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Dalekos G, Gatselis N, Drenth JP, Heneghan M, Jørgensen M, Lohse AW, Londoño M, Muratori L, Papp M, Samyn M, Tiniakos D, Lleo A. EASL Clinical Practice Guidelines on the management of autoimmune hepatitis. J Hepatol 2025:S0168-8278(25)00173-4. [PMID: 40348684 DOI: 10.1016/j.jhep.2025.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 05/14/2025]
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology which may affect any patient irrespective of age, sex, and ethnicity. At baseline, the clinical spectrum of the disease varies largely from asymptomatic cases to acute liver failure with massive hepatocyte necrosis. The aim of these EASL guidelines is to provide updated guidance on the diagnosis and management of AIH both in adults and children. Updated guidance on the management of patients with variants and specific forms of AIH is also provided, as is detailed guidance on the management of AIH-associated cirrhosis, including surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.
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Lv H, Deng A, Chen Y, Su Z. Clinical Performance of the Line Immunoassay and Digital Liquid Chip Method for Detecting Autoimmune Liver Disease Autoantibodies. Arch Pathol Lab Med 2025; 149:271-275. [PMID: 38830630 DOI: 10.5858/arpa.2024-0057-oa] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/01/2024] [Indexed: 06/05/2024]
Abstract
CONTEXT.— The identification of autoantibodies associated with autoimmune liver disease (ALD) is crucial for diagnosis and management. Various laboratory methods have been introduced to detect autoantibody profiles. However, the variable performance of these assays may create challenges for clinicians and patients. OBJECTIVE.— To investigate the concordance rates and diagnostic performance of 2 commercially available assays, line immunoassay (LIA) and digital liquid chip method (DLCM), in patients with ALD. DESIGN.— A total of 291 serum samples were collected, consisting of 180 sera from patients with ALD and 111 sera from controls. The samples were detected through LIA and DLCM. The agreement and diagnostic performance of each assay were analyzed. RESULTS.— There was substantial to almost perfect agreement among prevalent autoantibodies (anti-mitochondrial antibody M2; antibodies against gp210, Sp100, and Ro52). Nevertheless, the Cohen κ coefficient of some uncommon autoantibodies (anti-LKM-1, anti-LC-1, and anti-SLA/LP) between the 2 methods was not ideal. LIA showed slightly better sensitivity, accuracy, and negative predictive value, while DLCM exhibited slightly higher specificity and positive predictive value. CONCLUSIONS.— LIA and DLCM demonstrated comparable performance for the detection of common ALD-related autoantibodies. LIA seemed to be more sensitive, while DLCM displayed more specificity. However, standardization of ALD autoantibody detection still faces challenges between these diverse detection systems. Comprehensive interlaboratory validation is essential to mitigate potential misunderstanding and confusion among patients and clinicians.
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Affiliation(s)
- Heye Lv
- From the Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China (Lv, Su)
| | - Ao Deng
- the Department of Laboratory Medicine, West China Tianfu Hospital of Sichuan University, Chengdu, China (Deng, Chen)
| | - Yijun Chen
- the Department of Laboratory Medicine, West China Tianfu Hospital of Sichuan University, Chengdu, China (Deng, Chen)
| | - Zhenzhen Su
- From the Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, China (Lv, Su)
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Azariadis K, Gatselis NK, Lyberopoulou A, Arvaniti P, Zachou K, Gabeta S, Dalekos GN. PNPLA3 I148 M genetic variant in autoimmune hepatitis characterises advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related mortality. J Transl Autoimmun 2024; 9:100243. [PMID: 38974691 PMCID: PMC11225017 DOI: 10.1016/j.jtauto.2024.100243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 05/22/2024] [Accepted: 06/02/2024] [Indexed: 07/09/2024] Open
Abstract
Background Autoimmune hepatitis (AIH) is a relatively rare autoimmune disease with a strong genetic background. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148 M (rs738409 C/G) variant has been associated with hepatic inflammation and fibrosis in chronic hepatic diseases beyond metabolic dysfunction-associated steatotic liver disease (MASLD). Aim Our aim was to investigate the significance of PNPLA3 I148 M variant in AIH. Method Two hundred AIH patients, followed in our centre, were evaluated while 100 healthy subjects served as controls. Genotyping was performed with allelic discrimination end-point polymerase chain reaction (PCR). Results The I148 M variant was present in 95/200 (47.5 %) AIH patients compared to 47/100 (47 %) healthy controls (p = 1.000). Patients with GG/CG genotypes were more likely to present with decompensated cirrhosis at diagnosis (GG/CG 6.3 % vs. CC 1 %, p = 0.039). Comorbidity with cardiometabolic risk factors and concurrence of MASLD was similar across genotypes. Simple steatosis was present in 37/186 (19.9 %) and steatohepatitis in 14/186 (7.5 %) patients with available liver biopsy without correlation with PNPLA3 genotype. Fibrosis stage and grade of inflammation were not correlated with any genotype. Response to treatment was also independent of the presence of the I148 M variant, even though a longer time was needed to achieve complete biochemical response in those carrying the GG/CG genotypes (p = 0.07). On Kaplan Meier analysis homozygosity for the G allele corelated with reduced survival free of decompensation (p = 0.006), cirrhotic events (decompensation, liver transplantation, hepatocellular carcinoma; p = 0.001) and liver-related death or liver transplantation (p = 0.011) in treated patients. Conclusions The PNPLA3 I148 M variant in AIH patients is associated with increased risk of advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related death or liver transplantation, regardless of the presence of MASLD. This signifies a potential role for the PNPLA3 I148 M variant as a new AIH biomarker allowing to identify patients at increased risk of disease progression.
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Affiliation(s)
- Kalliopi Azariadis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - Nikolaos K. Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
- European Reference Network on Hepatological Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece
| | - Aggeliki Lyberopoulou
- 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
| | - 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
| | - Stella Gabeta
- 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
| | - 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
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SORRENTINO MC, a nome del GdS-AI SIPMeL, CARBONE T, CINQUANTA L, ALESSIO MG, INFANTINO M, DELEONARDI G, TREVISAN MT, PORCELLI B, TERZUOLI L, PLATZGUMMER S, BRUSCA I, ANTICO A, TAMPOIA M, PESCE G, VILLALTA D, BIZZARO N. Linee guida SIPMeL per la determinazione degli autoanticorpi nella diagnosi delle malattie autoimmuni del fegato. LA RIVISTA ITALIANA DELLA MEDICINA DI LABORATORIO 2024; 20. [DOI: 10.23736/s1825-859x.24.00226-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Huang Y, Gao X, He QY, Liu W. A Interacting Model: How TRIM21 Orchestrates with Proteins in Intracellular Immunity. SMALL METHODS 2024; 8:e2301142. [PMID: 37922533 DOI: 10.1002/smtd.202301142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/12/2023] [Indexed: 11/07/2023]
Abstract
Tripartite motif-containing protein 21 (TRIM21), identified as both a cytosolic E3 ubiquitin ligase and FcR (Fragment crystallizable receptor), primarily interacts with proteins via its PRY/SPRY domains and promotes their proteasomal degradation to regulate intracellular immunity. But how TRIM21 involves in intracellular immunity still lacks systematical understanding. Herein, it is probed into the TRIM21-related literature and raises an interacting model about how TRIM21 orchestrates proteins in cytosol. In this novel model, TRIM21 generally interacts with miscellaneous protein in intracellular immunity in two ways: For one, TRIM21 solely plays as an E3, ubiquitylating a glut of proteins that contain specific interferon-regulatory factor, nuclear transcription factor kappaB, virus sensors and others, and involving inflammatory responses. For another, TRIM21 serves as both E3 and specific FcR that detects antibody-complexes and facilitates antibody destroying target proteins. Correspondingly delineated as Fc-independent signaling and Fc-dependent signaling in this review, how TRIM21's interactions contribute to intracellular immunity, expecting to provide a systematical understanding of this important protein and invest enlightenment for further research on the pathogenesis of related diseases and its prospective application is elaborated.
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Affiliation(s)
- Yisha Huang
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Xuejuan Gao
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Qing-Yu He
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Wanting Liu
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
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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.
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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.
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Zachou K, Azariadis K, Lytvyak E, Snijders RJ, Takahashi A, Gatselis NK, Robles M, Andrade RJ, Schramm C, Lohse AW, Tanaka A, Drenth JP, Montano-Loza AJ, Dalekos GN, International Autoimmune Hepatitis Group (IAIHG). Treatment responses and outcomes in patients with autoimmune hepatitis and concomitant features of non-alcoholic fatty liver disease. JHEP Rep 2023; 5:100778. [PMID: 37456672 PMCID: PMC10339258 DOI: 10.1016/j.jhepr.2023.100778] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/31/2023] [Accepted: 04/11/2023] [Indexed: 07/18/2023] Open
Abstract
Background & Aims Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) affect 17-46% of Western countries, making coexistence with other liver diseases inevitable. We investigated the prevalence and clinical significance of NAFLD/NASH or the components of metabolic syndrome (MetS) in a large multicentric cohort of patients with autoimmune hepatitis (AIH). Methods Data from six academic centres (Greece, Canada, Japan, Germany, The Netherlands, and Spain) were evaluated. The presence of NAFLD/NASH in liver biopsy, MetS components, and clinical and laboratory parameters were recorded. Results A total of 640 patients (474 females, age 49 [4-87] years; follow-up 78 [1-521] months) were included. NAFLD was present in 146 (22.8%) patients (AIH/non-alcoholic fatty liver [NAFL] 115 [18%], AIH/NASH 31 [4.8%]). AIH/NAFL patients were older (p = 0.017), more frequently overweight or obese (p = 0.002), had hypertension (p = 0.001), and had diabetes (p = 0.016), whereas they less frequently had acute presentation (p = 0.002) and soluble liver antigen/liver pancreas positivity (p <0.05), lower transaminases (p <0.001), ALP (p = 0.028) and IgG (p = 0.004) and higher albumin (p <0.001) than patients with AIH only. Patients with AIH/NASH more frequently had cirrhosis at diagnosis (p = 0.036) and higher IgG (p = 0.009). Response to treatment did not differ between groups. Patients with cirrhosis with AIH/NAFL had higher frequency of decompensation compared with patients with AIH only (p <0.05). Patients with type 2 diabetes mellitus and dyslipidaemia had increased hazard of disease progression (p <0.05 for each). Conclusions The prevalence of NAFLD in AIH is similar to the general population. Concurrence of NASH in patients with AIH signifies a more severe disease, whereas that of NAFL may indicate a worse prognosis in patients with cirrhosis. T2DM and dyslipidaemia in AIH patients are associated with dismal parameters of outcome. Our findings suggest that NAFLD presence or even components of MetS in patients with AIH may affect prognosis, so closer follow-up of such patients is warranted. Impact and implications Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) affect many people, making coexistence with other liver diseases inevitable. We investigated the prevalence and clinical significance of NAFLD/NASH or the components of metabolic syndrome (MetS) in patients with autoimmune hepatitis (AIH). NAFLD and NASH presence in patients with AIH is as frequent as in the general population. The concurrence of NASH in patients with AIH seems to signify a more severe disease, whereas that of non-alcoholic fatty liver may indicate a worse prognosis in a specific subgroup of patients who already have cirrhosis at diagnosis. Diabetes or dyslipidaemia in patients with AIH were associated with worse prognosis. Therefore, it seems that closer follow-up of patients with concurrent AIH and NAFLD or AIH and components of MetS is needed.
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Affiliation(s)
- 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
| | - Kalliopi Azariadis
- 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
| | - Ellina Lytvyak
- Division of Preventive Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Romée J.A.L.M. Snijders
- Department of Gastroenterology and Hepatology, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Radboud UMC, Nijmegen, The Netherlands
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - 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
| | - Mercedes Robles
- Unidad De Gestión Clínica De Aparato Digestivo, Servicio De Farmacología Clínica, Hospital Universitario Virgen De La Visctoria, Universidad De Malaga, Malaga, Spain
| | - Raul J. Andrade
- Unidad De Gestión Clínica De Aparato Digestivo, Servicio De Farmacología Clínica, Hospital Universitario Virgen De La Visctoria, Universidad De Malaga, Malaga, Spain
| | - Christoph Schramm
- Department of Medicine and Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Ansgar W. Lohse
- Department of Medicine and Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Atsushi Tanaka
- Department of Medicine, Tokyo University, School of Medicine, Itabashi-Ku, Tokyo, Japan
| | - Joost P.H. Drenth
- Department of Gastroenterology and Hepatology, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Radboud UMC, Nijmegen, The Netherlands
| | - Aldo J. Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| | - 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
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Abstract
Autoimmune hepatitis is an inflammatory disease of the liver of unknown cause that may progress to liver cirrhosis and end stage liver failure if diagnosis is overlooked and treatment delayed. The clinical presentation is often that of acute hepatitis, sometimes very severe; less frequently, it can be insidious or completely asymptomatic. The disease can affect people of any age and is more common in women; its incidence and prevalence seem to be on the rise worldwide. An abnormal immune response targeting liver autoantigens and inducing persistent and self-perpetuating liver inflammation is the pathogenic mechanism of the disease. A specific set of autoantibodies, increased IgG concentrations, and histological demonstration of interface hepatitis and periportal necrosis are the diagnostic hallmarks of autoimmune hepatitis. Prompt response to treatment with corticosteroids and other immunomodulatory drugs is almost universal and supports the diagnosis. The aims of treatment are to induce and maintain long term remission of liver inflammation. Treatment can often even reverse liver fibrosis, thus preventing progression to advanced cirrhosis and its complications. Most patients need lifelong maintenance therapy, and repeated follow-up in experienced hands improves the quality of care and quality of life for affected patients.
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Affiliation(s)
- Luigi Muratori
- DIMEC, Università di Bologna and IRCCS Policlinico di Sant'Orsola, Bologna, Italy
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
| | - Ansgar W Lohse
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
| | - Marco Lenzi
- DIMEC, Università di Bologna and IRCCS Policlinico di Sant'Orsola, Bologna, Italy
- European Reference Network for Hepatological Diseases (ERN RARE-LIVER)
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Dalekos GN, Gatselis NK. Autoimmune serology testing in clinical practice: An updated roadmap for the diagnosis of autoimmune hepatitis. Eur J Intern Med 2023; 108:9-17. [PMID: 36400668 DOI: 10.1016/j.ejim.2022.11.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 11/04/2022] [Accepted: 11/06/2022] [Indexed: 11/18/2022]
Abstract
Diagnosis of autoimmune hepatitis (AIH) is in most cases challenging for clinicians as there is not a single specific laboratory or histological marker to diagnose or exclude the presence of the disease. The clinical spectrum of AIH varies from completely asymptomatic to acute-severe or even rarely fulminant hepatic failure, while everybody can be affected irrespective of age, gender, and ethnicity. The old revised and the newer simplified diagnostic scores have been established by the International Autoimmune Hepatitis Group (IAIHG) in 1999 and 2008, respectively, which are based on several clinical, laboratory and histological parameters. Additionally, a thorough differential diagnosis from other diseases mimicking AIH is absolutely indicated. In this context, autoantibodies detection in patients with suspected AIH is mandatory -even though not pathognomonic- not only for AIH diagnosis but furthermore, for AIH classification (AIH-type 1 and AIH-type 2). Although autoimmune serology can be supportive of AIH diagnosis in ≥95% of cases if testing has been performed according to the IAIHG guidelines, this is not the case under real-life circumstances in routine clinical laboratories. Clinicians should be careful both for the importance of the required testing and how to interpret the results and therefore, they should communicate and discuss with the laboratory personnel to achieve the maximum benefit for the patient. Herein, a detailed and updated review of the diagnostic work-up for AIH diagnosis under real-life conditions is given to minimize the underestimation and misdiagnosis of AIH which can result in progression of the disease and unfavourable outcomes.
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Affiliation(s)
- George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece.
| | - Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
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Cancado ELR, Goldbaum-Crescente J, Terrabuio DRB. HLA-related genetic susceptibility in autoimmune hepatitis according to autoantibody profile. Front Immunol 2022; 13:1032591. [PMID: 36311739 PMCID: PMC9606223 DOI: 10.3389/fimmu.2022.1032591] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
Although the prevalence of autoimmune hepatitis in first-degree relatives is small, the relationship between genetic markers, especially human leucocyte antigens (HLA), and susceptibility to this disease, has been studied for over three decades. The genetic susceptibility to AIH is believed to be different in the two subtypes of the disease, AIH type 1 and AIH type 2. Type 1 AIH has anti-smooth muscle and anti-nuclear antibodies as its main markers, while those of type 2 AIH are the anti-liver/kidney microsome type 1 and anti-liver cytosol type 1 antibodies. The anti-soluble liver antigen/liver-pancreas antibodies, which, in addition to being present in both subtypes, mark an important number of patients without serological markers. Therefore, a third type of disease is questionable. The vast majority of immunogenetic studies compare the differences between the two main types and make no difference between which antibodies are present to define the subtype. This review seeks to analyze what was most important published in the AIH in this context, trying to relate the HLA alleles according to the AIH marker autoantibodies.
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Affiliation(s)
- Eduardo Luiz Rachid Cancado
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Instituto de Medicina Tropical da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- *Correspondence: Eduardo Luiz Rachid Cancado,
| | - Juliana Goldbaum-Crescente
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Instituto de Medicina Tropical da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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11
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Chan EKL. Anti-Ro52 Autoantibody Is Common in Systemic Autoimmune Rheumatic Diseases and Correlating with Worse Outcome when Associated with interstitial lung disease in Systemic Sclerosis and Autoimmune Myositis. Clin Rev Allergy Immunol 2022; 63:178-193. [PMID: 35040083 DOI: 10.1007/s12016-021-08911-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2021] [Indexed: 01/13/2023]
Abstract
This review highlights the 30 plus years research progress since the discovery of autoantibody to Ro52/TRIM21 in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SjS). After the initial expression cloning of the Ro52 cDNA, it has taken many years to the current understanding in the interesting biological function of Ro52 as an E3 ubiquitin ligase and its role in innate immune clearance of intracellular IgG-bound complex. Early observations show that anti-Ro52, mostly associated with anti-SS-A/Ro60 and/or anti-SS-B/La, is commonly found in SLE (40-70%), SjS (70-90%), neonatal lupus erythematosus (NLE, 75-90%), and subacute cutaneous lupus erythematosus (50-60%). Anti-Ro52 has long been postulated to play a direct pathogenic role in congenital heart block in NLE as well as in the QT interval prolongation in some adults. The widespread availability of the anti-Ro52 assay has led to the detection of anti-Ro52 in other diseases including autoimmune hepatitis (20-40%), systemic sclerosis (10-30%), and autoimmune myositis (20-40%). More than ten studies have pointed to an association of anti-Ro52 with interstitial lung disease and, more importantly, correlating with poor outcome and worse survival. Other studies are implicating an interesting role for anti-Ro52 in the diagnosis of certain cancers. Future studies are needed to examine the mechanism in the pathogenesis of anti-Ro52 and carefully documenting its causal relationships in different disease conditions.
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Affiliation(s)
- Edward K L Chan
- Department of Oral Biology, University of Florida, 1395 Center Drive, Gainesville, FL, 32610-0424, USA.
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Muñoz-Sánchez G, Pérez-Isidro A, Ortiz de Landazuri I, López-Gómez A, Bravo-Gallego LY, Garcia-Ormaechea M, Julià MR, Viñas O, Ruiz-Ortiz E, on behalf of the 2020 GEAI-SEI Workshop Participants. Working Algorithms and Detection Methods of Autoantibodies in Autoimmune Liver Disease: A Nationwide Study. Diagnostics (Basel) 2022; 12:diagnostics12030697. [PMID: 35328252 PMCID: PMC8947365 DOI: 10.3390/diagnostics12030697] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 02/06/2023] Open
Abstract
Autoantibody detection is the cornerstone of autoimmune liver diseases (AILD) diagnosis. Standardisation of working algorithms among autoimmunity laboratories, as well as being aware of the sensitivity and specificity of various commercial techniques in daily practice, are still necessary. The aim of this nationwide study is to report the results of the 2020 Autoimmunity Workshop organised by the Autoimmunity Group of the Spanish Society of Immunology and to provide useful information to clinicians and laboratory specialists to improve the management of autoantibody detection in AILD diagnoses. Serum samples from 17 patients with liver diseases were provided by the organisers of the 2020 Autoimmunity Workshop and were subsequently analysed by the 40 participating laboratories. Each laboratory used different techniques for the detection of autoantibodies in each patients’ serum sample, according to their working algorithm. Thus, almost 680 total complete patient reports were obtained, and the number of results from different autoantibody detection techniques was >3000. Up to eight different working algorithms were employed, including indirect immunofluorescence assays (IFA) and antigen-specific techniques (AgST). The IFA of HEp-2 cells was more sensitive than IFA of rat triple tissue for the study of anti-nuclear autoantibodies (ANA) associated with AILD. The IFA of a human neutrophil study for the analysis of anti-neutrophil cytoplasmic autoantibodies was not carried out systemically in all patients, or by all laboratories. AgSTs were the most sensitive methods for the detection of anti-smooth muscle/F-actin, soluble liver antigen, liver cytosol-1, M2-mitochondrial autoantibodies, and ANA associated with primary biliary cholangitis. The main differences in AMA detection were due to patients with autoantibodies against the non-dominant epitope of pyruvate dehydrogenase complex. Given that they are complementary, IFA and AgST should be performed in parallel. If there is high suspicion of AILD, AgST should always be performed.
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Affiliation(s)
- Guillermo Muñoz-Sánchez
- Department of Immunology, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Villarroel 170-Escala 4, Planta 0, 08036 Barcelona, Spain; (G.M.-S.); (A.P.-I.); (I.O.d.L.); (L.Y.B.-G.); (O.V.)
| | - Albert Pérez-Isidro
- Department of Immunology, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Villarroel 170-Escala 4, Planta 0, 08036 Barcelona, Spain; (G.M.-S.); (A.P.-I.); (I.O.d.L.); (L.Y.B.-G.); (O.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
| | - Iñaki Ortiz de Landazuri
- Department of Immunology, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Villarroel 170-Escala 4, Planta 0, 08036 Barcelona, Spain; (G.M.-S.); (A.P.-I.); (I.O.d.L.); (L.Y.B.-G.); (O.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
| | - Antonio López-Gómez
- Department of Immunology, Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain; (A.L.-G.); (M.R.J.)
- Institut d’Investigació Sanitària Illes Balears, 07120 Palma de Mallorca, Spain
| | - Luz Yadira Bravo-Gallego
- Department of Immunology, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Villarroel 170-Escala 4, Planta 0, 08036 Barcelona, Spain; (G.M.-S.); (A.P.-I.); (I.O.d.L.); (L.Y.B.-G.); (O.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
| | | | - Maria Rosa Julià
- Department of Immunology, Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain; (A.L.-G.); (M.R.J.)
- Institut d’Investigació Sanitària Illes Balears, 07120 Palma de Mallorca, Spain
| | - Odette Viñas
- Department of Immunology, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Villarroel 170-Escala 4, Planta 0, 08036 Barcelona, Spain; (G.M.-S.); (A.P.-I.); (I.O.d.L.); (L.Y.B.-G.); (O.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
| | - Estíbaliz Ruiz-Ortiz
- Department of Immunology, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Villarroel 170-Escala 4, Planta 0, 08036 Barcelona, Spain; (G.M.-S.); (A.P.-I.); (I.O.d.L.); (L.Y.B.-G.); (O.V.)
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
- Correspondence:
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Gatselis NK, Azariadis K, Lyberopoulou A, Dalekos GN. Programmed cell death-1 rs11568821 and interleukin-28B rs12979860 polymorphisms in autoimmune hepatitis. J Transl Autoimmun 2021; 4:100126. [PMID: 34632357 PMCID: PMC8488593 DOI: 10.1016/j.jtauto.2021.100126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a relatively rare chronic liver disease of unknown etiology. The genetic background affects susceptibility, clinical phenotype, and prognosis. The programmed cell death-1 rs11568821 polymorphism (PD1.3) has been associated with susceptibility to autoimmune diseases. The interleukin-28B (IL28B) rs12979860 polymorphism has been associated with steatosis, inflammation, and fibrosis in liver diseases. AIM Our aim was to investigate for the first time the incidence and clinical significance of PD1.3 and IL28B rs12979860 in AIH. METHODS Two hundred patients with AIH were evaluated, while 100 healthy subjects were used as controls. Genotyping was performed with in-house allelic discrimination End-Point PCR. RESULTS The SNP PD1.3/A was present in 36/200 (18%) AIH patients compared to 28/100 (28%) healthy controls (p = 0.065). The AA/GA genotypes were not associated with the mode of presentation of AIH, the histological grade or stage, the presence of cirrhosis, risk of disease progression, response to treatment and survival. The IL28B rs12979860 genotype distribution was CC 79/200 (39.5%), TT 36/200 (18%) and CT 85/200 (42.5%), in similar rates with healthy controls (p = 0.878). Inflammatory activity and fibrosis stage did not differ between CC homozygotes and CT/TT carriers. LDL cholesterol was significantly higher in CC than CT/TT patients (P = 0.027), though no differences was found regarding the presence of steatosis or steatohepatitis. On-treatment response to immunosuppressive treatment was not affected by the IL28B rs12979860 polymorphism. However, CC homozygotes AIH patients achieved treatment withdrawal in significantly higher rates (OR 2.3, 95%CI: 1.1-4.7, P = 0.02) irrespective of the presence of steatosis or steatohepatitis. CONCLUSIONS The PD1.3 and IL28B rs12979860 variants are unlikely to contribute to AIH susceptibility, disease presentation and prognosis. The IL28B rs12979860 is not associated with the presence of concurrent steatosis or steatohepatitis. However, although on-treatment response rates to immunosuppression were not affected by the IL28B rs12979860 polymorphism, AIH patients with CC homozygosity were more likely to achieve complete treatment withdrawal. This novel finding needs validation and further clarification from larger multicenter studies.
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Key Words
- AIH, Autoimmune hepatitis.
- ANA, Antinuclear antibodies.
- Anti-LC1, Liver cytosol type-1 antibodies.
- Anti-LKM1, Liver kidney microsomal type-1 antibodies
- Anti-SLA/LP, Soluble liver antigen/liver pancreas antibodies.
- Autoimmune hepatitis
- CR, Complete response.
- HCC, Hepatocellular carcinoma.
- HCV, Hepatis C virus.
- HDL, High density lipoprotein.
- HLA, Human leukocyte antigen.
- HWE, Hardy-weinberg equilibrium.
- IL28B, Interleukin 28B.
- INR, International normalized ratio.
- IQR, Interquartile range.
- IgG, Immunoglobulin class G.
- Interleukin-28B
- LDL, Low density lipoprotein
- MetS, Metabolic syndrome.
- NAFLD, Non-alcoholic fatty liver disease.
- PCR, Polymerase chain reaction.
- PD1, Programmed cell death-1.
- Polymorphisms
- Programmed cell death-1
- SD, Standard deviation.
- SLE, Systemic lupus erythematosus.
- SMA, Smooth muscle antibodies.
- SNP, Single nucleotide polymorphism.
- ULN, Upper limit of normal.
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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, 41110, Larissa, Greece
| | - Kalliopi Azariadis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110, Larissa, 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, 41110, Larissa, Greece
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Bogdanos DP, Gkoutzourelas A, Papadopoulos V, Liaskos C, Patrikiou E, Tsigalou C, Saratziotis A, Hajiioannou J, Scheper T, Meyer W, Sakkas LI, Papandreou C. Anti-Ro52 antibody is highly prevalent and a marker of better prognosis in patients with ovarian cancer. Clin Chim Acta 2021; 521:199-205. [PMID: 34245687 DOI: 10.1016/j.cca.2021.07.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 06/13/2021] [Accepted: 07/05/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Anti-Ro52 antibody (Ab) reactivity is highly prevalent in autoimmune rheumatic diseases (ARDs), mainly Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE), but also in other inflammatory disorders. Thorough assessment of the prevalence, clinical significance and epitope specificity of Ro52-autoAbs in cancerous diseases is still lacking. MATERIAL AND METHODS Anti-Ro52 Ab reactivity was tested in a large cohort of 490 patients with various malignant diseases. Ro52-autoAb epitope mapping by an in house line immunoassay was carried out using 5 recombinant Ro52 polypeptides spanning Ro52. RESULTS Anti-Ro52 abs were significantly more prevalent in patients with ovarian cancer (30%) compared to patients with 6 other malignant diseases (median 8.1%, range 5.9-15.8%). The presence of anti-Ro52 abs in patients with ovarian cancer was strongly associated with better overall survival. Ro52 epitope mapping of patients with ovarian cancer was dissimilar to that of SLE and SjS ARDs, less frequently recognizing Ro52-1 and Ro52-4 fragments compared to patients with SLE and SjS. CONCLUSION We demonstrate for first time an unexpectedly high frequency of anti-Ro52 abs in patients with ovarian cancer, their presence indicating better overall survival. Their distinguishing epitope profile may suggest a non-SLE or SjS-related stimulus for autoAb production.
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Affiliation(s)
- Dimitrios P Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
| | - Athanasios Gkoutzourelas
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Vasilios Papadopoulos
- Department of Oncology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Christos Liaskos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Eleni Patrikiou
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Christina Tsigalou
- Laboratory of Microbiology, Democritus University of Thrace, Alexandroupolis, Greece
| | - Athanasios Saratziotis
- Department of Otolaryngology - Head and Neck Surgery, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - John Hajiioannou
- Department of Otolaryngology - Head and Neck Surgery, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Thomas Scheper
- Institute of Immunology Affiliated to Euroimmun AG, Lübeck, Germany
| | - Wolfgang Meyer
- Institute of Immunology Affiliated to Euroimmun AG, Lübeck, Germany
| | - Lazaros I Sakkas
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Christos Papandreou
- Department of Medical Oncology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Dalekos GN, Azariadis K, Lygoura V, Arvaniti P, Gampeta S, Gatselis NK. Autoimmune hepatitis in patients aged 70 years or older: Disease characteristics, treatment response and outcome. Liver Int 2021; 41:1592-1599. [PMID: 33896089 DOI: 10.1111/liv.14900] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/14/2021] [Accepted: 03/31/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Autoimmune hepatitis (AIH) affects both sexes and all age groups. However, very few studies have focused specifically on the characteristics and outcome of AIH in patients aged 70 y or older. METHODS 25/234 patients with well-established AIH and disease onset at ≥70-y (median: 73-y) were analysed and compared to the rest patients (median: 47 y). Treatment response was assessed in all patients from both groups who were eligible for treatment (n = 202). RESULTS Disease presentation was mainly insidious in both groups (19/25, 76% vs. 134/209, 64.1%; P = .313). At diagnosis, older patients had lower alaninoaminotrasferase (101[433] vs. 199[441] IU/L, P < .05) but were more frequently cirrhotic (12/25, 48% vs. 57/209, 27.3%; P = .03). Importantly, similar rates of on-treatment response (16/18, 89% vs. 154/184, 84%; P = .565), corticosteroid withdrawal (10/16, 62.5% vs. 113/154, 73.4%; P = .355) and complete withdrawal of immunosuppression (1/16, 6.3% vs. 40/154, 26%; P = .122) were achieved in both groups. Treatment-related adverse events were evenly observed between groups (6/18, 33% vs. 54/184, 29%; P = .724). In treated patients, the age ≥70 y was only associated with the overall mortality (HR 8.3 [95% CI: 2.1-36.4], P = .003), but not with the liver-related mortality (HR 3.4 [95% CI: 0.4-30.0], P = .268). CONCLUSION AIH should be seriously considered in patients ≥70 y with unexplained impaired liver function tests as the disease is not infrequent in this group and seems to bear an increased risk for advanced disease stage at diagnosis. However, if immunosuppression is started promptly, it seems as safe and effective as in younger patients.
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Affiliation(s)
- George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece.,Institute of Internal Medicine and Hepatology, Larissa, Greece
| | - Kalliopi Azariadis
- 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
| | - 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
| | - 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
| | - Stella Gampeta
- 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
| | - 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.,Institute of Internal Medicine and Hepatology, Larissa, Greece
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Zhang HP, Liu YM, Li Z, Ma YX, Li LJ, Zhao DT, Lou JL, Gao ZH, Yan HP. Clinical characteristics and HLA genotypes in Chinese patients with anti-SLA/LP-positive autoimmune hepatitis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:153. [PMID: 33569455 PMCID: PMC7867871 DOI: 10.21037/atm-20-8036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Anti-soluble liver antigen/liver pancreas (anti-SLA/LP) is a highly specific serological marker for the diagnosis of autoimmune hepatitis (AIH). The aim of the present study was to define the clinical characteristics and human leucocyte antigen (HLA) genotypes of Chinese patients with anti-SLA/LP positive AIH. Methods Ninety-one AIH patients who were anti-SLA/LP positive were enrolled in this case control study. Clinical information was obtained through reviewing patients’ clinical notes. High-resolution genotyping of HLA-A, B, C, DRB1, and DQB1 alleles was performed by sequence-based typing polymerase chain reaction on 62 of the 91 patients. Data from 500 healthy patients were used as baseline controls. Results Anti-SLA/LP-positive AIH patients were characterized as follows: adults (age 20–80 years), female (88%), and frequent anti-nuclear antibody positivity (91%). Genetically, compared with the controls, HLA-B*35:01 and C*08:01 were significantly more frequent in patients. The frequencies of HLA-B*08:01, B*40:02, DRB1*04:01, DRB1*04:05, DRB1*14:01, and DRB1*16:02 increased, and the frequency in DRB1*15:01 decreased in patients, but did not reach significance after Bonferroni’s correction. Patients with other autoimmune diseases had a higher DRB1*04:05 and DQB1*04:01 allele carrier frequency than those without. DRB1*04:05 and DQB1*04:01 alleles were found at increased frequency in patients with decompensated liver disease than those with compensated liver disease. Conclusions Chinese anti-SLA/LP-positive AIH patients have some distinct clinical characteristics than other populations reported in the literature. The presence of certain specific HLA alleles could potentially increase the risk of developing anti-SLA/LP-positive AIH or other autoimmune disease and decompensated liver disease in the Chinese population.
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Affiliation(s)
- Hai-Ping Zhang
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yan-Min Liu
- Department of Liver Disease Immunology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Zhao Li
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
| | - Yin-Xue Ma
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Li-Juan Li
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Dan-Tong Zhao
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jin-Li Lou
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Zu-Hua Gao
- Department of Pathology, McGill University, Montreal, Canada
| | - Hui-Ping Yan
- Clinical Laboratory Center and Clinical Research Center for Autoimmune Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China
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Tsouris Z, Liaskos C, Dardiotis E, Scheper T, Tsimourtou V, Meyer W, Hadjigeorgiou G, Bogdanos DP. A comprehensive analysis of antigen-specific autoimmune liver disease related autoantibodies in patients with multiple sclerosis. AUTOIMMUNITY HIGHLIGHTS 2020; 11:7. [PMID: 32308974 PMCID: PMC7147023 DOI: 10.1186/s13317-020-00130-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 03/28/2020] [Indexed: 01/14/2023]
Abstract
Introduction Abnormal liver function tests are frequently seen in patients with multiple sclerosis (MS) and their origin at times is attributed to the possible co-occurrence or the de novo induction of autoimmune liver diseases (AILD), namely autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), but comprehensive analysis of AILD-related autoantibody has not been carried out. Aim To assess the presence of AILD-related autoantibodies in a well-defined cohort of MS patients, and to assess their clinical significance. Materials and methods 133 MS (93 female) patients (102 RRMS, 27 SPMS, and 5 PPMS), mean age 42.7 ± 11.9 SD years, mean duration of disease 11.2 ± 7.2 years were studied. 150 age and sex-matched healthy individuals were tested as normal controls (NCs).Autoantibody testing was performed by indirect immunofluorescence (IF) using triple tissue and HEp-2, a multiparametric line immunoassay detecting anti-LKM1(anti-CYP2D6), anti-LC1(anti-FTCD), soluble liver antigen/liver-pancreas(anti-SLA/LP), AMA-M2, and AMA-MIT3 (BPO), PBC-specific ANA (anti-gp210, anti-sp100 and anti-PML), and ELISA for anti-F-actin SMA and anti-dsDNA antibodies. Results Reactivity to at least one autoantibody was more frequent in MS patients compared to NCs (30/133, 22.6% vs 12/150, 8%) NCs (p = 0.00058). SMAs by IIF were more frequent in MS patients (18/133, 13.53%) compared to NCs (6/150, 4%, p = 0.002%). The AIH-1 related anti-F-actin SMA by ELISA were present in 21 (15.8%), at relatively low titres (all but three of the SMA-VG pattern by IF); anti-dsDNA in 3 (2.3%), and anti-SLA/LP in none; AIH-2 anti-LKM1 autoantibodies in 1 (0.8%, negative by IF), and anti-LC1 in none; PBC-specific AMA-M2 in 2 (1.5%, both negative for AMA-MIT3 and AMA by IF) and PBC-specific ANA anti-PML in 6 (4.5%), anti-sp100 in 1 (0.8%) and anti-gp210 in 1 (0.8%). Amongst the 30 MS patients with at least one autoantibody positivity, only 4 (3%) had overt AILD (2 AIH-1 and 2 PBC). Autoantibody positivity did not differ between naïve MS patients and patients under treatment. Conclusions Despite the relatively frequent presence of liver autoantibodies, tested either by IF or molecular assays, overt AILD is rather infrequent discouraging autoantibody screening strategies of MS patients in the absence of clinical suspicion.
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Affiliation(s)
- Zisis Tsouris
- 1Department of Neurology, University General Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Christos Liaskos
- 2Department of Rheumatology and Clinical Immunology, University General Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa 40500 Greece
| | - Efthymios Dardiotis
- 1Department of Neurology, University General Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Thomas Scheper
- Institute of Experimental Immunology, Affiliated to EUROIMMUN AG, Lubeck, Germany
| | - Vana Tsimourtou
- 1Department of Neurology, University General Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Wolfgang Meyer
- Institute of Experimental Immunology, Affiliated to EUROIMMUN AG, Lubeck, Germany
| | - George Hadjigeorgiou
- 1Department of Neurology, University General Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.,4Department of Neurology, University of Nicosia, Nicosia, Cyprus
| | - Dimitrios P Bogdanos
- 2Department of Rheumatology and Clinical Immunology, University General Hospital of Larissa, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa 40500 Greece
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18
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Zachou K, Weiler-Normann C, Muratori L, Muratori P, Lohse AW, Dalekos GN. Permanent immunosuppression in SLA/LP-positive autoimmune hepatitis is required although overall response and survival are similar. Liver Int 2020; 40:368-376. [PMID: 31626725 DOI: 10.1111/liv.14280] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 09/16/2019] [Accepted: 10/06/2019] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Antibodies against soluble liver antigen/liver pancreas (anti-SLA/LP) are highly specific for autoimmune hepatitis (AIH) and have been linked with a more severe clinical course of the disease, frequent relapses after treatment withdrawal and worse outcome. To address definitely the clinical significance of anti-SLA/LP, we investigated a large number of anti-SLA/LP-positive and -negative patients followed in three referral centres. METHODS Prospectively collected data from 89 anti-SLA/LP-positive AIH patients (29 from Hamburg-Germany, 20 from Bologna-Italy and 40 from Larissa-Greece) were analysed retrospectively. Age- and sex-matched anti-SLA/LP-negative patients served as disease controls (n = 230; 1:2.5 ratio). RESULTS In respect to baseline characteristics, anti-SLA/LP-positive patients were more frequently asymptomatic compared to anti-SLA/LP-negative (P < .05). However, anti-SLA/LP-positive patients did not differ from anti-SLA/LP-negative in terms of the overall response to treatment, disease progression and survival even though, they were less likely to achieve corticosteroid withdrawal (P < .05), needed longer treatment duration to achieve first complete response (P < .001) and relapsed more frequently after treatment withdrawal compared to anti-SLA/LP-negative patients (P = <.001). CONCLUSIONS We showed that anti-SLA/LP antibodies do not characterize a group of AIH patients with distinct features and cannot identify patients with a more severe form of the disease or worse survival. Most importantly, however, anti-SLA/LP-positive patients appear to require lifelong immunosuppression as they are less likely to achieve the cessation of corticosteroids and present higher relapse rates after treatment withdrawal. Therefore, close long-term monitoring should be advised in all anti-SLA/LP-positive patients after withdrawal of immunosuppressive treatment.
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Affiliation(s)
- Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | | | - Luigi Muratori
- Department of Medical and Surgical Sciences, Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, Policlinico di Sant'Orsola, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Paolo Muratori
- Department of Medical and Surgical Sciences, Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, Policlinico di Sant'Orsola, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
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19
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Couto CA, Terrabuio DRB, Cançado ELR, Porta G, Levy C, Silva AEB, Bittencourt PL, Carvalho Filho RJD, Chaves DM, Miura IK, Codes L, Faria LC, Evangelista AS, Farias AQ, Gonçalves LL, Harriz M, Lopes EPDA, Luz GO, Oliveira PMC, Oliveira EMG, Schiavon JLN, Sevá-Pereira T. UPDATE OF THE BRAZILIAN SOCIETY OF HEPATOLOGY RECOMMENDATIONS FOR DIAGNOSIS AND MANAGEMENT OF AUTOIMMUNE DISEASES OF THE LIVER. ARQUIVOS DE GASTROENTEROLOGIA 2019; 56:232-241. [PMID: 31460591 DOI: 10.1590/s0004-2803.201900000-43] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 06/04/2019] [Indexed: 02/08/2023]
Abstract
New data concerning the management of autoimmune liver diseases have emerged since the last single-topic meeting sponsored by the Brazilian Society of Hepatology to draw recommendations about the diagnosis and treatment of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), overlap syndromes of AIH, PBC and PSC and specific complications and topics concerning AIH and cholestatic liver diseases. This manuscript updates those previous recommendations according to the best evidence available in the literature up to now. The same panel of experts that took part in the first consensus document reviewed all recommendations, which were subsequently scrutinized by all members of the Brazilian Society of Hepatology using a web-based approach. The new recommendations are presented herein.
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Affiliation(s)
- Cláudia Alves Couto
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Belo Horizonte, MG, Brasil
| | | | | | - Gilda Porta
- Hospital Menino Jesus, Hospital Sírio Libanês e Hospital A C Camargo Center, Grupo de Hepatologia e Transplante Hepático Pediátrico, São Paulo, SP, Brasil
| | - Cynthia Levy
- University of Miami, Schiff Center for Liver Diseases, USA
| | - Antônio Eduardo Benedito Silva
- Universidade Federal de São Paulo, Faculdade de Medicina, São Paulo, SP; Centro Universitário Lusíada (UNILUS), Santos, SP, Brasil
| | | | - Roberto José de Carvalho Filho
- Universidade Federal de São Paulo, Faculdade de Medicina, São Paulo, SP; Centro Universitário Lusíada (UNILUS), Santos, SP, Brasil
| | | | - Irene Kazue Miura
- Hospital Menino Jesus, Hospital Sírio Libanês e Hospital A C Camargo Center, Grupo de Hepatologia e Transplante Hepático Pediátrico, São Paulo, SP, Brasil
| | | | - Luciana Costa Faria
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Belo Horizonte, MG, Brasil
| | | | | | | | - Michelle Harriz
- Universidade de São Paulo, Faculdade de Medicina, São Paulo, SP, Brasil
| | | | | | | | - Elze Maria Gomes Oliveira
- Universidade Federal de São Paulo, Faculdade de Medicina, São Paulo, SP; Centro Universitário Lusíada (UNILUS), Santos, SP, Brasil
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20
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Dalekos GN, Gatselis NK. Variant and Specific Forms of Autoimmune Cholestatic Liver Diseases. Arch Immunol Ther Exp (Warsz) 2019; 67:197-211. [PMID: 31165900 DOI: 10.1007/s00005-019-00550-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Accepted: 05/31/2019] [Indexed: 12/12/2022]
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the main autoimmune cholestatic liver diseases. IgG4-associated sclerosing cholangitis is another distinct immune-mediated cholestatic disorder of unknown aetiology that is frequently associated with autoimmune pancreatitis or other IgG4-related diseases. Although the majority of PBC and PSC patients have a typical presentation, there are common and uncommon important variants or specific subgroups that observed in everyday routine clinical practice. In this updated review, we summarize the published data giving also our own experience on the variants and specific groups of autoimmune cholestatic liver diseases. Actually, we give in detail the underlining difficulties and the rising dilemmas concerning the diagnosis and management of these special conditions in the clinical spectrum of autoimmune cholestatic liver diseases including the IgG4-associated sclerosing cholangitis highlighting also the uncertainties and the potential new eras of the research agenda.
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Affiliation(s)
- George N Dalekos
- Institute of Internal Medicine and Hepatology, Larissa, Greece.
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, 41110, Larissa, Greece.
| | - Nikolaos K Gatselis
- Institute of Internal Medicine and Hepatology, Larissa, Greece
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, 41110, Larissa, Greece
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21
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Rigopoulou EI, Gyftaki S, Arvaniti P, Tsimourtou V, Koukoulis GK, Hadjigeorgiou G, Dalekos GN. Autoimmune hepatitis in patients with multiple sclerosis: The role of immunomodulatory treatment. Clin Res Hepatol Gastroenterol 2019; 43:e25-e32. [PMID: 30594597 DOI: 10.1016/j.clinre.2018.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 11/27/2018] [Accepted: 12/03/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Development of autoimmune hepatitis (AIH) has been sporadically reported in patients with multiple sclerosis (MS) either concurrently or after treatment with immunomodulatory drugs, including interferon-beta (IFN-β) and steroids. AIM To report a large cohort of 14 patients with MS diagnosed with AIH during an assessment of deranged liver function tests (LFTs). PATIENTS AND METHODS From 2005 to 2017, we prospectively identified 14 (13 women) patients with MS who suffered also from AIH after investigation in our department for the presence of deranged LFTs. Age at diagnosis of MS was 36.7 ± 9.3 years while at diagnosis of AIH 43.1 ± 12 years. RESULTS AIH diagnosis was based on elevation of aminotransferases in all patients [alanine aminotransferase: 520 IU/L (range: 115-1219)], elevation of IgG in 6, compatible autoantibody profile in all, including 5 patients with liver-specific autoantibodies and typical or compatible histological features in 11 patients. 5 patients were under treatment with IFN-β plus methylprednisolone pulses, 3 with IFN-β plus oral steroids, 1 with IFN-β, 4 with methylprednisolone pulses whereas 1 patient was free of treatment. The median time from IFN-β initiation to the development of hepatitis was 12 months (range:1-120). Treatment for AIH was initiated in 13 patients with prednisolone (0.5-1 mg/kg/day) plus mycophenolate myfetil (2 g/day) in 10 and prednisolone plus azathioprine in 3 with complete and partial response in 11 and 2 patients, respectively. CONCLUSIONS The differential diagnosis of hepatitis in MS patients should include AIH and in particular when immunomodulatory treatment has been preceded. Autoantibody testing and liver histology play fundamental role in establishing a prompt diagnosis of AIH in these patients. Treatment of AIH in patients with MS seems safe and efficient as complete or partial response was recorded in all of our patients.
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Affiliation(s)
- Eirini I Rigopoulou
- Institute of Internal Medicine and Hepatology, Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Sofia Gyftaki
- Institute of Internal Medicine and Hepatology, Larissa, Greece
| | - Pinelopi Arvaniti
- Institute of Internal Medicine and Hepatology, Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Vana Tsimourtou
- Department of Neurology, School of Medicine, University of Thessaly, Larissa, Greece
| | - George K Koukoulis
- Department of Pathology, School of Medicine, University of Thessaly, Larissa, Greece
| | | | - George N Dalekos
- Institute of Internal Medicine and Hepatology, Larissa, Greece; Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece.
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22
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Dalekos GN, Koskinas J, Papatheodoridis GV. Hellenic Association for the Study of the Liver Clinical Practice Guidelines: Autoimmune hepatitis. Ann Gastroenterol 2019; 32:1-23. [PMID: 30598587 PMCID: PMC6302199 DOI: 10.20524/aog.2018.0330] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a relatively rare acute or chronic liver disease of unknown etiology characterized by large heterogeneity. Its distribution is global, covering all ages, both sexes and all ethnic groups. The aim of the present Clinical Practice Guidelines (CPG) of the Hellenic Association for the Study of the Liver was to provide updated guidance and help to gastroenterologists, hepatologists, internists and general practitioners for AIH diagnosis and management. AIH diagnosis is based on clinicopathological characteristics: namely, polyclonal hypergammaglobulinemia, particularly of immunoglobulin G (IgG), circulating autoantibodies, interface hepatitis on liver histology, absence of viral hepatitis, and a favorable response to immunosuppression. Clinical manifestations at disease onset are variable, ranging from asymptomatic to the acute/severe form. Aminotransferase and bilirubin levels vary, while the presence of hepatitis at the histological level is a prerequisite for diagnosis. Autoantibodies are the hallmark for AIH diagnosis; therefore, the CPG describe the appropriate serological algorithm for their detection. AIH therapy should aim to achieve complete biochemical (normalization of IgG and aminotransferases) and histological remission. All patients who have active disease, even those with cirrhosis, should be treated with individualized and response-guided induction therapy using prednisolone in combination with azathioprine or mycophenolate mofetil as first-line therapy. Immunosuppression should be given for at least 3 years and for at least 2 years after the achievement of complete biochemical response, while a liver biopsy should be recommended before treatment discontinuation. Current CPG are also provided for several specific conditions and difficult-to-treat patients.
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Affiliation(s)
- George N. Dalekos
- Institute of Internal Medicine and Hepatology, Larissa (George N. Dalekos)
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa (George N. Dalekos)
| | - John Koskinas
- Second Department of Internal Medicine, National and Kapodistrian University of Athens, “Hippokratio” General Hospital of Athens, Athens (John Koskinas)
| | - George V. Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, “Laiko” General Hospital of Athens, Athens (George V. Papatheodoridis), Greece
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23
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Zachou K, Arvaniti P, Azariadis K, Lygoura V, Gatselis NK, Lyberopoulou A, Koukoulis GK, Dalekos GN. Prompt initiation of high-dose i.v. corticosteroids seems to prevent progression to liver failure in patients with original acute severe autoimmune hepatitis. Hepatol Res 2019; 49:96-104. [PMID: 30248210 DOI: 10.1111/hepr.13252] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 09/14/2018] [Accepted: 09/19/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Kalliopi Zachou
- Institute of Internal Medicine and Hepatology, Larissa, Greece.,Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Pinelopi Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Kalliopi Azariadis
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Vasiliki Lygoura
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, 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, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - George K Koukoulis
- Department of Pathology, Medical School, University of Thessaly, Larissa, Greece
| | - George N Dalekos
- Institute of Internal Medicine and Hepatology, Larissa, Greece.,Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
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24
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Gkoutzourelas A, Liaskos C, Mytilinaiou MG, Simopoulou T, Katsiari C, Tsirogianni A, Daoussis D, Scheper T, Meyer W, Bogdanos DP, Sakkas LI. Anti-Ro60 Seropositivity Determines Anti-Ro52 Epitope Mapping in Patients With Systemic Sclerosis. Front Immunol 2018; 9:2835. [PMID: 30581434 PMCID: PMC6293197 DOI: 10.3389/fimmu.2018.02835] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 11/16/2018] [Indexed: 12/14/2022] Open
Abstract
Epitope mapping of anti-Ro52 antibodies (Abs) has been extensively studied in patients with Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE). Comprehensive epitope mapping in systemic sclerosis (SSc), where anti-Ro52 antibodies are also frequently detected, has not been performed. The aim of the present study was to fully characterize Ro52 epitopes in anti-Ro52-positive SSc using Ro52 fragments spanning the full antigen. Further analysis was made according to anti-Ro60 status. Epitope mapping was performed in 43 anti-Ro52-positive SSc patients. Seventy eight anti-Ro52-positive pathological controls, including 20 patients with SjS, 28 patients with SLE, 15 patients with dermatomyositis (DM), and 15 patients with primary biliary cholangitis (PBC), and 20 anti-Ro52-negative healthy individuals as normal controls were also tested. Five recombinant Ro52 fragments [Ro52-1 (aa 1-127), Ro52-2 (aa 125-268), Ro52-3 (aa 268-475), Ro52-4 (aa 57-180), and Ro52-5 (aa 181-320) were used to test reactivity by line-immunoassay and in house ELISA. Anti-Ro60 reactivity was tested by ELISA. All anti-Ro52 positive sera reacted with Ro52-2; none recognized Ro52-3. Antibodies against Ro52-1 were less frequently found in SSc than in SjS/SLE (11.6 vs. 41.7%, p = 0.001); and antibodies against Ro52-4 were less frequently found in SSc than in SjS/SLE (27.9 vs. 50%, p = 0.03). In SSc patients, reactivity against Ro52-1 was more frequent in anti-Ro52+/anti-Ro60+ than in anti-Ro52+/anti-Ro60-patients (33.3 vs. 0%, p = 0.003). In this comprehensive analysis of Ro52 epitope mapping in SSc, the coiled coil domain remains the predominant epitope on Ro52. Contrary to SjS and SLE, patients with SSc fail to identify epitopic regions within the N-terminus of the protein, especially if they lack con-current anti-Ro60 reactivity.
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Affiliation(s)
- Athanasios Gkoutzourelas
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Christos Liaskos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Maria G. Mytilinaiou
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Theodora Simopoulou
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Christina Katsiari
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Alexandra Tsirogianni
- Department of Immunology-Histocompatibility, Evangelismos General Hospital, Athens, Greece
| | - Dimitrios Daoussis
- Department of Rheumatology, Patras University Hospital, Faculty of Medicine, University of Patras Medical School, Patras, Greece
| | - Thomas Scheper
- Institute of Immunology Affiliated to Euroimmun AG, Lübeck, Germany
| | - Wolfgang Meyer
- Institute of Immunology Affiliated to Euroimmun AG, Lübeck, Germany
| | - Dimitrios P. Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Lazaros I. Sakkas
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
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25
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Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. The clinical usage and definition of autoantibodies in immune-mediated liver disease: A comprehensive overview. J Autoimmun 2018; 95:144-158. [DOI: 10.1016/j.jaut.2018.10.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 10/09/2018] [Accepted: 10/11/2018] [Indexed: 02/06/2023]
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26
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Bossen L, Gerussi A, Lygoura V, Mells GF, Carbone M, Invernizzi P. Support of precision medicine through risk-stratification in autoimmune liver diseases – histology, scoring systems, and non-invasive markers. Autoimmun Rev 2018; 17:854-865. [DOI: 10.1016/j.autrev.2018.02.013] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 02/26/2018] [Indexed: 02/07/2023]
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27
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Sebode M, Weiler-Normann C, Liwinski T, Schramm C. Autoantibodies in Autoimmune Liver Disease-Clinical and Diagnostic Relevance. Front Immunol 2018; 9:609. [PMID: 29636752 PMCID: PMC5880919 DOI: 10.3389/fimmu.2018.00609] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 03/12/2018] [Indexed: 12/12/2022] Open
Abstract
Testing for liver-related autoantibodies should be included in the workup of patients with hepatitis or cholestasis of unknown origin. Although most of these autoantibodies are not disease specific, their determination is a prerequisite to diagnose autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), and they are components of the diagnostic scoring system in these diseases. In primary sclerosing cholangitis (PSC), on the other hand, autoantibodies are frequently present but play a minor role in establishing the diagnosis. In PSC, however, data on antibodies suggest a link between disease pathogenesis and the intestinal microbiota. This review will focus on practical aspects of antibody testing in the three major autoimmune liver diseases AIH, PBC, and PSC.
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Affiliation(s)
- Marcial Sebode
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Christina Weiler-Normann
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Timur Liwinski
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- 1st Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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28
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Sebode M, Hartl J, Vergani D, Lohse AW. Autoimmune hepatitis: From current knowledge and clinical practice to future research agenda. Liver Int 2018; 38:15-22. [PMID: 28432836 DOI: 10.1111/liv.13458] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 04/12/2017] [Indexed: 12/12/2022]
Abstract
Autoimmune hepatitis is a chronic inflammatory liver disease. Unknown triggers lead to a mainly T cell-mediated immune response targeting the liver, the main auto-antigen of which has not been identified yet. The diagnosis of autoimmune hepatitis is based on the elevation of immunoglobulin G/hypergammaglobulinemia, detection of characteristic autoantibodies as well as a typical pattern on liver histology. Exclusion of other causes of hepatitis and response to immunosuppressive treatment support the diagnosis of autoimmune hepatitis. The mainstay of autoimmune hepatitis treatment has, from its first description to the current time, consisted of predniso(lo)ne to induce remission, in combination with azathioprine, which is used to maintain it. Nonetheless, side effects and non-response with ongoing inflammation despite standard therapy demand treatment alternatives. Only through a better understanding of the pathogenesis of autoimmune hepatitis can a more selective and effective treatment be offered to patients in the future. Until this goal is reached, improvement of diagnostic approaches and optimization of current therapy rank highest on the research agenda for autoimmune hepatitis.
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Affiliation(s)
- Marcial Sebode
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Hartl
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Diego Vergani
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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29
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Polychronopoulou E, Lygoura V, Gatselis NK, Dalekos GN. Increased cholestatic enzymes in two patients with long-term history of ulcerative colitis: consider primary biliary cholangitis not always primary sclerosing cholangitis. BMJ Case Rep 2017; 2017:bcr-2017-220824. [PMID: 28951510 DOI: 10.1136/bcr-2017-220824] [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: 12/14/2022] Open
Abstract
Several hepatobiliary disorders have been reported in ulcerative colitis (UC) patients with primary sclerosing cholangitis (PSC) being the most specific. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, rarely occurs in UC. We present two PBC cases of 67 and 71 years who suffered from long-standing UC. Both patients were asymptomatic but they had increased cholestatic enzymes and high titres of antimitochondrial antibodies (AMA)-the laboratory hallmark of PBC. After careful exclusion of other causes of cholestasis by MRI/magnetic resonance cholangiopancreatography (MRCP), virological and microbiological investigations, a diagnosis of PBC associated with UC was established. The patients started ursodeoxycholic acid (13 mg/kg/day) with complete response. During follow-up, both patients remained asymptomatic with normal blood biochemistry. Although PSC is the most common hepatobiliary manifestation among patients with UC, physicians must keep also PBC in mind in those with unexplained cholestasis and repeatedly normal MRCP. In these cases, a reliable AMA testing can help for an accurate diagnosis.
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Affiliation(s)
- Erietta Polychronopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - Vasiliki Lygoura
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
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30
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Global Disparities and Their Implications in the Occurrence and Outcome of Autoimmune Hepatitis. Dig Dis Sci 2017; 62:2277-2292. [PMID: 28710658 DOI: 10.1007/s10620-017-4675-y] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 07/06/2017] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis has a variable occurrence, clinical phenotype, and outcome, and the factors contributing to this variability are uncertain. The goals of this review are to examine the global disparities in the occurrence and outcome of autoimmune hepatitis, suggest bases for these disparities, and encourage investigations that extend beyond single-center experiences. Disparities in the incidence and prevalence of autoimmune hepatitis in different age groups, genders, ethnicities, and geographical regions suggest that factors other than genetic predisposition are involved. Age- and gender-related antigen exposures from the external (infections, toxins, and medications) and internal (intestinal microbiome) environment may affect the incidence of the disease, and the timeliness and nature of treatment may influence its prevalence. The increasing incidence of autoimmune hepatitis in Spain, Denmark, and the Netherlands suggests that a new etiological trigger has been introduced or that the susceptible population has changed. Variations in mortality between Western and Asian-Pacific countries may result from differences in disease detection or management, and variations in gender predilection, peak age of onset, frequency of concurrent immune diseases, and serological profile may reflect gender-biased and age-related antigen exposures and genetic predispositions. Global collaborations, population-based epidemiological studies that identify case clustering, and controlled interview-based surveys are mechanisms by which to understand these disparities and improve management. In conclusion, autoimmune hepatitis has a rising incidence in some countries and variable occurrence, phenotype, and outcome between countries and subgroups within countries. These disparities suggest that unrecognized population-based environmental, infectious, or socioeconomic factors are affecting its character.
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A review of the role and clinical utility of anti-Ro52/TRIM21 in systemic autoimmunity. Rheumatol Int 2017; 37:1323-1333. [DOI: 10.1007/s00296-017-3718-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 04/06/2017] [Indexed: 01/23/2023]
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Zachou K, Gabeta S, Shums Z, Gatselis NK, Koukoulis GK, Norman GL, Dalekos GN. COMP serum levels: A new non-invasive biomarker of liver fibrosis in patients with chronic viral hepatitis. Eur J Intern Med 2017; 38:83-88. [PMID: 28100410 DOI: 10.1016/j.ejim.2017.01.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 12/22/2016] [Accepted: 01/09/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Recently we have shown that cartilage oligomeric matrix protein (COMP), a fibrillar collagen assembly regulator, is strongly associated with cirrhosis and hepatocellular carcinoma progression. Therefore, we assessed whether serum COMP levels can be used as a non-invasive fibrosis marker in patients with chronic viral hepatitis (CVH) and compared this marker with standard methods for disease stage assessment [histology, transient elastography (TE), APRI, FIB-4]. METHODS Sera from 116 CVH patients, 66 HBV [24 female; median age 53(22-76)] and 50 HCV [21 female; median age 48.5(25-69)] were investigated by COMP-ELISA. APRI and FIB-4 score was calculated in all along with TE. Liver biopsy was performed in 61. Patients were divided into two groups (F1/F2 and F3/F4) according to Metavir score. RESULTS 55/116 (47%) CVH patients were classified in F3/F4-group according to TE [14.3(9.3-75)kPa]. APRI score was >1.5 in 21/116 and FIB-4>3.25 in 20/116. Liver histology revealed 24/61 (39%) patients with significant fibrosis (stage 3-4), while 12/61 (19.7%) had cirrhosis. COMP levels correlated with TE measurements (r=0.5; p<0.001) and APRI score (r=0.23; p<0.02). The diagnostic accuracy of COMP in detecting cirrhosis was as good as TE, APRI and FIB-4 index (AUC 0.884) with sensitivity and specificity of 83.3% and 83.7% (cut-off 11.5U/L). CONCLUSIONS COMP serum levels performed as well as TE, APRI and FIB4 score in detecting cirrhosis in CVH patients, suggesting COMP as a sensitive non-invasive, easy to perform biomarker of liver fibrosis. Further studies are needed in order to validate our findings in CVH patients.
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Affiliation(s)
- Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, Thessaly University, Larissa, Greece
| | - Stella Gabeta
- Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, Thessaly University, Larissa, Greece
| | - Zakera Shums
- Inova Diagnostics, Inc., San Diego, CA, United States
| | - Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, Thessaly University, Larissa, Greece
| | - George K Koukoulis
- Department of Pathology, School of Medicine, University of Thessaly, Larissa, Greece
| | - Gary L Norman
- Inova Diagnostics, Inc., San Diego, CA, United States
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, Thessaly University, Larissa, Greece.
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Gatselis NK, Vakrakou AG, Zachou K, Androutsakos T, Azariadis K, Hatzis G, Manoussakis MN, Dalekos GN. Decreased serum DNase1-activity in patients with autoimmune liver diseases. Autoimmunity 2017; 50:125-132. [DOI: 10.1080/08916934.2017.1279610] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [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, School of Medicine, University of Thessaly, Larissa, Greece,
| | - Aigli G. Vakrakou
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece,
- Department of Molecular Medicine, Hellenic Pasteur Institute, Athens, Greece, and
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece,
| | - Theodoros Androutsakos
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece,
| | - Kalliopi Azariadis
- Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece,
| | - Gregorios Hatzis
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece,
| | - Menelaos N. Manoussakis
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece,
- Department of Molecular Medicine, Hellenic Pasteur Institute, Athens, Greece, and
- Joint Academic Rheumatology Program, National and Kapodistrian University of Athens, Athens, Greece
| | - George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece,
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Muratori P, Lalanne C, Bianchi G, Lenzi M, Muratori L. Predictive factors of poor response to therapy in Autoimmune Hepatitis. Dig Liver Dis 2016; 48:1078-1081. [PMID: 27378707 DOI: 10.1016/j.dld.2016.06.018] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 06/03/2016] [Accepted: 06/15/2016] [Indexed: 12/11/2022]
Abstract
AIM To evaluate "ex ante" the predictive factors of incomplete/absent response to the standard therapy in a well characterized series of Autoimmune Hepatitis (AIH) patients from Italy. METHODS Of 282 AIH patients screened from our database 166 (59%) had a sustained response and 116 (41%) had an incomplete/absent response to the therapy; all patients were analyzed for the clinical, serological and histological parameters at diagnosis. RESULTS The patients with incomplete/absent response were characterized by significantly younger age (30 aa vs 42 aa p=0.001) and a significantly higher frequency of cirrhosis at diagnosis than patients who had a complete response to therapy (26% vs 3% p<0.0001); furthermore, patients with incomplete/absent response were distinguished from those with a complete response for significantly lower serum levels of both AST (7.9×upper normal limit [unl] vs 13×unl p<0.005) and ALT (10.9×unl vs 18×unl p=0.002) at diagnosis, and by an increase in IgG serum levels (1.43×unl vs 1.27×unl p=0.009). After stepwise logistic regression, cirrhosis at diagnosis (p=0.003, OR 0.12, 95% CI 0.03-0.49) and younger age (p=0.001, OR 1.03, 95% CI 1.01-1.05) represent two independent variables of incomplete/absent response. CONCLUSIONS Younger age and cirrhosis are predictive of lack of response to the standard therapy in AIH patients.
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Affiliation(s)
- Paolo Muratori
- Centre for the study and therapy of Autoimmune liver Disease, Bologna, Italy; Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Alma Mater Studiorum - Università di Bologna, Italy.
| | - Claudine Lalanne
- Centre for the study and therapy of Autoimmune liver Disease, Bologna, Italy; Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Alma Mater Studiorum - Università di Bologna, Italy.
| | - Giampaolo Bianchi
- Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Alma Mater Studiorum - Università di Bologna, Italy.
| | - Marco Lenzi
- Centre for the study and therapy of Autoimmune liver Disease, Bologna, Italy; Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Alma Mater Studiorum - Università di Bologna, Italy.
| | - Luigi Muratori
- Centre for the study and therapy of Autoimmune liver Disease, Bologna, Italy; Dipartimento di Scienze Mediche e Chirurgiche (DIMEC), Alma Mater Studiorum - Università di Bologna, Italy.
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Zachou K, Gatselis NK, Arvaniti P, Gabeta S, Rigopoulou EI, Koukoulis GK, Dalekos GN. A real-world study focused on the long-term efficacy of mycophenolate mofetil as first-line treatment of autoimmune hepatitis. Aliment Pharmacol Ther 2016; 43:1035-47. [PMID: 26991238 DOI: 10.1111/apt.13584] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 10/20/2015] [Accepted: 02/18/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Front-line therapy with mycophenolate mofetil (MMF) in autoimmune hepatitis (AIH) has shown high on-treatment remission rates. AIM To study prospectively in a real-world fashion the long-term outcome of a large group of consecutive treatment-naïve AIH patients. METHODS Between 2000 and 2014, 158 patients were recruited but only 131 were eligible for treatment (109 MMF/prednisolone; 22 prednisolone ± azathioprine). Long-term data on outcome after drug withdrawal were evaluated. Patients stopped treatment after having achieved complete response (normal transaminases and IgG) for at least the last 2 years. RESULTS At diagnosis, 31.6% of patients had cirrhosis and 72.8% insidious presentation. A total of 102 of 109 (93.6%) responded initially to MMF within 2 (1-18) months. A total of 78 of 109 (71.6%) had complete response on treatment and 61 of 78 (78.2%) maintained remission off prednisolone. MMF-treated patients had increased probability of complete response compared to those receiving azathioprine (P = 0.03). Independent predictors of complete response were lower ALT at 6 months (P = 0.001) and acute presentation (P = 0.03). So far, treatment withdrawal was feasible in 40/109 patients and 30 (75%) are still in remission after 24 (2-129) months. Remission maintenance was associated with longer MMF treatment (P = 0.005), higher baseline ALT (P < 0.02), lower IgG on 6 months (P = 0.004) and histological improvement. CONCLUSIONS Mycophenolate mofetil proved to be an efficient first-line treatment for AIH, achieving so far the highest rates of remission maintenance off treatment (75%) ever published for at least a median of 2 years, although the remission criteria used were strict. However, the risk of potential bias and overestimation of intervention benefits from MMF cannot be completely excluded as this is a real world and not a randomised controlled trial.
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Affiliation(s)
- K Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - N K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - P Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - S Gabeta
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - E I Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - G K Koukoulis
- Department of Pathology, Medical School, University of Thessaly, Larissa, Greece
| | - G N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
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Stokkeland K, Ludvigsson JF, Hultcrantz R, Ekbom A, Höijer J, Bottai M, Stephansson O. Increased risk of preterm birth in women with autoimmune hepatitis - a nationwide cohort study. Liver Int 2016; 36:76-83. [PMID: 26098001 DOI: 10.1111/liv.12901] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 06/12/2015] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS The aim of our study was to investigate the risks of pregnancy and childbirth complications in women with autoimmune hepatitis compared to the population controls. METHODS In a nationwide cohort study of all pregnancies between 2006 and 2011 we investigated the risks of adverse pregnancy outcome in 171 births in women with diagnosed autoimmune hepatitis using the data from the Swedish Medical Birth and Patient Registries. Births to women without autoimmune hepatitis served as population controls (n = 576 642). Relative risks (RR) with 95% confidence intervals (CI) were calculated using Poisson regression models adjusting for potential confounders. RESULTS Women with AIH had an increased risk of gestational diabetes (RR = 4.35, 95% CI 2.21-8.57), of preterm birth (RR = 3.21, 95% CI 1.97-4.92) and of low-birth-weight child (RR = 2.51, 95% CI 1.51-4.19). We found no statistically significant association between autoimmune hepatitis and pre-eclampsia, caesarean section, low 5-min Apgar score, small for gestational age birth, congenital malformation and neonatal mortality. CONCLUSIONS Autoimmune hepatitis is a risk factor for adverse pregnancy outcomes. High quality prenatal and antenatal care is important for women with autoimmune hepatitis and their infants.
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Affiliation(s)
- Knut Stokkeland
- Department of Medicine, Visby Hospital, Visby, Sweden.,Gastroenterology and Hepatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Jonas F Ludvigsson
- Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Rolf Hultcrantz
- Gastroenterology and Hepatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.,Division of Hepatology, Karolinska Hospital, Stockholm, Sweden
| | - Anders Ekbom
- Clinical Epidemiology Unit, Department of Medicine, Karolinska Hospital and Institutet, Solna, Stockholm, Sweden
| | - Jonas Höijer
- Unit of Biostatistics, IMM, Karolinska Institutet, Stockholm, Sweden
| | - Matteo Bottai
- Unit of Biostatistics, IMM, Karolinska Institutet, Stockholm, Sweden
| | - Olof Stephansson
- Clinical Epidemiology Unit, Department of Medicine, Karolinska Hospital and Institutet, Solna, Stockholm, Sweden.,Department of Women's and Children's Health, Karolinska Hospital and Institutet, Stockholm, Sweden
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Kirstein MM, Metzler F, Geiger E, Heinrich E, Hallensleben M, Manns MP, Vogel A. Prediction of short- and long-term outcome in patients with autoimmune hepatitis. Hepatology 2015; 62:1524-35. [PMID: 26178791 DOI: 10.1002/hep.27983] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 07/09/2015] [Indexed: 12/22/2022]
Abstract
UNLABELLED Autoimmune hepatitis (AIH) is a chronic inflammatory disease characterized by a loss of tolerance toward the hepatocellular epithelium. Liver transplantation (LT) represents the ultimate therapeutic option for a fulminant course or end-stage liver disease. The aim of this study was to elucidate the clinical, serological, and genetic features of remission, relapse, and overall and LT-free survival. Between 2000 and 2014, 354 AIH patients from Hannover Medical School were included. Clinical, laboratory, and histological reports were analyzed. DRB1 allele analyses were performed in 264 AIH and 399 non-AIH patients. Cox's regression analysis was performed to identify factors significantly associated with survival. Patients diagnosed in childhood were at higher risk for relapses (P=0.003), requirement for LTs (P=0.014, log rank), and had a reduced life expectancy (P<0.001, log rank). Detection of soluble liver antigen/liver pancreas antigen (SLA/LP) antibodies was significantly associated with reduced overall and LT-free survival (P=0.037; P=0.021). Cirrhosis, which was evident in 25% at first diagnosis, was found to be a predictor of poor survival and requirement for LT (P=0.003; P=0.009). DRB1*04:01-positive phenotype was associated with a higher rate of complete remissions and with a lower frequency of cirrhosis and LTs. There were no significant differences for subsequent relapses or survival in patients achieving either partial or complete remission. CONCLUSION Diagnosis<18 years, histological cirrhosis at first diagnosis and SLA/LP antibodies are major risk factors for a poor short- and long-term outcome. These patients are in need of high surveillance. Separating patients with positive SLA/LP antibodies into a third group may be reconsidered. DRB1*04:01 positivity has been identified in association with a favorable clinical outcome.
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Affiliation(s)
- Martha M Kirstein
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | - Frauke Metzler
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | - Elena Geiger
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | - Eyk Heinrich
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | | | - Michael P Manns
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | - Arndt Vogel
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
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Affiliation(s)
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- EASL office, 7 Rue Daubin, CH 1203 Geneva, Switzerland,
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Chen ZX, Shao JG, Shen Y, Zhang J, Hua Y, Wang LJ, Qin G. Prognostic Implications of Antibodies to Soluble Liver Antigen in Autoimmune Hepatitis: A PRISMA-Compliant Meta-Analysis. Medicine (Baltimore) 2015; 94:e953. [PMID: 26061326 PMCID: PMC4616476 DOI: 10.1097/md.0000000000000953] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Prognostic evaluation is important for the management of patients with autoimmune hepatitis (AIH). Although some autoantibodies have been associated with disease activity and outcomes, the implication of antibodies to soluble liver antigen (anti-SLA) remains controversial. To conduct a meta-analysis of observational studies which addressed differences in clinical characteristics by anti-SLA status in patients with AIH. Three databases PUBMED, EMBASE, and OVID were systemically searched up to January 2015 using the terms "soluble liver antigen" or "liver-pancreas antigen" and "autoimmune hepatitis" with restriction to English-language. Studies were included if at least 50 patients with objective diagnosis of AIH were enrolled, anti-SLA detection was performed for the patients, and prognostic outcomes and/or disease severity were reported. Two investigators independently reviewed retrieved literature and evaluated eligibility. Discrepancy was resolved by discussion and a third investigator. Quality of included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale (NOS). Data were pooled using fixed-effect or random-effect models. Prognostic outcomes included death from hepatic failure or requirement for liver transplantation, and responses to immunosuppressive therapy regarding remission or relapse. Results were combined on the odds ratio (OR) or standardized mean difference (SMD) scales. Eight studies were enrolled in this study, involving a total of 1297 AIH patients among whom 195 with anti-SLA. Pooled serum AST levels tended to be lower in anti-SLA seropositive patients. The presence of anti-SLA conferred 3.1-fold increased risk of hepatic death in AIH patients. The remission rates were comparable between anti-SLA seropositive and seronegative AIH patients, while anti-SLA positivity was associated with nearly 2-fold increased risk of relapse after drug withdrawal. Human leukocyte antigen (HLA) allotype DR3 was positively associated with anti-SLA. Antibodies to SLA may be an indicator of increased risks of hepatic death and treatment relapse for AIH patients. Our findings suggest that the anti-SLA seropositive patients should be maintained indefinitely on individually adjusted medication to improve their prognosis.
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Affiliation(s)
- Zhi-Xian Chen
- From the Department of Clinical Pharmacy, Nantong Health College of Jiangsu Province, China (Z-XC); Center for Liver Diseases, Nantong Third People's Hospital, Nantong University, China (J-GS, YH, L-JW, GQ); and Department of Epidemiology and Medical Statistics, Nantong University, China (YS, JZ)
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Gatselis NK, Zachou K, Koukoulis GK, Dalekos GN. Autoimmune hepatitis, one disease with many faces: Etiopathogenetic, clinico-laboratory and histological characteristics. World J Gastroenterol 2015; 21:60-83. [PMID: 25574080 PMCID: PMC4284362 DOI: 10.3748/wjg.v21.i1.60] [Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 10/30/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is an unresolving progressive liver disease of unknown etiology characterized by hypergammaglobulinemia, autoantibodies detection and interface hepatitis. Due to the absence of specific diagnostic markers and the large heterogeneity of its clinical, laboratory and histological features, AIH diagnosis may be potentially difficult. Therefore, in this in-depth review we summarize the substantial progress on etiopathogenesis, clinical, serological and histological phenotypes of AIH. AIH has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations vary from asymptomatic to severe or rarely fulminant hepatitis. Hypergammaglobulinemia with selective elevation of IgG is found in most cases. Autoimmune attack is perpetuated, possibly via molecular mimicry, and favored by the impaired control of T-regulatory cells. Histology (interface hepatitis, emperipolesis and hepatic rosette formation) and autoantibodies detection although not pathognomonic, are still the hallmark for a timely diagnosis. AIH remains a major diagnostic challenge. AIH should be considered in every case in the absence of viral, metabolic, genetic and toxic etiology of chronic or acute hepatitis. Laboratory personnel, hepato-pathologists and clinicians need to become more familiar with disease expressions and the interpretation of liver histology and autoimmune serology to derive maximum benefit for the patient.
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