala I, Pereira SP, Thain C, Thorburn D, Tiniakos D, Walmsley M, Webster G, Jones DEJ. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. Gut 2018; 67:1568-1594. [PMID: 29593060 PMCID: PMC6109281 DOI: 10.1136/gutjnl-2017-315259] [Citation(s) in RCA: 213] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 01/22/2018] [Accepted: 01/23/2018] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.
Collapse
Affiliation(s)
- Gideon M Hirschfield
- NIHR Birmingham Biomedical Research Centre, Birmingham, UK
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Jessica K Dyson
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom
| | - Graeme J M Alexander
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
| | - Michael H Chapman
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Jane Collier
- Translational Gastroenterology Unit, Oxford University Hospitals, University of Oxford, Oxford, UK
| | - Stefan Hübscher
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Imran Patanwala
- Department of Gastroenterology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
- University of Liverpool, Liverpool, UK
| | - Stephen P Pereira
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | | | - Douglas Thorburn
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
| | - Dina Tiniakos
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | | | - George Webster
- Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, London, UK
| | - David E J Jones
- Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
- NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom
| |
Collapse
|
|
29
|
Chascsa DM, Lindor KD. Antimitochondrial Antibody-Negative Primary Biliary Cholangitis: Is It Really the Same Disease? Clin Liver Dis 2018; 22:589-601. [PMID: 30259855 DOI: 10.1016/j.cld.2018.03.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Antimitochondrial antibody (AMA)-negative primary biliary cholangitis (PBC) is a term reserved for patients with clinical and histopathological findings consistent with PBC but without positive AMA. There does not seem to be a natural progression from AMA negativity to positivity. Antinuclear and antismooth muscle antibodies are frequently found in the absence of histologic autoimmune hepatitis features. The disease course may be more severe than AMA-positive. Response to standard therapy for PBC and autoimmune hepatitis varies. Nevertheless, there is insufficient evidence to suggest AMA-negative PBC is different enough to warrant classification as a separate disease from AMA-positive PBC.
Collapse
Affiliation(s)
- David M Chascsa
- Division of Gastroenterology and Hepatology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA; Office of the Provost, Arizona State University, 550 North 3rd Street, Phoenix, AZ 85004, USA.
| |
Collapse
|
|
30
|
Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C, Vincent C, Rust C, Parés A, Mason A, Marschall H, Shapiro D, Adorini L, Sciacca C, Beecher‐Jones T, Böhm O, Pencek R, Jones D, for the Obeticholic Acid PBC Monotherapy Study Group. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology 2018; 67:1890-1902. [PMID: 29023915 PMCID: PMC5947631 DOI: 10.1002/hep.29569] [Citation(s) in RCA: 219] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 08/24/2017] [Accepted: 09/27/2017] [Indexed: 12/11/2022]
Abstract
UNLABELLED Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double-blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg -53.9% [-62.5, -29.3], OCA 50 mg -37.2% [-54.8, -24.6]) compared to placebo (-0.8% [-6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open-label extension treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus. CONCLUSION OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of open-label extension treatment. (Hepatology 2018;67:1890-1902).
Collapse
Affiliation(s)
| | - Velimir Luketic
- Virginia Commonwealth University and McGuire Research InstituteMcGuire DVAMCRichmondVA
| | - Roger Chapman
- Department of Gastroenterology, John Radcliffe HospitalHeadingtonOxfordUK
| | - Gideon M. Hirschfield
- Centre for Liver Research and NIHR Biomedical Research CentreUniversity of BirminghamBirminghamUK
| | | | - Christoph Schramm
- 1st Department of MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | | | - Christian Rust
- Department of Medicine 2, GrosshadernUniversity of MunichMunichGermany
| | - Albert Parés
- Liver Unit, Hospital Clinic, IDIBAPS, CIBERehdUniversity of BarcelonaBarcelonaSpain
| | - Andrew Mason
- Division of GastroenterologyUniversity of AlbertaEdmontonAlbertaCanada
| | - Hanns‐Ulrich Marschall
- Sahlgrenska AcademyDepartment of Molecular and Clinical Medicine, University of GothenburgGothenburgSweden
| | | | | | | | | | | | | | - David Jones
- Institute of Cellular MedicineNewcastle UniversityNewcastle‐upon‐TyneUK
| | | |
Collapse
|
|
31
|
Infantino M, Meacci F, Grossi V, Manfredi M, Benucci M, Merone M, Soda P. The burden of the variability introduced by the HEp-2 assay kit and the CAD system in ANA indirect immunofluorescence test. Immunol Res 2018; 65:345-354. [PMID: 27456204 DOI: 10.1007/s12026-016-8845-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
According to the recent recommendations of the American College of Rheumatology, ANA Task Force, IIF technique should be considered the gold standard in antinuclear antibodies (ANAs) testing. To overcome the lack of standardization, biomedical industries have developed several computer-aided diagnosis (CAD) systems. Two hundred and sixty-one consecutive samples with suspected autoimmune diseases were tested for ANA by means of IIF on routinely HEp-2 assay kit (Euroimmun AG). Assignment of result was made if consensus for positive/negative was reached by at least 2 out of 3 expert physicians. ANA-IIF was also carried out using 3 CAD systems: Zenit G-Sight (n = 84), Helios (n = 85) and NOVA View (n = 92); human evaluation was repeated on the same substrate of each CAD system (Immco, Aesku and Inova HEp-2 cells, respectively). To anonymize the results, we randomly named these three systems as A, B and C. We ran a statistical analysis computing several measures of agreement between the ratings, and we also improved the evaluation by using the Wilcoxon's test for nonparametric data. Agreement between the human readings on routinely HEp-2 assay kit and human readings on CAD HEp-2 assay was substantial for A (k = 0.82) and B (k = 0.72), and almost perfect for C (k = 0.89). Such readings were statistically different only in case A. Comparing experts' readings with the readings of CAD systems, when the samples were prepared using CAD HEp-2 assay kits, we found almost perfect agreement for B and C (k = 0.86; k = 0.82) and substantial agreement for A (k = 0.73). Again, human and CAD readings were statistically different only in A. When we compared the readings of medical experts on routinely HEp-2 assay kit with the output of the CAD systems that worked using their own slides, we found substantial agreement for all the systems (A: k = 0.62; B: k = 0.65; C: k = 0.71). Such readings were not statistically different. The change of the assay kit and/or the introduction of a CAD system affect the laboratory reporting, with an evident impact on the autoimmune laboratory workflow. The CAD systems may represent one of the most important novel elements of harmonization in the autoimmunity field, reducing intra- and inter-laboratory variability in a new vision of the diagnostic autoimmune platform.
Collapse
Affiliation(s)
- M Infantino
- Immunology and Allergy Laboratory, S.Giovanni di Dio Hospital, Via Torregalli, 3, 50143, Florence, Italy.
| | - F Meacci
- Immunology and Allergy Laboratory, S.Giovanni di Dio Hospital, Via Torregalli, 3, 50143, Florence, Italy
| | - V Grossi
- Immunology and Allergy Laboratory, S.Giovanni di Dio Hospital, Via Torregalli, 3, 50143, Florence, Italy
| | - M Manfredi
- Immunology and Allergy Laboratory, S.Giovanni di Dio Hospital, Via Torregalli, 3, 50143, Florence, Italy
| | - M Benucci
- Rheumatology Unit, S.Giovanni di Dio Hospital, Via Torregalli, 3, 50143, Florence, Italy
| | - M Merone
- Computer Systems & Bioinformatics Laboratory, Department of Engineering, University Campus Bio-Medico, Rome, Italy
| | - P Soda
- Computer Systems & Bioinformatics Laboratory, Department of Engineering, University Campus Bio-Medico, Rome, Italy
| |
Collapse
|
|
32
|
Diagnostic accuracy of two tests for determination of anti-m2 in the diagnosis of primary biliary cirrhosis: Is it possible to predict the course of the disease? Immunol Res 2018; 65:299-306. [PMID: 27475095 DOI: 10.1007/s12026-016-8838-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
To evaluate the analytical agreement between results obtained from the indirect immunofluorescence methods and from the multiplexed line-blot assay and EliA-M2, to analyze the diagnostic accuracy in a cohort of primary biliary cirrhosis (PBC) patients and in control patients of two different types of tests for anti-M2 and assess whether, with the advent of a quantitative test, the possibility exists to correlate disease activity with the value of AMA. Serum analysis of 67 patients with fluorescence patterns detected on Hep-2 cells suggestive of PBC-related antibodies and three groups of patients (15 PBC, 16 PBC suspect and 48 disease controls) was carried out. All samples were tested by both a qualitative test multiplexed line-blot Autoimmune Liver Disease Profile Euroline and by a quantitative test EliA-M2 IgG. In order to evaluate a possible correlation between the quantitative M2 and disease activity, we divided patients mixed in a further three groups based on the value EliA-M2. For each of these groups were calculated the average values of the main indices of cholestasis. A perfect agreement was shown between the EliA-M2 and the multiplexed line-blot method for AMA detection. All sera of patients with PBC were positive with both tests, with a 100 % sensitivity. Forty-seven of the 48 sera of the control group were negative for both tests with a 100 % next specificity, and only 70 % for the AMA-IIF. We had also observed in the other three groups of patients that the average of the values of γ-glutamyl transpeptidase and alkaline phosphatase increases with the increase of the value EliA-M2. The difference between the mean values of the most significant parameter which the alkaline phosphatase of the three groups is significant, with a statistically significant difference between the first and the third group (p value 0.023). Both the qualitative method Profile Euroline and the quantitative EliA-M2 have a high diagnostic accuracy for PBC, with a specificity higher than the immunofluorescence method. These preliminary data might suggest the possibility of using the dosage EliA-M2 not only in the diagnosis phase but also in the monitoring of disease activity.
Collapse
|
|
33
|
Selmi C, Generali E, Gershwin ME. Rheumatic Manifestations in Autoimmune Liver Disease. Rheum Dis Clin North Am 2018; 44:65-87. [PMID: 29149928 DOI: 10.1016/j.rdc.2017.09.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|
|
34
|
Tanaka T, Zhang W, Sun Y, Shuai Z, Chida A, Kenny TP, Yang GX, Sanz I, Ansai A, Bowlus CL, Ippolito GC, Coppel RL, Okazaki K, He XS, Leung PSC, Gershwin ME. Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics. Hepatology 2017; 66:885-895. [PMID: 28470667 PMCID: PMC5570636 DOI: 10.1002/hep.29245] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 04/13/2017] [Accepted: 04/26/2017] [Indexed: 02/06/2023]
Abstract
UNLABELLED A major problem in autoimmunity has been identification of the earliest events that lead to breach of tolerance. Although there have been major advances in dissecting effector pathways and the multilineage immune responses to mitochondrial self-antigens in primary biliary cholangitis, the critical links between environmental factors and tolerance remain elusive. We hypothesized that environmental xenobiotic modification of the E2 subunit of the pyruvate dehydrogenase (PDC-E2) inner lipoyl domain can lead to loss of tolerance to genetically susceptible hosts. Previously we demonstrated that serum anti-PDC-E2 autoantibodies cross-react with the chemical xenobiotics 2-octynoic acid and 6,8-bis (acetylthio) octanoic acid and further that there is a high frequency of PDC-E2-specific peripheral plasmablasts. Herein we generated 104 recombinant monoclonal antibodies (mAbs) based on paired heavy-chain and light-chain variable regions of individual plasmablasts derived from primary biliary cholangitis patients. We identified 32 mAbs reactive with native PDC-E2, including 20 specific for PDC-E2 and 12 cross-reactive with both PDC-E2 and 2-octynoic acid and 6,8-bis (acetylthio) octanoic acid. A lower frequency of replacement somatic hypermutations, indicating a lower level of affinity maturation, was observed in the complementarity-determining regions of the cross-reactive mAbs in comparison to mAbs exclusively recognizing PDC-E2 or those for irrelevant antigens. In particular, when the highly mutated heavy-chain gene of a cross-reactive mAb was reverted to the germline sequence, the PDC-E2 reactivity was reduced dramatically, whereas the xenobiotic reactivity was retained. Importantly, cross-reactive mAbs also recognized lipoic acid, a mitochondrial fatty acid that is covalently bound to PDC-E2. CONCLUSION Our data reflect that chemically modified lipoic acid or lipoic acid itself, through molecular mimicry, is the initial target that leads to the development of primary biliary cholangitis. (Hepatology 2017;66:885-895).
Collapse
Affiliation(s)
- Toshihiro Tanaka
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA
| | - Weici Zhang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA
| | - Ying Sun
- Center for the Treatment and Research of Non-Infectious Liver Diseases, Beijing 302 Hospital, Beijing, 100039, China
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei 230002, China
| | - Asiya Chida
- Department of Medicine, Emory University, Atlanta, GA 303222, USA
| | - Thomas P. Kenny
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA
| | - Guo-Xiang Yang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA
| | - Ignacio Sanz
- Department of Medicine, Emory University, Atlanta, GA 303222, USA
| | - Aftab Ansai
- Department of Pathology, Emory University, Atlanta, GA 303222, USA
| | - Christopher L. Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Davis, CA 95616, USA
| | - Gregory C. Ippolito
- Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA
| | - Ross L. Coppel
- Department of Microbiology, Monash University, Clayton, Victoria, Australia
| | - Kazuichi Okazaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
| | - Xiao-Song He
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA
| | - Patrick SC Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA
| |
Collapse
|
|
35
|
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.
Collapse
|
|
36
|
Hirschfield GM, Beuers U, Corpechot C, Invernizzi P, Jones D, Marzioni M, Schramm C. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017; 67:145-172. [PMID: 28427765 DOI: 10.1016/j.jhep.2017.03.022] [Citation(s) in RCA: 882] [Impact Index Per Article: 110.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 03/23/2017] [Indexed: 02/07/2023]
Abstract
Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune cholestatic liver disease, which when untreated will culminate in end-stage biliary cirrhosis. Diagnosis is usually based on the presence of serum liver tests indicative of a cholestatic hepatitis in association with circulating antimitochondrial antibodies. Patient presentation and course can be diverse and risk stratification is important to ensure all patients receive a personalised approach to their care. The goals of treatment and management are the prevention of end-stage liver disease, and the amelioration of associated symptoms. Pharmacologic approaches in practice, to reduce the impact of the progressive nature of disease, currently include licensed therapies (ursodeoxycholic acid and obeticholic acid) and off-label therapies (fibric acid derivatives, budesonide). These clinical practice guidelines summarise the evidence for the importance of a structured, life-long and individualised, approach to the care of patients with PBC, providing a framework to help clinicians diagnose and effectively manage patients.
Collapse
|
|
37
|
Floreani A, Tanaka A, Bowlus C, Gershwin ME. Geoepidemiology and changing mortality in primary biliary cholangitis. J Gastroenterol 2017; 52:655-662. [PMID: 28365879 DOI: 10.1007/s00535-017-1333-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 03/16/2017] [Indexed: 02/04/2023]
Abstract
Primary biliary cholangitis (PBC), formerly called primary biliary cirrhosis, is a chronic cholestatic disease characterized by an autoimmune-mediated destruction of small and medium-sized intrahepatic bile ducts. Originally PBC was considered to be rare and almost invariably fatal, mainly because the diagnosis was made in patients presenting with advanced symptomatic disease (jaundice and decompensated cirrhosis). However, the development of a reproducible indirect immunofluorescence assay for antimitochondrial antibody made it possible to diagnose the disease at an earlier stage, and introduction of ursodeoxycholic acid therapy as the first-line therapy for PBC drastically changed PBC-related mortality. At present, patients with an early histological stage have survival rates similar to those of an age- and sex-matched control population. Although 30% of patients treated with ursodeoxycholic acid may exhibit incomplete responses, obeticholic acid and drugs currently in development are expected to be effective for these patients and improve outcomes. Meanwhile, more etiology and immunopathology studies using new technologies and novel animal models are needed to dissect variances of clinical course, treatment response, and outcome in each patient with PBC. Precision medicine that is individualized for each patient on the basis of the cause identified is eagerly awaited.
Collapse
Affiliation(s)
- Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, via Giustiniani, 2, Padova, Italy
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Christopher Bowlus
- Division of Gastroenterology and Hepatology, School of Medicine, University of California, Davis, Davis, CA, USA
| | - Merrill Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, Davis, CA, USA.
| |
Collapse
|
|
38
|
Shuai Z, Wang J, Badamagunta M, Choi J, Yang G, Zhang W, Kenny TP, Guggenheim K, Kurth MJ, Ansari AA, Voss J, Coppel RL, Invernizzi P, Leung PS, Gershwin ME. The fingerprint of antimitochondrial antibodies and the etiology of primary biliary cholangitis. Hepatology 2017; 65:1670-1682. [PMID: 28100006 PMCID: PMC5397331 DOI: 10.1002/hep.29059] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/30/2017] [Accepted: 12/20/2016] [Indexed: 12/17/2022]
Abstract
The identification of environmental factors that lead to loss of tolerance has been coined the holy grail of autoimmunity. Our work has focused on the reactivity of antimitochondrial autoantibodies (AMA) to chemical xenobiotics and has hypothesized that a modified peptide within PDC-E2, the major mitochondrial autoantigen, will have been immunologically recognized at the time of loss of tolerance. Herein, we successfully applied intein technology to construct a PDC-E2 protein fragment containing amino acid residues 177-314 of PDC-E2 by joining a recombinant peptide spanning residues 177-252 (PDC-228) with a 62-residue synthetic peptide from 253 to 314 (PP), which encompasses PDC-E2 inner lipoyl domain (ILD). We named this intein-constructed fragment PPL. Importantly, PPL, as well as lipoic acid conjugated PPL (LA-PPL) and xenobiotic 2-octynoic acid conjugated PPL (2OA-PPL), are recognized by AMA. Of great importance, AMA has specificity for the 2OA-modified PDC-E2 ILD peptide backbone distinct from antibodies that react with native lipoylated PDC-E2 peptide. Interestingly, this unique AMA subfraction is of the immunoglobulin M isotype and more dominant in early-stage primary biliary cholangitis (PBC), suggesting that exposure to 2OA-PPL-like compounds occurs early in the generation of AMA. To understand the structural basis of this differential recognition, we analyzed PPL, LA-PPL, and 2OA-PPL using electron paramagnetic resonance spectroscopy, with confirmations by enzyme-linked immunosorbent assay, immunoblotting, and affinity antibody analysis. We demonstrate that the conformation of PDC-E2 ILD is altered when conjugated with 2OA, compared to conjugation with lipoic acid. CONCLUSION A molecular understanding of the conformation of xenobiotic-modified PDC-E2 is critical for understanding xenobiotic modification and loss of tolerance in PBC with widespread implications for a role of environmental chemicals in the induction of autoimmunity. (Hepatology 2017;65:1670-1682).
Collapse
Affiliation(s)
- Zongwen Shuai
- Division of Rheumatology/Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis California USA
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Jinjun Wang
- Division of Rheumatology/Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis California USA
| | - Madhu Badamagunta
- Department of Molecular Medicine, University of California Davis School of Medicine, Davis, California, USA
| | - Jinjung Choi
- Division of Rheumatology/Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis California USA
| | - Guoxiang Yang
- Division of Rheumatology/Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis California USA
| | - Weici Zhang
- Division of Rheumatology/Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis California USA
| | - Thomas P. Kenny
- Division of Rheumatology/Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis California USA
| | - Kathryn Guggenheim
- Department of Chemistry, University of California Davis School of Medicine, Davis California, USA
| | - Mark J. Kurth
- Department of Chemistry, University of California Davis School of Medicine, Davis California, USA
| | - Aftab A. Ansari
- Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - John Voss
- Department of Molecular Medicine, University of California Davis School of Medicine, Davis, California, USA
| | - Ross L Coppel
- Department of Microbiology, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Pietro Invernizzi
- Section of Digestive Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy
| | - Patrick S.C. Leung
- Division of Rheumatology/Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis California USA
| | - M. Eric Gershwin
- Division of Rheumatology/Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis California USA
| |
Collapse
|
|
39
|
Tanaka A. Anti-mitochondrial autoantibodies-milestone or byway to primary biliary cholangitis? ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:50. [PMID: 28251129 PMCID: PMC5326641 DOI: 10.21037/atm.2017.01.42] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 01/05/2017] [Indexed: 08/30/2023]
Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
40
|
Juliusson G, Imam M, Björnsson ES, Talwalkar JA, Lindor KD. Long-term outcomes in antimitochondrial antibody negative primary biliary cirrhosis. Scand J Gastroenterol 2016; 51:745-52. [PMID: 26776319 DOI: 10.3109/00365521.2015.1132337] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Antimitochondrial antibodies (AMA) are a sensitive and specific marker for primary biliary cirrhosis (PBC). AMAs are present in 95% of patients with PBC. However, 5% do not have AMAs and data on these patients is scarce. We aim to evaluate the long-term outcomes of patients with AMA negative PBC. METHODS A retrospective chart review of 71 AMA negative PBC patients. Disease presentation, laboratory results, and clinical endpoints were recorded. AMA negative patients were matched on year of diagnosis to a control group of 71 AMA positive patients. RESULTS Ninety-six percent of the AMA negative patients were of female gender with a median age at diagnosis of 55 years and a length of follow-up of 7.5 years vs. 86% females, a median age of 56 and a follow-up of 8.3 years in the control group. Mean total bilirubin and alkaline phosphatase levels were 0.7 mg/dL vs. 0.6 and 570 U/L vs 341, in AMA negative vs. AMA positive patients at presentation, respectively (p = NS). AMA negative patients did not differ in terms of age, serum IgM levels, ANA status, or length of follow-up. Notably, AMA negative patients had a significantly reduced survival free of liver-related complications including transplantation and death compared to AMA positive patients (p = 0.0182). CONCLUSION In this large experience, AMA negative PBC patients had a significantly worse prognosis compared to AMA positive PBC patients. The reason for the difference in prognosis is unclear, as it may be true difference or reflect delays in case detection among AMA negative patients.
Collapse
Affiliation(s)
- Gunnar Juliusson
- a Faculty of Medicine , University of Iceland , Reykjavík , Iceland
| | - Mohamad Imam
- b Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA
| | - Einar S Björnsson
- a Faculty of Medicine , University of Iceland , Reykjavík , Iceland ;,c Department of Gastroenterology and Hepatology , Landspitali University Hospital , Reykjavík , Iceland
| | - Jayant A Talwalkar
- b Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA
| | - Keith D Lindor
- d Arizona State University , College of Health Solutions , Phoenix , AZ , USA
| |
Collapse
|
|
41
|
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
| |
Collapse
|
|
42
|
Carbone M, Ronca V, Bruno S, Invernizzi P, Mells GF. Toward precision medicine in primary biliary cholangitis. Dig Liver Dis 2016; 48:843-50. [PMID: 27324985 DOI: 10.1016/j.dld.2016.05.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 05/24/2016] [Accepted: 05/25/2016] [Indexed: 12/11/2022]
Abstract
Primary biliary cholangitis is a chronic, cholestatic liver disease characterized by a heterogeneous presentation, symptomatology, disease progression and response to therapy. In contrast, clinical management and treatment of PBC is homogeneous with a 'one size fits all' approach. The evolving research landscape, with the emergence of the -omics field and the availability of large patient cohorts are creating a unique opportunity of translational epidemiology. Furthermore, several novel disease and symptom-modifying agents for PBC are currently in development. The time is therefore ripe for precision medicine in PBC. In this manuscript we describe the concept of precision medicine; review current approaches to risk-stratification in PBC, and speculate how precision medicine in PBC might develop in the near future.
Collapse
Affiliation(s)
- Marco Carbone
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom; MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom; Liver Unit, Humanitas Clinical and Research Institute, Rozzano (Milan), Italy
| | - Vincenzo Ronca
- Liver Unit, Humanitas Clinical and Research Institute, Rozzano (Milan), Italy
| | - Savino Bruno
- Liver Unit, Humanitas Clinical and Research Institute, Rozzano (Milan), Italy
| | - Pietro Invernizzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - George F Mells
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom; MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom
| |
Collapse
|
|
43
|
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.
Collapse
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.
| |
Collapse
|
|
44
|
Vierling JM. Autoimmune Hepatitis and Overlap Syndromes: Diagnosis and Management. Clin Gastroenterol Hepatol 2015; 13:2088-108. [PMID: 26284592 DOI: 10.1016/j.cgh.2015.08.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 08/11/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
Affiliation(s)
- John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Baylor-St Luke's Medical Center, Houston, Texas.
| |
Collapse
|
|
45
|
Cancado ELR, Harriz M. The Importance of Autoantibody Detection in Primary Biliary Cirrhosis. Front Immunol 2015; 6:309. [PMID: 26157439 PMCID: PMC4477174 DOI: 10.3389/fimmu.2015.00309] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Accepted: 05/29/2015] [Indexed: 01/27/2023] Open
Affiliation(s)
- Eduardo Luiz Rachid Cancado
- Department of Gastroenterology, Clinical Gastroenterology and Clinical Hepatology of Hospital das Clinicas, University of São Paulo School of Medicine , São Paulo , Brazil ; Laboratory of Immunopathology of Schistosomiasis, Institute of Tropical Medicine, University of São Paulo , São Paulo , Brazil ; Laboratory of Tropical Gastroenterology and Hepatology, Institute of Tropical Medicine , São Paulo , Brazil
| | - Michelle Harriz
- Department of Gastroenterology, Clinical Gastroenterology and Clinical Hepatology of Hospital das Clinicas, University of São Paulo School of Medicine , São Paulo , Brazil
| |
Collapse
|
|
46
|
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.
Collapse
|
|
47
|
|
|
48
|
Villalta D, Sorrentino MC, Girolami E, Tampoia M, Alessio MG, Brusca I, Daves M, Porcelli B, Barberio G, Bizzaro N. Autoantibody profiling of patients with primary biliary cirrhosis using a multiplexed line-blot assay. Clin Chim Acta 2015; 438:135-8. [DOI: 10.1016/j.cca.2014.08.024] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 08/19/2014] [Accepted: 08/20/2014] [Indexed: 12/18/2022]
|
|
49
|
Shovman O, Agmon-Levin N, Gilburd B, Martins T, Petzold A, Matthias T, Shoenfeld Y. A fully automated IIF system for the detection of antinuclear antibodies and antineutrophil cytoplasmic antibodies. Immunol Res 2014; 61:135-40. [DOI: 10.1007/s12026-014-8588-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
|
|
50
|
Bizzaro N, Tozzoli R, Villalta D. Autoimmune diagnostics: the technology, the strategy and the clinical governance. Immunol Res 2014; 61:126-34. [PMID: 25398640 DOI: 10.1007/s12026-014-8587-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|