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Aoyagi T, Goya T, Imoto K, Azuma Y, Hioki T, Kohjima M, Tanaka M, Oda Y, Ogawa Y. Two types of regenerative cell populations appear in acute liver injury. Stem Cell Reports 2025:102503. [PMID: 40345206 DOI: 10.1016/j.stemcr.2025.102503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 04/10/2025] [Accepted: 04/10/2025] [Indexed: 05/11/2025] Open
Abstract
The liver has a robust regenerative capacity. However, the mechanisms underlying this process remain unclear. Numerous studies on liver regeneration have been previously conducted using partial hepatectomy models, which may not fully represent acute liver injury with inflammation and necrosis. This is commonly observed in the majority of clinical cases. In this study, we conducted a single-cell RNA sequencing (RNA-seq) analysis of liver regeneration in acetaminophen-treated mice using publicly available data. We found that two distinct populations of regenerative cells simultaneously appeared within the same regenerative process. The two populations significantly differed in terms of cell morphology, differentiation, localization, proliferation rate, and signal response. Moreover, one of the populations was induced by contact with necrotic tissue and demonstrated a higher proliferative capacity with a dedifferentiated feature. These findings provide new insights into liver regeneration and therapeutic strategies for liver failure.
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Affiliation(s)
- Tomomi Aoyagi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Goya
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koji Imoto
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuki Azuma
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomonobu Hioki
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Motoyuki Kohjima
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Gastroenterology, NHO Kyushu Medical Center, Fukuoka, Japan
| | - Masatake Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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2
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Myoteri D, Sakellariou S, Tiniakos DG. Histopathology of Autoimmune Hepatitis: An Update. Adv Anat Pathol 2025:00125480-990000000-00148. [PMID: 40255040 DOI: 10.1097/pap.0000000000000500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/22/2025]
Abstract
Autoimmune hepatitis (AIH) is a rare immune-mediated chronic liver disease that is diagnosed based on a combination of biochemical, immunologic, and histologic features and the exclusion of other causes of liver disease. According to the new consensus criteria of the International Autoimmune Hepatitis Pathology Group (IAIHPG), the likely histologic features include a chronic hepatitis pattern of injury with a lymphoplasmacytic portal infiltrate, interface activity, and portal-based fibrosis. More than mild lobular hepatitis with any of the above features can also be diagnosed as likely AIH in the absence of features of another liver disease. Centrilobular injury with prominent hepatocellular necrosis and mononuclear inflammation may represent an acute-onset disease and indicate possible AIH in the absence of concurrent liver disease. Kupffer cell hyaline bodies and portal lymphocyte apoptosis are significantly associated with AIH, whereas emperipolesis and hepatocellular rosette formation are nonspecific features indicative of disease severity. Liver histology is an integral part of the clinical diagnostic scoring system and is required to confirm or support AIH diagnosis. Substitution of the histologic component of the simplified AIH scoring system with the consensus IAIHPG criteria has been proposed to optimize clinical diagnosis. This review explores the significant role of histopathology in AIH by analyzing its main features and current histologic diagnostic criteria, different AIH presentations, differential diagnosis, assessment of concurrent liver disease, and identification of AIH variants with primary cholangiopathy.
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Affiliation(s)
| | - Stratigoula Sakellariou
- 1st Department of Pathology, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Dina G Tiniakos
- Department of Pathology, Aretaieion Hospital, Medical School
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
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3
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Gleeson D, Bornand R, Brownlee A, Dhaliwal H, Dyson JK, Hails J, Henderson P, Kelly D, Mells GF, Miquel R, Oo YH, Sutton A, Yeoman A, Heneghan MA. British Society of Gastroenterology guidelines for diagnosis and management of autoimmune hepatitis. Gut 2025:gutjnl-2024-333171. [PMID: 40169244 DOI: 10.1136/gutjnl-2024-333171] [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: 06/22/2024] [Accepted: 10/22/2024] [Indexed: 04/03/2025]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if untreated, often leads to cirrhosis, liver failure and death. The last British Society of Gastroenterology (BSG) guideline for the management of AIH was published in 2011. Since then, our understanding of AIH has advanced in many areas. This update to the previous guideline was commissioned by the BSG and developed by a multidisciplinary group. The aim of this guideline is to review and summarise the current evidence, in order to inform and guide diagnosis and management of patients with AIH and its variant syndromes. The main focus is on AIH in adults, but the guidelines should also be relevant to older children and adolescents.
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Affiliation(s)
- Dermot Gleeson
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Division of Clinical Medicine, School of Medicine and Population Science, University of Sheffield, Sheffield, UK
| | | | | | - Harpreet Dhaliwal
- Department of Gastroenterology, Manchester Royal Infirmary, Manchester, UK
| | - Jessica K Dyson
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Janeane Hails
- Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK
| | - Paul Henderson
- Royal Hospital for Children and Young People, Edinburgh, UK
| | - Deirdre Kelly
- Birmingham Women's & Children's Hospital, Birmingham, UK
- University of Birmingham, Birmingham, UK
| | - George F Mells
- Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Rosa Miquel
- Liver Histopathology Laboratory, Institute of Liver Studies, King's College London, London, UK
| | - Ye H Oo
- Centre for Liver and Gastroenterology research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- NIHR Biomedical Research Centre, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
- Centre for Rare Diseases, European Reference Network on Hepatological Diseases (ERN-RARE-LIVER) centre, Birmingham, UK
| | - Anthea Sutton
- Sheffield Centre for Health and Related Research, The University of Sheffield, Sheffield, UK
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4
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Engel B, Assis DN, Bhat M, Clusmann J, Drenth JPH, Gerussi A, Londoño MC, Oo YH, Schregel I, Sebode M, Taubert R, the International Autoimmune Hepatitis Group (IAIHG) collaborators, the European Reference Network for Rare Liver Diseases (ERN RARE-LIVER). Quo vadis autoimmune hepatitis? - Summary of the 5 th international autoimmune hepatitis group research workshop 2024. JHEP Rep 2025; 7:101265. [PMID: 39897612 PMCID: PMC11783120 DOI: 10.1016/j.jhepr.2024.101265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/28/2024] [Accepted: 10/30/2024] [Indexed: 02/04/2025] Open
Abstract
Autoimmune hepatitis (AIH) is a rare chronic liver disease with an increasing incidence in many countries. Chronic autoimmune responses against the liver can cause hepatic and extrahepatic symptoms, decreased quality of life and reduced liver transplant-free survival if inadequately treated. Although standard treatment with corticosteroids and thiopurines improves the life expectancy of patients with AIH, remission rates and tolerability are generally overestimated and the development of alternative first-line and salvage therapies has been disappointingly slow compared to in rheumatological diseases or inflammatory bowel disease. Other gaps include the lack of disease-specific diagnostic markers for AIH. Similarly, the new entity of drug-induced autoimmune-like hepatitis underscores the need to re-evaluate previous diagnostic criteria. The International AIH Group (IAIHG) has initiated a series of research workshops over the last decade to promote the identification of research gaps and subsequently improve the pace of scientific progress by stimulating collaboration between expert centres. This review reports on the results of the 5th Research Workshop, held in Hannover, Germany in June 2024, and summarises the progress made since the 4th Workshop in 2022. Patient representatives from the European Reference Network (ERN) Rare Liver Youth Panel participated in the workshop. The specific objectives of this year's 5th Workshop were: (1) To further improve diagnostics. (2) Initiate clinical trials including knowledge transfer on drugs from extrahepatic immune-mediated diseases, including B cell-depleting CAR T cells. (3) Utilisation of multi-omics approaches to improve the understanding of disease pathogenesis. (4) Application of machine learning-based approaches established in oncology or transplantation medicine to improve diagnosis and outcome prediction in AIH.
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Affiliation(s)
- Bastian Engel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Mamatha Bhat
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Jan Clusmann
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Joost PH. Drenth
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, The Netherlands
| | - Alessio Gerussi
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Centre for Autoimmune Liver Diseases & Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - María-Carlota Londoño
- Liver Unit, Hospital Clínic Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Universitat de Barcelona, Centro de investigación biomédica en red Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Ye Htun Oo
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust & Centre for Liver and Gastro Research, NIHR Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Ida Schregel
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Marcial Sebode
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - the International Autoimmune Hepatitis Group (IAIHG) collaborators
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Yale School of Medicine, New Haven, CT USA
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, The Netherlands
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Centre for Autoimmune Liver Diseases & Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
- Liver Unit, Hospital Clínic Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Universitat de Barcelona, Centro de investigación biomédica en red Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust & Centre for Liver and Gastro Research, NIHR Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - the European Reference Network for Rare Liver Diseases (ERN RARE-LIVER)
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Yale School of Medicine, New Haven, CT USA
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, The Netherlands
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- Centre for Autoimmune Liver Diseases & Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
- Liver Unit, Hospital Clínic Barcelona, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Universitat de Barcelona, Centro de investigación biomédica en red Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust & Centre for Liver and Gastro Research, NIHR Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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Chen W, Noel G, Amin M, Chen F. The utility of the mHAI scoring system in pediatric autoimmune hepatitis diagnosis and its association with treatment response. Ann Diagn Pathol 2024; 73:152381. [PMID: 39418718 DOI: 10.1016/j.anndiagpath.2024.152381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 10/07/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory autoimmune disease with either acute or chronic presentation. Previous scoring systems have primarily focused on chronic hepatitis, but none have been validated in an acute setting of pediatric patients. This study aimed to: 1) summarize the clinicopathologic characteristics of pediatric AIH patients; 2) assess if the modified Hepatic Activity Index (mHAI) can be used in both acute and chronic presentations of pediatric AIH; 3) evaluate the association of initial mHAI scores with treatment response at various endpoints. Thirty-one pediatric AIH patients were categorized into acute and chronic presentation groups. Biopsies were reviewed using the mHAI grading and staging system. AIH treatment endpoints were analyzed: 4 weeks (response vs. non-response), 6 months (complete vs. insufficient response), and approximately 12 months (histological remission vs. non-remission). Patients with acute AIH had higher mean mHAI scores and more prominent interface activity. Those achieving complete response at 6 months had significantly higher mean mHAI scores compared to those with an insufficient response. Notably, patients demonstrating fibrosis reversal at the 1-year follow-up often had higher initial mHAI scores. The mHAI can be used to evaluate acute and chronic presentations of pediatric AIH. Acute pediatric AIH has a higher mHAI score with more severe activity. The patients with a higher mHAI have a greater likelihood of achieving a complete response to treatment at 6 months and subsequent improvement in fibrosis status.
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Affiliation(s)
- Wei Chen
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
| | - Gillian Noel
- Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
| | - Mansi Amin
- Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
| | - Fengming Chen
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
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6
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Khonde P, Choudhury S, Spies NC, Naz N, Stoll J, Fleckenstein J, He M, Ballentine S, Kulkarni S. Worse fibro-inflammatory activity on diagnostic liver biopsy adversely impacts biochemical remission in autoimmune hepatitis. Clin Res Hepatol Gastroenterol 2024; 48:102442. [PMID: 39103121 DOI: 10.1016/j.clinre.2024.102442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 08/03/2024] [Indexed: 08/07/2024]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) patients can present with advanced fibrosis at diagnosis or may progress to the same if biochemical remission on treatment is not achieved. METHODS We conducted a single-center retrospective analysis of 34 pediatrics and 39 adult AIH patients. Three pathologists, blinded to clinical information, reviewed the diagnostic liver biopsy (DLB) slides of AIH patients. We evaluated the impact of clinical, laboratory, and histopathologic parameters on outcomes including biochemical remission (BR). RESULTS Incidence of advanced (Ludwig stage 3 or 4) fibrosis on DLB was 45.2 %. AIH patients with advanced fibrosis had higher median Ishak score (p < 0.001) and higher IgG level (p = 0.01) at diagnosis. The incidence of BR at 6-month (31.2% vs. 88.6 %, p = 0.001) and 1-year (68.8% vs. 88.6 %, p = 0.04) post-diagnosis was significantly lower in AIH patients with advanced fibrosis. Although not statistically significant, a higher proportion of AIH patients with advanced fibrosis were on high dose of steroids (58% vs. 37.9 %, p = 0.1) at 1 year post diagnosis. Higher serum IgG level at diagnosis was associated with lower odds of achieving BR at 6-month (p = 0.004) and 1-year (p = 0.03) post-diagnosis in multivariate analysis. Pediatric age at diagnosis (p = 0.02) was associated with higher steroid dose at 1-year post-diagnosis in univariate analysis. CONCLUSIONS Findings of advanced fibrosis on DLB of AIH patients was accompanied by more pronounced necro-inflammatory activity and higher serum IgG level, which translated to lower rates of BR and higher exposure to steroids during the first year after diagnosis.
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Affiliation(s)
- Pooja Khonde
- Department of Pathology and Immunology, Washington University in St. Louis, MO, USA
| | - Shelley Choudhury
- Department of Pediatrics, Washington University in St. Louis, MO, USA
| | - Nicholas C Spies
- Department of Pathology and Immunology, Washington University in St. Louis, MO, USA
| | - Nadia Naz
- Department of Pediatrics, University of Iowa, Iowa City, IA, USA
| | - Janis Stoll
- Department of Pediatrics, Washington University in St. Louis, MO, USA
| | | | - Mai He
- Department of Pathology and Immunology, Washington University in St. Louis, MO, USA
| | - Samuel Ballentine
- Department of Pathology and Immunology, Washington University in St. Louis, MO, USA
| | - Sakil Kulkarni
- Department of Pediatrics, Washington University in St. Louis, MO, USA.
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7
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Fujiwara K, Fukuda Y, Sanada M, Koizumi S, Seza K, Saito M, Yokosuka O, Kato N. Analysis of autoimmune hepatitis with acute presentation in the early stage of illness. J Gastroenterol Hepatol 2024; 39:2120-2128. [PMID: 38860418 DOI: 10.1111/jgh.16657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 05/08/2024] [Accepted: 05/29/2024] [Indexed: 06/12/2024]
Abstract
BACKGROUND AND AIM There is no gold standard for making the diagnosis of autoimmune hepatitis (AIH), and the diagnosis of acute onset AIH (A-AIH) is most challenging. A-AIH sometimes develops into acute liver failure with poor prognosis if the diagnosis is delayed. Therefore, it is most important for the better prognosis to diagnose non-severe A-AIH early and treat appropriately. However, features in the early stage of A-AIH are unclear. We examined initial characteristics of non-severe A-AIH in detail and tried to find novel clinical features for the early diagnosis. METHODS Clinical, biochemical, immunological, radiological, and histological features of 71 patients (54 women, mean age 57.9 ± 14.3 years) with non-severe A-AIH admitted to community hospitals between 2001 and 2022 were analyzed retrospectively. RESULT Forty-six had no symptom on onset and liver injuries were discovered by regular medical checkups. The mean duration from onset to consultation was 25.0 ± 29.3 days. Liver histology showed acute hepatitis in 59% and chronic hepatitis in 41%. Patients with symptoms revealed more male sex (P = 0.039), higher alanine aminotransferase (P < 0.001), higher total bilirubin (P < 0.001), and higher rate of histological acute hepatitis (P = 0.0013) than those without symptoms significantly. Male sex, presence of symptoms on onset, occurrence of jaundice in the course, and histological acute hepatitis were correlated. CONCLUSIONS Sixty-five percent of non-severe A-AIH patients were asymptomatic on onset, suggesting that A-AIH would develop insidiously and present a longer clinical course than that reported. Male patients more often revealed true acute hepatitis clinically, biochemically, and histologically than female ones.
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Affiliation(s)
- Keiichi Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoshihiro Fukuda
- Department of Gastroenterology, Seikeikai Chiba Medical Center, Chiba, Japan
| | - Masahiko Sanada
- Department of Gastroenterology, Yusokai Saisei Hospital, Chiba, Japan
| | - Shuko Koizumi
- Department of Gastroenterology, Seikeikai Chiba Medical Center, Chiba, Japan
| | - Katsushi Seza
- Department of Gastroenterology, Seikeikai Chiba Medical Center, Chiba, Japan
| | - Masaya Saito
- Department of Gastroenterology, Seikeikai Chiba Medical Center, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
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8
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Huong NTC, Hai NP, Van Khanh C, Kamel MG, Vinh Chau NV, Truong NT, Vinh NT, Elsheikh R, Makram AM, Elsheikh A, Canh HN, Iqtadar S, Hirayama K, Le Hoa PT, Huy NT. New biomarkers for liver involvement by dengue infection in adult Vietnamese patients: a case-control study. BMC Infect Dis 2024; 24:800. [PMID: 39118006 PMCID: PMC11308448 DOI: 10.1186/s12879-024-09527-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 06/17/2024] [Indexed: 08/10/2024] Open
Abstract
Liver injury with marked elevation of aspartate aminotransferase enzyme (AST) is commonly observed in dengue infection. To understand the pathogenesis of this liver damage, we compared the plasma levels of hepatic specific, centrilobular predominant enzymes (glutamate dehydrogenase, GLDH; glutathione S transferase-α, αGST), periportal enriched 4-hydroxyphenylpyruvate dioxygenase (HPPD), periportal predominant arginase-1 (ARG-1), and other non-specific biomarkers (paraoxonase-1, PON-1) in patients with different outcomes of dengue infection. This hospital-based study enrolled 87 adult dengue patients, stratified into three groups based on plasma AST levels (< 80, 80-400, > 400 U/L) in a 1:1:1 ratio (n = 40, n = 40, n = 40, respectively. The new liver enzymes in the blood samples from the 4th to 6th days of their illness were measured by commercial enzyme-linked immunosorbent assay (ELISA) or colorimetric kits. Based on the diagnosis at discharge days, our patients were classified as 40 (46%) dengue without warning signs (D), 35 (40.2%) dengue with warning signs (DWS), and 11 (12.6%) severe dengue (SD) with either shock (two patients) or AST level over 1000 U/L (nine patients), using the 2009 WHO classification. The group of high AST (> 400 U/L) also had higher ALT, GLDH, ARG-1, and HPPD than the other groups, while the high (> 400 U/L) and moderate (80-400 U/L) AST groups had higher ALT, αGST, ARG-1, and HPPD than the low AST group (< 80 U/L). There was a good correlation between AST, alanine aminotransferase enzyme (ALT), and the new liver biomarkers such as GLDH, αGST, ARG-1, and HPPD. Our findings suggest that dengue-induced liver damage initiates predominantly in the centrilobular area toward the portal area during the dengue progression. Moreover, these new biomarkers should be investigated further to explain the pathogenesis of dengue and to validate their prognostic utility.
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Affiliation(s)
- Nguyen Thi Cam Huong
- Department of Infectious Diseases, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
| | - Nguyen Phuong Hai
- Department of Infectious Diseases, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam
- Department of Infectious Diseases, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam
| | - Chau Van Khanh
- School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan
- Institute of Malariology, Parasitology, and Entomology Quy Nhon, Quy Nhon, Vietnam
| | - Mohamed Gomaa Kamel
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan
- Ipswich Hospital, East Suffolk and North Essex NHS Foundation Trust, Colchester, UK
| | | | | | | | - Randa Elsheikh
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan
- Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK
| | - Abdelrahman M Makram
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan.
- Department of Anesthesia and Intensive Care Medicine, October 6 University, Giza, Egypt.
| | - Aya Elsheikh
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan
- Faculty of Medicine, Mansoura Manchester University, Mansoura, Egypt
| | - Hiep Nguyen Canh
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
- Center of Pathology and Cytopathology, Bach Mai Hospital, Hanoi, Vietnam
| | - Somia Iqtadar
- Department of Medicine, King Edward Medical University, Lahore, Pakistan
| | - Kenji Hirayama
- School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
| | - Pham Thi Le Hoa
- Department of Infectious Diseases, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam.
- Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
| | - Nguyen Tien Huy
- School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
- Online Research Club (http://www.onlineresearchclub.org), Nagasaki, Japan.
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam.
- School of Medicine and Pharmacy, Duy Tan University, Da Nang, Vietnam.
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9
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Oliveira EMG, Amaral ACDC, Oliveira PMC, Lanzoni VP, Perez RM, Narciso-Schiavon JL, Whale RC, Carvalho-Filho RJ, Silva AEB, Ferraz MLCG. Clinical Characteristics of Genuine Acute Autoimmune Hepatitis. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2024; 31:173-181. [PMID: 38757065 PMCID: PMC11095594 DOI: 10.1159/000531018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 04/17/2023] [Indexed: 05/18/2024]
Abstract
INTRODUCTION Autoimmune hepatitis (AIH) has a spectrum of symptoms ranging from asymptomatic disease to acute severe hepatitis, chronic hepatitis, and decompensated cirrhosis. The acute presentation is not rare and could represent genuine acute AIH (GAAIH) or acute exacerbation of chronic autoimmune hepatitis. We aimed to identify the prevalence, clinical features, and prognostic factors associated with GAAIH and compare these cases with acute exacerbation of chronic AIH. METHODS This cross-sectional observational study evaluated patients with acute AIH presentation, defined as total bilirubin >5 times the upper limit of normality (xULN) and/or alanine aminotransferase >10 xULN, and no prior history of liver disease. Histology findings of acute disease defined GAAIH. Bivariate analyses were performed to identify factors associated with the GAAIH, when compared with acute exacerbation of chronic AIH. RESULTS Seventy-two patients with acute presentation of AIH were included and six (8.3%) of them presented GAAIH. Comparative analysis between patients with GAAIH and patients with acute exacerbation of chronic AIH revealed that prothrombin activity (96% [74-100] vs. 61% [10-100]; p = 0.003) and albumin levels (3.9 ± 0.2 g/dL vs. 3.4 ± 0.5 g/dL; p < 0.001) were higher in patients with GAAIH. The International Autoimmune Hepatitis Group score was higher in patients with acute exacerbation of chronic AIH (18.5 [8-23] vs. 16.5 [15-17]; p = 0.010). Compared to 15.2% of acute exacerbation of chronic AIH, complete therapeutic response to treatment was achieved in 67.7% of cases with GAAIH (p = 0.018). CONCLUSIONS GAAIH was rare (8.3%), and patients with this presentation exhibited more preserved liver function tests, suggesting that most cases presenting with loss of function are acute exacerbation of chronic AIH. Additionally, patients with GAAIH had a better complete therapeutic response, suggesting a more preserved liver function at presentation, and early diagnosis has a positive therapeutic implication.
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Affiliation(s)
- Elze Maria Gomes Oliveira
- Division of Gastroenterology, Federal University of Sao Paulo, Sao Paulo, Brazil
- Centro Universitário Lusíada, Santos, Brazil
| | | | | | | | - Renata Mello Perez
- Department of Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Janaína Luz Narciso-Schiavon
- Division of Gastroenterology, Department of Internal Medicine, Federal University of Santa Catarina, Florianópolis, Brazil
| | - Raul Carlos Whale
- Division of Gastroenterology, Federal University of Sao Paulo, Sao Paulo, Brazil
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10
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Sakhuja P, Goyal S. Autoimmune Hepatitis: From Evolution to Current Status-A Pathologist's Perspective. Diagnostics (Basel) 2024; 14:210. [PMID: 38248086 PMCID: PMC10814110 DOI: 10.3390/diagnostics14020210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/03/2024] [Accepted: 01/15/2024] [Indexed: 01/23/2024] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic, relapsing and remitting, immune-mediated liver disease that progresses to cirrhosis if left untreated. A significant number of patients may present with acute hepatitis or acute liver failure, which are often misdiagnosed as toxic liver injury. AIH shows a preponderance in young women but may be seen in children and the elderly. Diagnosis requires the integration of clinical, biochemical, and serologic parameters, along with supportive liver histology and exclusion of other causes of liver disease. Liver biopsy is a prerequisite for diagnosis of AIH, to assess severity and stage of disease, exclude other entities, and recognize any concurrent morbidities. No single biomarker or histologic feature is pathognomonic for AIH. The diagnostic and histologic criteria have undergone several modifications since the original scoring system was proposed by the International Autoimmune Hepatitis Group (IAIHG) in 1993. Recently, the IAIHG has proposed consensus recommendations for histologic criteria, relevant for both acute and chronic AIH. This review article will describe the evolving diagnostic criteria for AIH, with their limitations and utility, and with an emphasis on the role of liver histology in the diagnosis and management of AIH.
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11
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Enciso J, Vasavada-Patel R, Lien K. A Rare Presentation of Drug-Induced Autoimmune Hepatitis and the Role of Male Enhancement Supplements. Cureus 2024; 16:e51770. [PMID: 38322090 PMCID: PMC10844770 DOI: 10.7759/cureus.51770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 01/06/2024] [Indexed: 02/08/2024] Open
Abstract
Autoimmune hepatitis (AIH) is a condition characterized by an autoimmune response resulting in chronic inflammatory liver disease. Its presentation is marked by significant increases in serum immunoglobulins and the production of active autoantibodies that target liver tissue. AIH is often associated with other autoimmune disorders, which can lead to overlapping clinical syndromes. However, alternative theories propose that exposure to specific environmental triggers can initiate this autoimmune cascade. We present the case of a 45-year-old male who sought evaluation for abdominal discomfort and was subsequently diagnosed with drug-induced AIH (DIAIH) following prolonged use of an over-the-counter male-enhancing supplement.
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Affiliation(s)
- Juan Enciso
- Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, USA
| | - Ruhi Vasavada-Patel
- Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, USA
| | - Kyle Lien
- Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, USA
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12
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Elshafey SA, Brown RS. Nonviral or Drug-Induced Etiologies of Acute-on-Chronic Liver Failure (Autoimmune, Vascular, and Malignant). Clin Liver Dis 2023; 27:649-657. [PMID: 37380288 DOI: 10.1016/j.cld.2023.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Abstract
Vascular, autoimmune hepatitis, and malignant causes of acute-on-chronic liver failure are rare but important to consider and investigate in patients with underlying liver disease who present with acute deterioration and other more common etiologies have been excluded. Vascular processes including Budd-Chiari syndrome and portal vein thrombosis require imaging for diagnosis and anticoagulation is the mainstay of therapy. Patients may require advanced interventional therapy including transjugular intrahepatic portosystemic shunt or consideration of liver transplantation. Autoimmune hepatitis is a complex disease entity that requires a high degree of clinical suspicion and can present heterogeneously.
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Affiliation(s)
- Suzanne A Elshafey
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 1305 York Avenue, 4th Floor, New York, NY 10021, USA
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 1305 York Avenue, 4th Floor, New York, NY 10021, USA.
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13
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Snijders RJALM, Assis DN, Oo YH, Sebode M, Taubert R, Willemse J, Tomsin B, Lohse AW, Drenth JPH, Gevers TJG. Research gaps and opportunities in autoimmune hepatitis-Results of the international autoimmune hepatitis group research workshop 2022. Liver Int 2023; 43:1375-1384. [PMID: 37035872 DOI: 10.1111/liv.15573] [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: 09/26/2022] [Revised: 03/17/2023] [Accepted: 03/22/2023] [Indexed: 04/11/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare autoimmune liver disease that is characterised by a chronic inflammatory immune reaction directed against hepatocytes. The disease results in a substantial reduction in quality of life and potentially leads to liver-related complications or death. The International Autoimmune Hepatitis Group (IAIHG) initiated a series of research workshops to uncover the scientific gaps and opportunities in AIH. This review summarises the results of the latest workshop in Maastricht in 2022 and reviews the current challenges in adult AIH, particularly in relation to four important aspects of AIH: diagnostics; new immunomodulatory therapies; clinical trial design; and unmet clinical needs. This review also summarises the progress made since the AIH workshop in 2017. Patients and patient representatives were actively involved in the parallel working groups alongside clinicians and researchers. Despite 40 years of experience with diagnosing and treating AIH, false diagnoses occur and treatment is still based on nonselective immunosuppression. In addition to the need for more specific diagnostic tests, prognostic markers and tailor-based treatments, a major unmet clinical need was identified in areas of care delivery and health-related quality of life.
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Affiliation(s)
- Romée J A L M Snijders
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - David N Assis
- Department of Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut, USA
| | - Ye H Oo
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust & Centre for Liver and Gastro Research, NIHR Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Marcial Sebode
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - José Willemse
- Dutch Liver Patients Association, Hoogland, The Netherlands
| | - Bert Tomsin
- Dutch Liver Patients Association, Hoogland, The Netherlands
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Tom J G Gevers
- Department of Gastroenterology and Hepatology, MUMC+, Maastricht, The Netherlands
- Nutrim School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
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14
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Shingina A, Mukhtar N, Wakim-Fleming J, Alqahtani S, Wong RJ, Limketkai BN, Larson AM, Grant L. Acute Liver Failure Guidelines. Am J Gastroenterol 2023; 118:1128-1153. [PMID: 37377263 DOI: 10.14309/ajg.0000000000002340] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 04/04/2023] [Indexed: 06/29/2023]
Abstract
Acute liver failure (ALF) is a rare, acute, potentially reversible condition resulting in severe liver impairment and rapid clinical deterioration in patients without preexisting liver disease. Due to the rarity of this condition, published studies are limited by the use of retrospective or prospective cohorts and lack of randomized controlled trials. Current guidelines represent the suggested approach to the identification, treatment, and management of ALF and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence was reviewed using the Grading of Recommendations, Assessment, Development and Evaluation process to develop recommendations. When no robust evidence was available, expert opinions were summarized using Key Concepts. Considering the variety of clinical presentations of ALF, individualization of care should be applied in specific clinical scenarios.
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Affiliation(s)
- Alexandra Shingina
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Nizar Mukhtar
- Department of Gastroenterology, Kaiser Permanente, San Francisco, California, USA
| | - Jamilé Wakim-Fleming
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland Ohio, USA
| | - Saleh Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, USA
- Liver Transplantation Unit, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Robert J Wong
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, Gastroenterology Section, Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA
| | | | - Anne M Larson
- Division of Gastroenterology and Hepatology, University of Washington, Seattle, Washington, USA
| | - Lafaine Grant
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA
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15
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Schinas G, Polyzou E, Dimakopoulou V, Tsoupra S, Gogos C, Akinosoglou K. Immune-mediated liver injury following COVID-19 vaccination. World J Virol 2023; 12:100-108. [PMID: 37033146 PMCID: PMC10075055 DOI: 10.5501/wjv.v12.i2.100] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/23/2022] [Accepted: 01/23/2023] [Indexed: 03/21/2023] Open
Abstract
Liver injury secondary to vaccination is a rare adverse event that has recently come under attention thanks to the continuous pharmacovigilance following the widespread implementation of coronavirus disease 2019 (COVID-19) vaccination protocols. All three most widely distributed severe acute respiratory syndrome coronavirus 2 vaccine formulations, e.g., BNT162b2, mRNA-1273, and ChAdOx1-S, can induce liver injury that may involve immune-mediated pathways and result in autoimmune hepatitis-like presentation that may require therapeutic intervention in the form of corticosteroid administration. Various mechanisms have been proposed in an attempt to highlight immune checkpoint inhibition and thus establish causality with vaccination. The autoimmune features of such a reaction also prompt an in-depth investigation of the newly employed vaccine technologies. Novel vaccine delivery platforms, e.g., mRNA-containing lipid nanoparticles and adenoviral vectors, contribute to the inflammatory background that leads to an exaggerated immune response, while patterns of molecular mimicry between the spike (S) protein and prominent liver antigens may account for the autoimmune presentation. Immune mediators triggered by vaccination or vaccine ingredients per se, including autoreactive antibodies, cytokines, and cytotoxic T-cell populations, may inflict hepatocellular damage through well-established pathways. We aim to review available data associated with immune-mediated liver injury associated with COVID-19 vaccination and elucidate potential mechanisms underlying its pathogenesis.
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Affiliation(s)
- Georgios Schinas
- Department of Medicine, University of Patras, Patras 26504, Greece
| | - Eleni Polyzou
- Department of Internal Medicine, University of Patras, Patras 26504, Greece
| | | | - Stamatia Tsoupra
- Department of Internal Medicine, University of Patras, Patras 26504, Greece
| | - Charalambos Gogos
- Department of Internal Medicine, University of Patras, Patras 26504, Greece
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16
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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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17
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Zhang X, Jain D. The many faces and pathologic diagnostic challenges of autoimmune hepatitis. Hum Pathol 2023; 132:114-125. [PMID: 35753409 DOI: 10.1016/j.humpath.2022.06.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 06/16/2022] [Accepted: 06/17/2022] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis (AIH) is an immune-mediated chronic inflammatory liver disease, characterized by hypergammaglobulinemia, the presence of specific autoantibodies, and typical abnormalities in liver histology. Prompt diagnosis and initiation of immunosuppressive treatment are necessary for both chronic and acute onset AIH to prevent progression to end-stage liver disease or fatal liver failure. However, the diagnosis of AIH is challenging mainly because of its heterogeneous clinical, serological and pathological features. Although portal lymphoplasmacytosis and interface hepatitis are the most typical histological features of AIH, many other histological features can be observed in AIH, including emperipolesis, hepatocyte rosettes, and Kupffer cell hyaline globules. Recent studies have questioned emperipolesis and hepatocyte rosette formation as typical features of AIH, and atypical clinical and histological presentations have also been recognized. This led an international working group to propose the modified AIH diagnostic criteria. However, it is well recognized that there are no pathognomonic characteristics that can be used to diagnose AIH and careful clinicopathological correlation is required to arrive at the correct diagnosis. The aim of this review is to summarize the histological features of AIH, its varied histopathologic spectrum, recent updates and major differential diagnoses in routine clinical practice.
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Affiliation(s)
- Xuchen Zhang
- Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, United States.
| | - Dhanpat Jain
- Department of Pathology, Yale School of Medicine, New Haven, CT, 06520, United States.
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18
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Zhang Y, Niazi B, Auda A, Chacko AA, Jarri A, Mohamed A, Ali S, Zhu H, Sirajuddin S. A Novel Presentation of Autoimmune Hepatitis with IgG1 Elevation. Case Rep Gastroenterol 2023; 17:281-286. [PMID: 37928974 PMCID: PMC10624941 DOI: 10.1159/000530517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/27/2023] [Indexed: 11/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a common and debilitating pathology that has acute, subacute, and chronic presentation, requiring prompt diagnosis and early intervention. Several serologic markers are found to be associated with the pathogenesis and progression of autoimmune hepatitis, most notably antinuclear antibodies and anti-smooth muscle antibodies [Front Immunol. 2018;9:609]. In addition, AIH is also characterized by the elevation of gamma globulin levels, mainly immunoglobulin G (IgG) [World J Gastroenterol. 2015;21(1):60-83]. Although the literature has well established the presence of increased IgG levels in AIH, few studies have evaluated the subtypes of IgG and their differential levels associated with AIH. Here, we present a rare case of AIH that lacks the common serologic markers but instead reveals an elevation in IgG1 level. Our patient was subsequently placed on corticosteroids, and her symptoms quickly resolved. We intend to introduce this case to the medical community in the hope of aiding in the proper diagnosis and timely intervention of subsequent cases with similar presentations.
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Affiliation(s)
- Yujiao Zhang
- Department of Internal Medicine, HMH-Palisades Medical Center, North Bergen, NJ, USA
| | - Bilal Niazi
- Department of Internal Medicine, HMH-Palisades Medical Center, North Bergen, NJ, USA
| | - Auda Auda
- Department of Internal Medicine, HMH-Palisades Medical Center, North Bergen, NJ, USA
| | - Angel Ann Chacko
- Department of Internal Medicine, HMH-Palisades Medical Center, North Bergen, NJ, USA
| | - Amer Jarri
- Department of Internal Medicine, HMH-Palisades Medical Center, North Bergen, NJ, USA
| | - Abdifatah Mohamed
- Department of Internal Medicine, HMH-Palisades Medical Center, North Bergen, NJ, USA
| | - Saad Ali
- Department of Gastroenterology, HMH-Palisades Medical Center, North Bergen, NJ, USA
| | - Hongfa Zhu
- Department of Pathology, HMH-Palisades Medical Center, North Bergen, NJ, USA
| | - Syed Sirajuddin
- Department of Internal Medicine, HMH-Palisades Medical Center, North Bergen, NJ, USA
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Fujiwara K, Fukuda Y, Seza K, Saito M, Koizumi S, Yokosuka O, Kato N. Analysis of non-severe acute onset autoimmune hepatitis according to the presence of radiological heterogeneity. Hepatol Res 2022; 52:804-810. [PMID: 35639341 DOI: 10.1111/hepr.13799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 01/11/2023]
Abstract
AIM Diagnosis of acute onset autoimmune hepatitis (A-AIH) has been difficult in that patients may not have typical clinicopathological features of AIH. In our previous reports of severe and fulminant AIH, two-thirds of them showed radiological heterogeneity: hepatic heterogeneous hypoattenuation on unenhanced computed tomography (CT) reflecting heterogeneous distribution of massive hepatic necrosis (severe centrilobular necrosis), which would be beneficial for the diagnosis. In the present study, we analyzed non-severe A-AIH patients with or without radiological heterogeneity and tried to find novel clinical features for supporting the early diagnosis. METHODS Clinical, biochemical, immunological, radiological and histological features of 42 patients with non-severe A-AIH at community hospitals between 2010 and 2020 were analyzed. RESULTS Of 42, 28 patients on whom CT scans were performed and who could be fully analyzed were enrolled. Five patients showed hepatic heterogeneous hypoattenuation on unenhanced CT. There was no significant difference in clinical, biochemical, immunological and histological features at diagnosis between the two groups according to the presence of radiological heterogeneity, although mean minimum prothrombin time activity during the course was lower in patients with heterogeneity without statistical significance (p = 0.080). All responded to treatment well and achieved initial remission within 3 months. CONCLUSIONS It is possible that patients with non-severe A-AIH show radiological heterogeneity reflecting centrilobular necrosis which is one of important diagnostic features of A-AIH. Accordingly, radiological heterogeneity might be beneficial for the diagnosis of A-AIH in combination with conventional clinicopathological features if it is detected in the absence of features suggestive of other liver diseases.
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Affiliation(s)
- Keiichi Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoshihiro Fukuda
- Department of Gastroenterology, Seikeikai Chiba Medical Center, Chiba, Japan
| | - Katsushi Seza
- Department of Gastroenterology, Seikeikai Chiba Medical Center, Chiba, Japan
| | - Masaya Saito
- Department of Gastroenterology, Seikeikai Chiba Medical Center, Chiba, Japan
| | - Shuko Koizumi
- Department of Gastroenterology, Seikeikai Chiba Medical Center, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
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Ueda K, Aizawa Y, Kinoshita C, Nagano T, Ishida J, Saeki C, Oikawa T, Harada T, Hokari A, Saruta M. Centrilobular zonal necrosis is a unique subtype of autoimmune hepatitis: A cohort study. Medicine (Baltimore) 2022; 101:e29484. [PMID: 35866813 PMCID: PMC9302312 DOI: 10.1097/md.0000000000029484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 04/12/2022] [Accepted: 05/02/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUNDS Centrilobular zonal necrosis (CZN) is described as a histological feature present in a small number of autoimmune hepatitis (CZN-AIH) patients. CZN may be detected in the absence of significant interface hepatitis, which is the most important histological finding of AIH. The clinical and histopathological spectra of CZN-AIH were not homogeneous, and the concept of CZN-AIH as a distinctive subtype of AIH remains controversial, due to the rarity of CZN-AIH and the ambiguous definition of CZN. METHODS To elucidate the clinical and immunogenetic features of CZN-AIH, a total of 102 biopsy samples of AIH, obtained at The Jikei University Katsushika Medical Center and Jikei University Hospital from 2000 to 2018, were reviewed. The 32 patients whose biopsies showed CZN were selected as the CZN-AIH group, and the remaining 70 were grouped as the non-CZN-AIH controls (control AIH). Data on clinical, histopathologic, and immunogenetic features were statistically compared between the CZN-AIH and the control AIH group. Additionally, the impact of the onset pattern (acute or chronic) and coexistent significant interface hepatitis in CZN-AIH was determined. RESULTS In CZN-AIH, the frequency of acute-onset cases was significantly higher than that in control AIH (56.2% vs 32.9%; P < .05), and the number of cases with moderate-to-severe interface hepatitis in liver histology was significantly lower (37.5% vs 87.1%; P < .001). Compared to the control AIH, cases of CZN-AIH had lower immunoglobulin G level (P < .001), lower antinuclear antibodies titer (P < .001), and lower AIH score (P < .001). The immunogenetic disproportionate distribution of HLA-DR phenotypes in control AIH (increased HLA-DR4 and decreased HLA-DR9) was not found in CZN-AIH. Moreover, CZN-AIH was less frequently relapsed (P < .05). For the acute-onset CZN-AIH cases, the clinical features were hardly indistinguishable from the chronic CZN-AIH cases. Similarly, the existence of interface hepatitis did not influence on the pathophysiology of CZN-AIH. Moreover, the acute-onset CZN-AIH cases is clinically distinguishable from acute-onset control AIH. CONCLUSION CZN can characterize as a distinct AIH subtype, regardless of onset-pattern or coexistence of significant interface hepatitis. To further strengthen this hypothesis, collection of more CZN-AIH cases is needed.
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Affiliation(s)
- Kaoru Ueda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Yoshio Aizawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, Tokyo, Japan
| | - Chika Kinoshita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tomohisa Nagano
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, Tokyo, Japan
| | - Jinya Ishida
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Toru Harada
- Division of Pathology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Atsushi Hokari
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, Tokyo, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
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Ohira H, Takahashi A, Zeniya M, Abe M, Arinaga-Hino T, Joshita S, Takaki A, Nakamoto N, Kang JH, Suzuki Y, Sogo T, Inui A, Koike K, Harada K, Nakamoto Y, Kondo Y, Genda T, Tsuneyama K, Matsui T, Tanaka A. Clinical practice guidelines for autoimmune hepatitis. Hepatol Res 2022; 52:571-585. [PMID: 35533021 DOI: 10.1111/hepr.13776] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/22/2022] [Accepted: 04/28/2022] [Indexed: 02/08/2023]
Affiliation(s)
- Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Mikio Zeniya
- Akasaka Sanno Medical Center, International University of Health and Welfare, Tokyo, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | | | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Nobuhiro Nakamoto
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Jong-Hon Kang
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | | | - Tsuyosi Sogo
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology and Hepatology, The Third Hospital of Jikei University School of Medicine, Tokyo, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yasuteru Kondo
- Department of Hepatology, Sendai Kousei Hospital, Sendai, Japan
| | - Takuya Genda
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Takushima, Japan
| | - Tsuyoshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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22
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Lohse AW, Sebode M, Bhathal PS, Clouston AD, Dienes HP, Jain D, Gouw ASH, Guindi M, Kakar S, Kleiner DE, Krech T, Lackner C, Longerich T, Saxena R, Terracciano L, Washington K, Weidemann S, Hübscher SG, Tiniakos D. Consensus recommendations for histological criteria of autoimmune hepatitis from the International AIH Pathology Group: Results of a workshop on AIH histology hosted by the European Reference Network on Hepatological Diseases and the European Society of Pathology: Results of a workshop on AIH histology hosted by the European Reference Network on Hepatological Diseases and the European Society of Pathology. Liver Int 2022; 42:1058-1069. [PMID: 35230735 DOI: 10.1111/liv.15217] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 12/23/2021] [Accepted: 01/18/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS Diagnostic histological criteria for autoimmune hepatitis (AIH) have not been clearly established. Previously published criteria focused mainly on chronic AIH, in which inflammatory changes mainly occur in portal/periportal regions and may not be applicable to acute presentation of AIH, in which inflammatory changes are typically predominantly lobular in location. International consensus criteria for the diagnosis and assessment of disease severity in both acute and chronic AIH are thus urgently needed. METHODS Seventeen expert liver pathologists convened at an international workshop and subsequently used a modified Delphi panel approach to establish consensus criteria for the histopathological diagnosis of AIH. RESULTS The consensus view is that liver biopsy should remain standard for diagnosing AIH. AIH is considered likely, if there is a predominantly portal lymphoplasmacytic hepatitis with more than mild interface activity and/or more than mild lobular hepatitis in the absence of histological features suggestive of another liver disease. AIH is also considered likely if there is predominantly lobular hepatitis with or without centrilobular necroinflammation and at least one of the following features: portal lymphoplasmacytic hepatitis, interface hepatitis or portal-based fibrosis, in the absence of histological features suggestive of another liver disease. Emperipolesis and hepatocellular rosettes are not regarded as being specific for AIH. CONCLUSIONS The criteria proposed in this consensus statement provide a uniform approach to the histological diagnosis of AIH, which is relevant for patients with an acute as well as a chronic presentation and to more accurately reflect the current understanding of liver pathology in AIH.
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Affiliation(s)
- Ansgar W Lohse
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Marcial Sebode
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Prithi S Bhathal
- Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
| | - Andrew D Clouston
- Molecular and Cellular Pathology, The University of Queensland and Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Hans P Dienes
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Dhanpat Jain
- Department of Anatomic Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Annette S H Gouw
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Maha Guindi
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Sanjay Kakar
- Department of Pathology, University of California, San Francisco, California, USA
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Till Krech
- Department of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Carolin Lackner
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Thomas Longerich
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Romil Saxena
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Luigi Terracciano
- Department of Biomedical Sciences, Humanitas University Pieve Emanuele, Milan, Italy.,IRCCS Humanitas Research Hospital, Milan, Italy
| | - Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Sören Weidemann
- Department of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan G Hübscher
- Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, UK.,Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Dina Tiniakos
- Department of Pathology, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens, Greece.,Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK
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23
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Disseminated Histoplasmosis Mimicking Acute Liver Failure in a Patient Treated With a Tumor Necrosis Factor Inhibitor. ACG Case Rep J 2022; 9:e00722. [PMID: 34977265 PMCID: PMC8716095 DOI: 10.14309/crj.0000000000000722] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 07/27/2021] [Indexed: 12/01/2022] Open
Abstract
Disseminated histoplasmosis (DH) is typically seen in patients with organ transplantation or human immunodeficiency virus and rarely presents with acute liver failure. Tumor necrosis factor inhibitors may be immunosuppressive but unlikely to result in DH. A 70-year-old woman with a history of psoriatic arthritis on infliximab presented with altered mental status, fevers, and severe liver injury. She was found to have DH, which resolved on antifungal agents. Because the use of tumor necrosis factor inhibitors has increased, providers should consider this uncommon infection in patients who present with cryptogenic severe liver injury.
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24
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Armandi A, Actis GC, Ribaldone DG. Autoimmunity of the liver. TRANSLATIONAL AUTOIMMUNITY 2022:309-331. [DOI: 10.1016/b978-0-12-824466-1.00012-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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25
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Lemoinne S, Heurgue A, Bouzbib C, Hanslik B, Gournay J, Nguyen-Khac E, Bureau C, de Lédinghen V, Ganne-Carrié N, Bourlière M. Non-invasive diagnosis and follow-up of autoimmune hepatitis. Clin Res Hepatol Gastroenterol 2022; 46:101772. [PMID: 34332126 DOI: 10.1016/j.clinre.2021.101772] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 07/23/2021] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis (AIH) is a liver disease characterised by necrotico-inflammatory lesions of hepatocytes, the presence of specific autoantibodies and response to corticosteroid treatment. AIH must be considered in any patient with acute or chronic liver disease. As there is no pathognomonic sign of AIH, the diagnosis is based on a combination of clinical, biological, immunological and histological findings, after excluding other causes of liver disease. The clinical and biological presentation of AIH is variable and AIH can be associated with an autoimmune biliary disease, primary biliary cholangitis or primary sclerosing cholangitis in an overlap syndrome. For these reasons, diagnosis of AIH can be challenging. Even if liver histology remains essential in the diagnosis of AIH, non-invasive tests can be used at different steps of the management of AIH: diagnosis of AIH, notably diagnosis of an overlap syndrome, assessment of severity of AIH, searching for extra-hepatic disease frequently associated to AIH, evaluation of response to therapy, decision of treatment withdrawal. This review aims to provide practical guidelines for the use of non-invasive tests for the diagnosis and the follow-up of AIH.
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Affiliation(s)
- Sara Lemoinne
- Assistance publique-hopitaux de Paris (AP-HP), Service d'hépatologie, Centre de référence pour les maladies inflammatoires des voies biliaires et les hépatites auto-immunes ( CMR MIVB-H, ERN RARE-LIVER), Hôpital Saint-Antoine, Paris France; Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of cardiometabolism and Nutrition ( ICAN), Paris, France.
| | - Alexandra Heurgue
- Service d'hépato-gastroentérologie et cancérologie digestive, CHU Reims, Reims, France
| | - Charlotte Bouzbib
- Service d'Hépatologie, Hopital Pitié Salpêtrière, APHP, Paris, France
| | - Bertrand Hanslik
- Centre Montpelliérain des maladies du foie et de l'appareil digestif, Montpellier, France
| | - Jérôme Gournay
- Service d'hépato-gastroentérologie, cancérologie digestive et assistance nutritionnelle, CHU Nantes, Nantes, France
| | - Eric Nguyen-Khac
- Service d'hépato-gastroentérologie, CHU Amiens-Picardie, Amiens, France
| | - Christophe Bureau
- Service d'hépatologie, Hôpital Rangueil, CHU Toulouse, Toulouse, France
| | - Victor de Lédinghen
- Service d'hépato-gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, pessac & INSERM U1053, Université de Bordeaux, Bordeaux, France
| | - Nathalie Ganne-Carrié
- Service d'hépatologie, Hôpital Avicenne, APHP, Université Sorbonne Paris Nord, Bobigny & INSERM UMR 1138, Centre de Recherche des Cordeliers, Université de Paris, France
| | - Marc Bourlière
- Service d'hépato-gastroentérologie, Hôpital Saint Joseph & INSERM UMR 1252 IRD SESSTIM Aix Marseille Université, Marseille, France
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26
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Kawada A, Iwamura S, Yorita K, Daike R, Tanaka Y, Kuroda N, Zen Y, Okazaki M, Uchita K. The Acute Onset of Autoimmune Hepatitis During Pregnancy in the Absence of Hypergammaglobulinemia and Autoantibodies. Intern Med 2021; 60:3231-3237. [PMID: 33840701 PMCID: PMC8580773 DOI: 10.2169/internalmedicine.7155-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The onset of autoimmune hepatitis (AIH) during pregnancy is rare and often poses a diagnostic challenge. A 29-year-old Japanese woman experienced epigastric pain and nausea during the third trimester of her third pregnancy. Three days after the symptom onset, an emergency Caesarean section was performed because of suspected acute fatty liver of pregnancy; however, the patient's liver dysfunction worsened afterward. Despite normal serum IgG concentration and absence of autoantibodies, biopsy-proven severe hepatitis with centrilobular zonal necrosis and good biochemical response to corticosteroids led to a diagnosis of AIH. Therefore, AIH should be included in the differential diagnosis of liver dysfunction during pregnancy.
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Affiliation(s)
- Ai Kawada
- Department of Internal Medicine, Japanese Red Cross Kochi Hospital, Japan
| | - Shinichi Iwamura
- Department of Internal Medicine, Japanese Red Cross Kochi Hospital, Japan
| | - Kenji Yorita
- Department of Diagnostic Pathology, Japanese Red Cross Kochi Hospital, Japan
| | - Rikiya Daike
- Department of Internal Medicine, Japanese Red Cross Kochi Hospital, Japan
| | - Yu Tanaka
- Department of Obstetrics and Gynecology, Japanese Red Cross Kochi Hospital, Japan
| | - Naoto Kuroda
- Department of Internal Medicine, Kobe Kyodo Hospital, Japan
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital and King's College London, UK
| | - Michiyo Okazaki
- Department of Internal Medicine, Japanese Red Cross Kochi Hospital, Japan
| | - Kunihisa Uchita
- Department of Internal Medicine, Japanese Red Cross Kochi Hospital, Japan
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27
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Wang H, Zhao Y, Ren B, Qin Y, Li G, Kong D, Qin H, Hao J, Sun D, Wang H. Endometrial regenerative cells with galectin-9 high-expression attenuate experimental autoimmune hepatitis. Stem Cell Res Ther 2021; 12:541. [PMID: 34654474 PMCID: PMC8518235 DOI: 10.1186/s13287-021-02604-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
Background Autoimmune hepatitis (AIH) is a T cell-mediated immune disease that activates abnormally against hepatic antigens. We have previously reported that endometrial regenerative cells (ERCs) were a novel source of adult stem cells, which exhibiting with powerful immunomodulatory effects. Galectin-9 (Gal-9) is expressed in ERCs and plays an important role in regulating T cell response. This study aims to explore the role of ERCs in attenuation of AIH and to determine the potential mechanism of Gal-9 in ERC-mediated immune regulation. Methods ERCs were obtained from menstrual blood of healthy female volunteers. In vitro, ERCs were transfected with lentivirus vectors carrying LGALS9 gene and encoding green fluoresce protein (GFP-Gal-9-LVs) at a MOI 50, Gal-9 expression in ERCs was detected by ELISA and Q-PCR. CD4+ T cells isolated from C57BL/6 mouse spleen were co-cultured with ERCs. The proliferation of CD4+ T cells was detected by CCK-8 kit and the level of Lck/zap-70/LAT protein was measured by western blot. Furthermore, AIH was induced by ConA in C57BL/6 mice which were randomly assigned to untreated, unmodified ERC-treated and Gal-9 high-expressing ERC-treated groups. Histopathological score, liver function, CD4+/CD8+ cell infiltration in liver tissues, the proportion of immune cells in the spleen and liver, and ERC tracking were performed accordingly to assess the progression degree of AIH. Results After transfecting with GFP-Gal-9-LVs, Gal-9 expression in ERCs was significantly increased. Additionally, Gal-9 high-expressing ERCs effectively inhibited CD4+ T cell proliferation and downregulated CD4+ T cell active related proteins p-Lck/p-ZAP70/p-LAT in vitro. Furthermore, treatment with Gal-9 high-expressing ERCs restored liver function, ameliorated liver pathological damage, inhibit CD4+ and CD8+ T cell proliferation and suppress Th1 and Th17 cell response in the hepatitis mice. In addition, Gal-9 high-expressing ERCs further markedly enhanced the level of IL-10 but reduced the levels of IFN-γ, TNF-α, and IL-4 in mouse sera and liver. Cell tracking also showed that ERCs could migrate to the damaged liver organs. Conclusions The results suggested that Gal-9 was an essential modulator, which was required by ERCs in regulating T cell response and attenuating ConA-induced experimental hepatitis. And also, it provides a novel idea for the clinical treatment of AIH.
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Affiliation(s)
- Hongda Wang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Yiming Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China.,Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bingbing Ren
- Department of Pediatric Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Yafei Qin
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Guangming Li
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Dejun Kong
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Hong Qin
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.,Tianjin General Surgery Institute, Tianjin, China
| | - Jingpeng Hao
- Tianjin General Surgery Institute, Tianjin, China.,Department of Anorectal Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Daqing Sun
- Department of Pediatric Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China. .,Tianjin General Surgery Institute, Tianjin, China.
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Covelli C, Sacchi D, Sarcognato S, Cazzagon N, Grillo F, Baciorri F, Fanni D, Cacciatore M, Maffeis V, Guido M. Pathology of autoimmune hepatitis. Pathologica 2021; 113:185-193. [PMID: 34294936 PMCID: PMC8299324 DOI: 10.32074/1591-951x-241] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 12/14/2020] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a relatively rare non-resolving chronic liver disease, which mainly affects women. It is characterized by hypergammaglobulinemia, circulating autoantibodies, interface hepatitis on liver histology and a favourable response to immunosuppression. The putative mechanism for the development of autoimmune hepatitis is thought to be the interaction between genetic predisposition, environmental triggers and failure of the native immune system. AIH still remains a major diagnostic and therapeutic challenge, mainly because it is a very heterogeneous disease. Prompt and timely diagnosis is crucial since, if left untreated, AIH has a high mortality rate. Histological demonstration of hepatitis is required for the diagnosis of AIH and, therefore, liver biopsy is mandatory in the initial diagnostic work-up, before treatment. In this review, we summarize the histological features of AIH with the main aim of highlighting the most important clinical-pathological hallmarks useful in the routine diagnostic practice.
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Affiliation(s)
- Claudia Covelli
- Pathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Diana Sacchi
- Pathology Department Azienda ULSS 2 Marca Trevigiana, Treviso, Italy
| | | | - Nora Cazzagon
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Federica Grillo
- Unit of Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova and Ospedale Policlinico San Martino IRCCS, Genoa, Italy
| | | | - Daniela Fanni
- Pathology Unit, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
| | | | - Valeria Maffeis
- Pathology Department Azienda ULSS 2 Marca Trevigiana, Treviso, Italy
| | - Maria Guido
- Pathology Department Azienda ULSS 2 Marca Trevigiana, Treviso, Italy.,Department of Medicine-DIMED, University of Padova, Padova, Italy
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29
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Wang G, Tanaka A, Zhao H, Jia J, Ma X, Harada K, Wang FS, Wei L, Wang Q, Sun Y, Hong Y, Rao H, Efe C, Lau G, Payawal D, Gani R, Lindor K, Jafri W, Omata M, Sarin SK. The Asian Pacific Association for the Study of the Liver clinical practice guidance: the diagnosis and management of patients with autoimmune hepatitis. Hepatol Int 2021; 15:223-257. [PMID: 33942203 PMCID: PMC8144150 DOI: 10.1007/s12072-021-10170-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/27/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Guiqiang Wang
- Peking University First Hospital, Beijing, China.
- Peking University International Hospital, Beijing, China.
| | | | - Hong Zhao
- Peking University First Hospital, Beijing, China
- Peking University International Hospital, Beijing, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine Kanazawa, Kanazawa, Japan
| | - Fu-Sheng Wang
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Lai Wei
- Beijing Tsinghua Changgung Hospital, Beijing, China
| | - Qixia Wang
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Sun
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yuan Hong
- Peking University First Hospital, Beijing, China
| | - Huiying Rao
- Peking University People's Hospital, Beijing, China
| | - Cumali Efe
- Department of Gastroenterology, Harran University, Şanlıurfa, Turkey
| | - George Lau
- Humanity and Health Medical Group, Hong Kong Special Administrative Region, China
| | - Diana Payawal
- Department of Hepatology, Cardinal Santos Medical Center, Manila, Philippines
| | - Rino Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Keith Lindor
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | | | - Masao Omata
- Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Kofu-City, Yamanashi, Japan
- The University of Tokyo, Tokyo, Japan
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30
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Mühling T, Rohrbach H, Schepp W, Gundling F. Overlap of concurrent extrahepatic autoimmune diseases is associated with milder disease severity of newly diagnosed autoimmune hepatitis. Hepatobiliary Pancreat Dis Int 2021; 20:21-27. [PMID: 32830050 DOI: 10.1016/j.hbpd.2020.06.019] [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: 02/01/2020] [Accepted: 06/26/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Concurrent extrahepatic autoimmune disorders (CEHAID) are frequently observed in autoimmune hepatitis (AIH). It is not clear whether there is any prognostic significance of CEHAID on AIH. The aim of this study was to examine the prognostic impact of CEHAID and the correlation with the disease severity of AIH. METHODS This study included 65 hospitalized subjects who fulfilled the accepted criteria for AIH during an 8-year period (2009-2016). All records were manually screened for presence of associated autoimmune diseases. Disease severity of AIH was assessed by liver laboratory tests including the ratio of aspartate aminotransferase to alanine aminotransferase (AST/ALT) and liver histology. RESULTS Among the enrolled patients, 52 (80%) were female (median age 61 years, IQR 45-75). Fifty-six (86.2%) were classified as type-1 AIH. In 26 (40%) patients at least one additional extrahepatic autoimmune disease was diagnosed. Thirty-four subjects were referred to our hospital because of acute presentation of AIH (supposed by an acute elevation of hepatic enzymes) for subsequent liver biopsy resulting in initial diagnosis of AIH. This group was stratified into 3 subgroups: (A) AIH alone (n = 14); (B) overlap with primary biliary cirrhosis (PBC) / primary sclerosing cholangitis (PSC) (n = 11); and (C) with CEHAID (n = 9). AST/ALT ratio was the lowest in subgroup C (median 0.64, IQR 0.51-0.94; P = 0.023), compared to subgroup A (median 0.91, IQR 0.66-1.10) and subgroup B (median 1.10, IQR 0.89-1.36). Patients with AIH alone showed a trend to the highest grade of fibrosis (mean 2.3; 95% CI: 1.5-3.0) with no statistical significance compared to subjects with CEHAID (lowest grade of fibrosis; mean 1.5; 95% CI: 0.2-2.8; P = 0.380) whereas the ongoing inflammation was comparable. CONCLUSIONS AST/ALT ratio and extent of fibrosis were lower in subjects with AIH and CEHAID, compared to subjects with only AIH. Therefore, the occurrence of CEHAID might be a predictor for lower disease severity of newly diagnosed acute onset AIH, possibly caused by an earlier diagnosis or different modes of damage.
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Affiliation(s)
- Tobias Mühling
- Department of Gastroenterology, Internal Medicine II, University of Würzburg, Würzburg, Germany
| | - Helmut Rohrbach
- Department of Pathology, Academic Teaching Hospital Bogenhausen, Technical University of Munich, Munich 81925, Germany
| | - Wolfgang Schepp
- Department of Gastroenterology, Hepatology and Gastrointestinal Oncology, Academic Teaching Hospital Bogenhausen, Technical University of Munich, Munich 81925, Germany
| | - Felix Gundling
- Department of Gastroenterology, Hepatology and Gastrointestinal Oncology, Academic Teaching Hospital Bogenhausen, Technical University of Munich, Munich 81925, Germany; Department of Internal Medicine, Division of Gastroenterology, Gastrointestinal Oncology and Diabetology, Kemperhof Koblenz, Koblenz, Germany.
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Biewenga M, Inderson A, Tushuizen ME, Crobach ASL, van Hoek B. Early Predictors of Short-Term Prognosis in Acute and Acute Severe Autoimmune Hepatitis. Liver Transpl 2020; 26:1573-1581. [PMID: 32997870 PMCID: PMC7756691 DOI: 10.1002/lt.25906] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022]
Abstract
Presentation of autoimmune hepatitis (AIH) can differ from nonacute to acute autoimmune hepatitis (A-AIH) with jaundice and acute severe autoimmune hepatitis (AS-AIH) with jaundice and coagulopathy. The aim of the study was to evaluate the short-term prognosis of different presentations of AIH and the influence of liver function improvement on short-term prognosis. In this single-center retrospective cohort study, AIH patients with repeatedly tested liver function at diagnosis and during at least 1 year of follow-up were included. A-AIH was defined as bilirubin >45 µmol and international normalized ratio (INR) <1.5. AS-AIH was defined as bilirubin level >45 µmol/L and INR ≥1.5. Of the 81 included patients, 17 (21%) presented with A-AIH, and 14 (17%) presented with AS-AIH. After the start of immunosuppressive therapy, bilirubin, albumin, and INR normalized in 70%, 77%, and 69%, respectively, in a median of 2.6 months, 3 months, and 4 weeks, respectively, in patients with A-AIH and AS-AIH. Liver transplantation (LT)-free survival rate was 100% in nonacute AIH, 94% in A-AIH, and 57% in AS-AIH at 12 months after diagnosis. An increase of INR or bilirubin at 2 weeks was the best predictive factor for the need of LT within 12 months with a Youden's index of 0.85. A-AIH was present in 21%, and AS-AIH was present in 17% of AIH patients. In the majority of patients, bilirubin, albumin, and INR normalized in the first months of treatment. Deterioration of liver function after 2 weeks of treatment should lead to rapid evaluation for LT and consideration of second-line medication.
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Affiliation(s)
- Maaike Biewenga
- Department of Gastroenterology and HepatologyLeiden University Medical CenterLeiden2300 RCthe Netherlands
| | - Akin Inderson
- Department of Gastroenterology and HepatologyLeiden University Medical CenterLeiden2300 RCthe Netherlands
| | - Maarten E. Tushuizen
- Department of Gastroenterology and HepatologyLeiden University Medical CenterLeiden2300 RCthe Netherlands
| | | | - Bart van Hoek
- Department of Gastroenterology and HepatologyLeiden University Medical CenterLeiden2300 RCthe Netherlands
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Rahim MN, Miquel R, Heneghan MA. Approach to the patient with acute severe autoimmune hepatitis. JHEP Rep 2020; 2:100149. [PMID: 32995712 PMCID: PMC7509236 DOI: 10.1016/j.jhepr.2020.100149] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/09/2020] [Accepted: 07/15/2020] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis is associated with varied clinical presentations and natural history, as well as somewhat unpredictable treatment responses. Understanding how to stratify patients who require further escalation of therapy will help clinicians manage these patients. The presentation of acute severe autoimmune hepatitis (AS-AIH) is relatively uncommon, although its prevalence is potentially greater than currently perceived. Previous studies consist of small retrospective single-centre series and are not directly comparable due to the diversity of presentations, disease definitions and non-standardised treatment regimens. We define AS-AIH as those who present acutely with AIH and are icteric with an international normalised ratio ≥1.5 and no evidence of hepatic encephalopathy. Those with hepatic encephalopathy should be defined as having AS-AIH with acute liver failure. In this review, we provide a structured practical approach for diagnosing and managing this unique group of patients.
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Key Words
- ACLF, acute-on-chronic liver failure
- AIH, autoimmune hepatitis
- ALF, acute liver failure
- ALI, acute liver injury
- ALT, alanine aminotransferase
- ANA, anti-nuclear antibody
- AS-AIH, acute severe autoimmune hepatitis
- ASMA, anti-smooth muscle antibody
- AST, aspartate aminotransferase
- AUROC, analysis of area under the receiver operator characteristic curve
- Acute liver failure
- Acute severe presentation
- Autoimmune hepatitis
- CT, computed tomography
- Corticosteroids
- DILI, drug-induced liver injury
- EBV, Epstein-Barr virus
- HE, hepatic encephalopathy
- HLA, human leukocyte antigen
- IAIHG, International Autoimmune Hepatitis Group
- INR, international normalised ratio
- LT, liver transplantation
- Liver transplantation
- MELD, model for end-stage liver disease
- MELD-Na, model for end-stage liver disease-sodium
- MHN, massive hepatic necrosis
- NAC, N-acetylcysteine
- PT, prothrombin time
- UKELD, United Kingdom end-stage liver disease
- USALF, United States Acute Liver Failure
- anti-LC-1, anti-liver cytosol-1
- anti-LKM, anti-liver kidney microsomal
- anti-SLA/LP, anti-soluble liver antigen/liver pancreas
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Affiliation(s)
- Mussarat N. Rahim
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK
| | - Rosa Miquel
- Liver Histopathology Laboratory, King's College Hospital, London, SE5 9RS, UK
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Mathapathi S, Preziosi M. Multiple Hepatic Micro-Hypodensities as a Presenting Sign in Systemic Lupus Erythematosus- A Case Report. Open Rheumatol J 2020. [DOI: 10.2174/1874312902014010022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Systemic Lupus Erythematosus (SLE) is a chronic multisystemic inflammatory disorder that can present with a wide array of signs and symptoms. Hepatic involvement is commonly limited to a subclinical biochemical transaminitis while clinically significant liver disease is rare. A case of a 22-year-old female who presented with abdominal pain, fevers, arthralgia, and several hepatic hypodense lesions with normal liver function tests is reported in this study. She failed to improve with antibiotics and infectious workup was largely unrevealing. She was found to have a positive ANA, high titers of anti-double-stranded DNA antibody, and was ultimately diagnosed with new-onset SLE with hepatic aseptic micro-abscesses. Her symptoms were self-limiting, and she was later started on a low-dose prednisone taper and hydroxychloroquine. This case demonstrates that hepatic involvement, despite normal liver function tests, should be considered in SLE patients presenting with abdominal pain.
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Tsutsui A, Harada K, Tsuneyama K, Nguyen Canh H, Ando M, Nakamura S, Mizobuchi K, Baba N, Senoh T, Nagano T, Shibata H, Aoki T, Takaguchi K. Histopathological analysis of autoimmune hepatitis with "acute" presentation: Differentiation from drug-induced liver injury. Hepatol Res 2020; 50:1047-1061. [PMID: 32515851 DOI: 10.1111/hepr.13532] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 05/23/2020] [Accepted: 05/31/2020] [Indexed: 12/24/2022]
Abstract
AIM Presently, no standardized definition or acceptable diagnostic criteria have been established for acute presentation of autoimmune hepatitis (AP-AIH), making it difficult to differentiate that condition from drug-induced liver injury (DILI). This study aimed to characterize clinical and histological features for distinguishing between AP-AIH and DILI. METHODS Clinical, biochemical, and histological characteristics of AP-AIH and DILI in clinically well-characterized cases were compared in a standardized manner to clarify differences. RESULTS In clinical evaluations, immunoglobulin G level and rate of anti-nuclear antibody positivity were greater in AP-AIH than DILI cases. As for diagnosis of each condition, significant (P < 0.01) differences were found for 10 features: lobular necrosis/inflammation, cobblestone appearance of hepatocytes, plasma cell infiltration in liver parenchyma, centrilobular fibrosis, hepatic rosette formation in areas with cobblestone appearance, portal inflammation, interface hepatitis, prominent plasma cells in portal areas, bile duct injury, and hepatic rosette formation in periportal areas. The area under the curve and cut-off values for the combination of these 10 features were 0.95 and 9 (sensitivity 86%, specificity 90%), respectively. CONCLUSION Combinations of histological features were found to be helpful for differentiating AP-AIH from DILI, but we were not able to statistically identify an individual feature as definitive.
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Affiliation(s)
- Akemi Tsutsui
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Tokushima University Graduate School, Tokushima
| | - Hiep Nguyen Canh
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa
| | - Midori Ando
- Department of Pathology, Kagawa Prefectural Central Hospital, Takamatsu
| | - Satoko Nakamura
- Department of Pathology, Kagawa Prefectural Central Hospital, Takamatsu
| | - Koichi Mizobuchi
- Department of Pathology, Kagawa Prefectural Central Hospital, Takamatsu
| | - Nobuyuki Baba
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu
| | - Tomonori Senoh
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu
| | - Takuya Nagano
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu
| | - Hiroshi Shibata
- Department of Gastroenterology, Tokushima Prefectural Central Hospital, Tokushima
| | - Tomoko Aoki
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osakasayama, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu
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Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease, characterized by the elevation of aminotransferases, presence of anti-nuclear antibody or anti-smooth muscle antibody, elevated immunoglobulin G (IgG), and interface hepatitis/plasma-lymphocytic inflammation based on histology. Recent epidemiological studies have indicated an increasing trend in the prevalence of AIH worldwide, especially in male patients; this trend may suggest the alteration of environmental triggers of disease onset over time. As no disease-specific biomarker or histological finding is currently available, AIH requires a clinical diagnosis, and a validated diagnostic scoring system with acceptable specificity and sensitivity has been proposed. Regarding treatment, corticosteroids and azathioprine are recommended, and in those who exhibit an incomplete response or those who are intolerant to these drugs, second-line therapy, such as mycophenolate mofetil, is considered. Overall, the long-term outcome is excellent in patients with complete biochemical responses, while life-long maintenance treatment may be required since the cessation of immunosuppressive agents frequently leads to the relapse of the disease. Acute-onset AIH does occur, and the diagnosis is very challenging due to the lack of serum autoantibodies or elevated IgG. The unmet needs include earlier diagnosis, intervention with disseminated clinical practice guidelines, and recognition and improvement of patients’ health-related quality of life with the development of novel corticosteroid-free treatment regimens.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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Seike T, Komura T, Shimizu Y, Omura H, Kumai T, Kagaya T, Ohta H, Kawashima A, Harada K, Kaneko S, Unoura M. The Serum Mac-2-binding Protein Glycosylation Isomer Dynamics in Acute Liver Injury. Intern Med 2020; 59:1581-1588. [PMID: 32269188 PMCID: PMC7402970 DOI: 10.2169/internalmedicine.3867-19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Objective We aimed to examine the dynamics of serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with acute liver injury. Methods Serum M2BPGi levels at the time of the diagnosis (n=77) and normalization of the serum alanine aminotransferase (ALT) level (n=26) were examined retrospectively. The difference in the serum M2BPGi level according to the etiology, and the correlations with other laboratory parameters were evaluated. Results The serum M2BPGi level at the time of the diagnosis was increased in 59 of 77 patients [2.3 cutoff index (COI); range, 0.31-11.1 COI] and was significantly decreased at the time of serum ALT normalization (0.68 COI; range, 0.15-1.87 COI; p<0.0001). The serum M2BPGi level was positively correlated with the duration for which serum ALT normalization was achieved (n=46, Spearman rho=0.53, p<0.0001). A multivariate analysis identified total bilirubin (T-bil), albumin, ALT, alkaline phosphatase, and etiology (e.g., drug-induced liver injury or etiology unknown) as independent factors for increased serum M2BPGi. In patients with infectious mononucleosis, the serum M2BPGi level was higher relative to the degree of increase of serum ALT or T-bil levels in comparison to other etiologies. Conclusion The serum M2BPGi level in patients with acute liver injury reflects the magnitude and duration of liver injury. However, it should be noted that the degree of increase of serum M2BPGi in patients with acute liver injury may differ according to the etiology.
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Affiliation(s)
- Takuya Seike
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
- System Biology, Graduate School of Advanced Preventive Medical Science, Kanazawa University, Japan
| | - Takuya Komura
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
| | - Yoshiaki Shimizu
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
| | - Hitoshi Omura
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
| | - Tatsuo Kumai
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
| | - Takashi Kagaya
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
| | - Hajime Ohta
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
| | - Atsuhiro Kawashima
- Department of Clinical Laboratory, National Hospital Organization Kanazawa Medical Center, Japan
| | - Kenichi Harada
- Department of Pathology, Kanazawa University Graduate School of Medical Science, Japan
| | - Shuichi Kaneko
- System Biology, Graduate School of Advanced Preventive Medical Science, Kanazawa University, Japan
| | - Masashi Unoura
- Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center, Japan
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Deng G, Li Y, Ma S, Gao Z, Zeng T, Chen L, Ye H, Yang M, Shi H, Yao X, Zeng Z, Chen Y, Song Y, Liu B, Gao L. Caveolin-1 dictates ferroptosis in the execution of acute immune-mediated hepatic damage by attenuating nitrogen stress. Free Radic Biol Med 2020; 148:151-161. [PMID: 31877357 DOI: 10.1016/j.freeradbiomed.2019.12.026] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 12/16/2019] [Accepted: 12/20/2019] [Indexed: 02/06/2023]
Abstract
Ferroptosis is a new regulated cells death manner defined as results of iron-dependent accumulation of lipid peroxidation. However, the specific mechanisms of regulating ferroptosis remain unclear. In our present study, we demonstrated that Caveolin-1 (Cav-1) played a central role in protecting hepatocytes against ferroptosis in autoimmunity-mediated hepatitis (AIH). The down-regulated Cav-1 in liver tissues, accompanied by ferroptotic events and RNS production, were contributed to the outcome of ConA-induced hepatic damage, which were rescued by ferrostatin-1 (an inhibitor of ferroptosis) in vivo and in vitro. Additionally, Cav-1 deficiency aggravated ConA-induced hepatocellular death and ferroptosis associated with excessive nitrogen stress response. Short hairpin RNA of Cav-1 in hepatocytes promoted ferroptosis and nitrative stress in response to erastin in vitro, which was ameliorated by Cav-1 over-expression. Meanwhile, administration of the iNOS inhibitor (1400W) or ONOO- scavenger (Fe-TMPyP), diminished reactive nitrogen species (RNS), remarkably reduced hepatocytes ferroptosis and attenuated ConA-induced liver damage. Furthermore, immune inhibition by gadolinium chloride (GdCl3), a well-known Kupffer cell depletor, elevated hepatic Cav-1 but inhibited ferroptosis and nitrative stress under ConA exposure. In conclusion, these data revealed a novel molecular mechanism of ferroptosis with the Cav-1 regulation was essential for pathogenesis of ConA-induced hepatitis. Downstream of Cav-1, RNS-mediated ferroptosis was a pivotal step that drives the execution of acute immune-mediated hepatic damage.
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Affiliation(s)
- Guanghui Deng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Yunjia Li
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Shuoyi Ma
- Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China
| | - Zhuowei Gao
- Shunde Hospital, Guangzhou University of Chinese Medicine, Foshan, 528333, Guangdong, China; Shunde Hospital, Southern Medical University, Foshan, 528308, Guangdong, China
| | - Ting Zeng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Limei Chen
- Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China
| | - Haixin Ye
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Menghan Yang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Hao Shi
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Xiaofen Yao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Zhiyun Zeng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Yuyao Chen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Yuhong Song
- Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, Guangdong, China.
| | - Bing Liu
- Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.
| | - Lei Gao
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China.
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38
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Amano N, Sato S, Murata A, Tsuzura H, Tomishima K, Sato S, Matsumoto K, Shimada Y, Iijima K, Harada K, Genda T. A case of primary biliary cholangitis overlapping with type 2 autoimmune hepatitis. Clin J Gastroenterol 2019; 13:79-82. [PMID: 31286423 DOI: 10.1007/s12328-019-01017-2] [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: 03/07/2019] [Accepted: 06/28/2019] [Indexed: 11/28/2022]
Abstract
A 42-year-old woman was admitted to our hospital with cholestatic liver injury. Serological examination revealed anti-mitochondrial M2 antibody positivity and anti-nuclear antibody and anti-smooth muscle antibody negativity. Histological examination of the first liver biopsy revealed chronic nonsuppurative destructive cholangitis with epithelioid granulomas. Ursodeoxycholic acid therapy successfully treated her cholestasis. Sixteen months later, she developed acute icteric hepatitis with elevation of serum aspartate and alanine aminotransferase levels. Anti-mitochondrial M2 positivity and anti-nuclear antibody and anti-smooth muscle antibody negativity persisted at that time. However, it became clear that anti-liver kidney microsomal type 1 antibody was positive. Histological examination of the second liver biopsy demonstrated scarce interface hepatitis and evident parenchymal inflammation and centrilobular zonal necrosis. Her liver biochemical test results promptly improved with the addition of prednisolone therapy. Considering the findings, she was diagnosed with primary biliary cholangitis-type 2 autoimmune hepatitis overlap syndrome. According to a literature review, this is an extremely rare autoimmune overlap syndrome.
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Affiliation(s)
- Nozomi Amano
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka, 410-2295, Japan
| | - Sho Sato
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka, 410-2295, Japan
| | - Ayato Murata
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka, 410-2295, Japan
| | - Hironori Tsuzura
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka, 410-2295, Japan
| | - Ko Tomishima
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka, 410-2295, Japan
| | - Shunsuke Sato
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka, 410-2295, Japan
| | - Kohei Matsumoto
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka, 410-2295, Japan
| | - Yuji Shimada
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka, 410-2295, Japan
| | - Katsuyori Iijima
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka, 410-2295, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Takuya Genda
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka, 410-2295, Japan.
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Rahim MN, Liberal R, Miquel R, Heaton ND, Heneghan MA. Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation? Liver Transpl 2019; 25:946-959. [PMID: 30900368 DOI: 10.1002/lt.25451] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 03/17/2019] [Indexed: 12/13/2022]
Abstract
Acute severe presentations of autoimmune hepatitis (AIH) represent a challenge for the transplant community. As a disease, it is poorly characterized, and there is a weak evidence base to guide diagnosis and treatment. Early identification of acute severe AIH is key because it determines the initiation of corticosteroids, which can be lifesaving. However, their use in this setting remains controversial. The Model for End-Stage Liver Disease score, severity of coagulopathy, and grade of encephalopathy may be predictors of outcome with corticosteroid therapy. The optimal timing of liver transplantation (LT) can be difficult to determine and, as such, the decision to proceed to transplantation should not be delayed by protracted courses of corticosteroids. The aim of this review is to better characterize this subset of patients; to differentiate them clinically, serologically, and histologically from chronic AIH and other causes of acute liver failure; and to present the role, predictors, and optimal timings of corticosteroid therapy and LT. Although this review is specific to adults, many principles hold true for the pediatric population.
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Affiliation(s)
- Mussarat N Rahim
- Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, United Kingdom
| | - Rodrigo Liberal
- Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, United Kingdom
| | - Rosa Miquel
- Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, United Kingdom
| | - Nigel D Heaton
- Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, United Kingdom
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, United Kingdom
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40
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Aljumah AA, Al-Ashgar H, Fallatah H, Albenmousa A. Acute onset autoimmune hepatitis: Clinical presentation and treatment outcomes. Ann Hepatol 2019; 18:439-444. [PMID: 31040094 DOI: 10.1016/j.aohep.2018.09.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 09/10/2018] [Accepted: 09/13/2018] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND AIM Autoimmune hepatitis (AIH) may present acutely, which can rapidly progress to fulminant type. This pattern has been described worldwide but is generally under-reported. We aim to describe the clinical presentation and treatment outcomes of patients with acute onset AIH. MATERIALS AND METHODS A multicenter retrospective cohort study of patients with acute onset AIH. Clinical, biochemical, and histological data were analyzed and the outcomes were reported. RESULTS Seventy patients were included. The mean age was 33.8±1.5 years and 58.6% were female. Upon initial presentation, 94% had jaundice, 44% had fatigue, 31% had pruritus, and 29% had abdominal pain. Biochemical analysis revealed elevated alanine transaminase (733±463.6), aspartate transaminase (699±423), and total bilirubin (210±181.8). Antinuclear antibody (ANA) was positive in 61% of patients, anti-smooth muscle antibody (ASMA) in 69%, and both in 31%; immunoglobulin G (IgG) was elevated in 86% of patients. Advanced fibrosis was found in 39%. Complete remission was achieved in 74.3%, two patients required liver transplants and six died. No specific biomarkers were identified as predictive of remission; however, advanced age was associated with poor prognosis. CONCLUSION Acute onset AIH is a disease that requires early diagnosis and management. We confirmed that elevated transaminases are the hallmark of biochemical presentation of acute AIH. High IgG, ANA and ASMA are typically present in such patients upon presentation, however, their absence does not totally exclude the diagnosis. Initial response to treatment was excellent; however, the long-term mortality was higher than the general patient population.
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Affiliation(s)
- Abdulrahman A Aljumah
- Hepatology Division, Department of Hepatobiliary Sciences and Organ Transplant Center, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
| | - Hamad Al-Ashgar
- Section of Gastroenterology, Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Hind Fallatah
- Division of Gastroenterology and Hepatology, Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ali Albenmousa
- Department of Gastroenterology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
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41
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Perdigoto DN, Tomé L, Diogo D, Ferrão J, Martins R, Oliveira P, Tralhão G, Furtado E. Auxiliary Liver Transplantation as a Transient Treatment for Acute Liver Failure: Two Cases. GE-PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2019; 26:54-58. [PMID: 30675504 DOI: 10.1159/000487155] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 01/25/2018] [Indexed: 12/30/2022]
Abstract
Introduction Acute liver failure is an uncommon condition associated with a high mortality. Most patients do not survive without liver transplantation. In the last decades, auxiliary liver transplantation has emerged as a therapeutic option. Clinical Case The authors present two cases of acute liver failure that required liver transplantation. Given the patients' young age and the preserved macroscopic liver pattern evaluated in surgery, auxiliary liver transplantation was executed using different surgical approaches. Afterwards, following confirmed full native liver regeneration, the patients were submitted to auxiliary liver hepatectomy, which was accomplished without complications. Conclusion Auxiliary liver transplantation can be regarded as an effective temporary treatment for acute liver failure in selected cases, allowing an immunosuppression-free life.
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Affiliation(s)
- David N Perdigoto
- Gastroenterology Department, Coimbra University and Hospital Centre, Coimbra, Portugal
| | - Luís Tomé
- Gastroenterology Department, Coimbra University and Hospital Centre, Coimbra, Portugal.,Adult and Paediatric Liver Transplantation Unit, Coimbra University and Hospital Centre, Coimbra, Portugal
| | - Dulce Diogo
- Adult and Paediatric Liver Transplantation Unit, Coimbra University and Hospital Centre, Coimbra, Portugal
| | - José Ferrão
- Adult and Paediatric Liver Transplantation Unit, Coimbra University and Hospital Centre, Coimbra, Portugal
| | - Ricardo Martins
- Adult and Paediatric Liver Transplantation Unit, Coimbra University and Hospital Centre, Coimbra, Portugal
| | - Pedro Oliveira
- Adult and Paediatric Liver Transplantation Unit, Coimbra University and Hospital Centre, Coimbra, Portugal
| | - Guilherme Tralhão
- Adult and Paediatric Liver Transplantation Unit, Coimbra University and Hospital Centre, Coimbra, Portugal.,General Surgery Department, Coimbra University and Hospital Centre, Coimbra, Portugal
| | - Emanuel Furtado
- Adult and Paediatric Liver Transplantation Unit, Coimbra University and Hospital Centre, Coimbra, Portugal
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42
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Muratori P, Carbone M, Stangos G, Perini L, Lalanne C, Ronca V, Cazzagon N, Bianchi G, Lenzi M, Floreani A, Invernizzi P, Muratori L. Clinical and prognostic implications of acute onset of Autoimmune Hepatitis: An Italian multicentre study. Dig Liver Dis 2018; 50:698-702. [PMID: 29567415 DOI: 10.1016/j.dld.2018.02.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 02/21/2018] [Accepted: 02/23/2018] [Indexed: 02/06/2023]
Abstract
Autoimmune Hepatitis (AIH) can present under clinical profile as acute hepatitis of unexplained cause. We analyzed clinical, therapeutical and prognostic implications of AIH presenting as acute hepatitis in a cohort of patients admitted to 3 referral Centres in Italy. AIH onset was considered acute when transaminases were higher than 10 times the normal limit and/or bilirubin higher than 5 mg/ml (irrespectively from the histology, available only in 62% of cases). Among 479 patients diagnosed as AIH, 202 (43%) met the criteria of acute onset. This former group of patients on the basis of the histology has been subdivided in the "genuine" acute onset (83 pts) and acute "on chronic" onset (45 pts) At onset, clinical acute AIH showed significantly higher ALT, bilirubin and INR levels (p < 0.001 for all), lower albumin values (p = 0.001), similar IgG levels; Response to treatment was similar between the two groups. The progression to liver cirrhosis or its complications was significantly less frequent in acute onset AIH (13% vs. 22%, p = 0.02). The "genuine" acute patients showed a higher albumin serum levels (40 vs. 36, p = 0.001), lower INR levels (1.12 vs. 1.26, p = 0.002) and less tendency to the progression of liver disease (7% vs. 12%, p = NS) with respect to acute "on chronic" onset patients. Clinical acute hepatitis represents a common presentation of AIH, responds to standard immunosuppression regimen and would seem to be correlated with a better long-term prognosis.
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Affiliation(s)
- Paolo Muratori
- Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, University of Bologna, Bologna, Italy; Centro di Ricerca per lo Studio delle Epatiti Policlinico di Sant'Orsola, University of Bologna, Bologna, Italy.
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of MIlan-Bicocca, Milan, Italy
| | - Giorgia Stangos
- Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, University of Bologna, Bologna, Italy
| | - Lisa Perini
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Claudine Lalanne
- Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, University of Bologna, Bologna, Italy; Centro di Ricerca per lo Studio delle Epatiti Policlinico di Sant'Orsola, University of Bologna, Bologna, Italy
| | - Vincenzo Ronca
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of MIlan-Bicocca, Milan, Italy
| | - Nora Cazzagon
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Giampaolo Bianchi
- Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, University of Bologna, Bologna, Italy; Centro di Ricerca per lo Studio delle Epatiti Policlinico di Sant'Orsola, University of Bologna, Bologna, Italy
| | - Marco Lenzi
- Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, University of Bologna, Bologna, Italy; Centro di Ricerca per lo Studio delle Epatiti Policlinico di Sant'Orsola, University of Bologna, Bologna, Italy
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of MIlan-Bicocca, Milan, Italy
| | - Luigi Muratori
- Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, University of Bologna, Bologna, Italy; Centro di Ricerca per lo Studio delle Epatiti Policlinico di Sant'Orsola, University of Bologna, Bologna, Italy
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43
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Abstract
Acute liver failure (ALF) is a rare but highly fatal condition. The most common causes include drug-induced and viral hepatitis, but other less common etiologies, especially autoimmune hepatitis, Budd-Chiari syndrome, and Wilson disease, need to be considered. Because diagnosis is frequently tied to potential for reversibility of ALF and prognosis, early identification in a timely manner is crucial. Other causes of ALF are more easily recognizable based on specific circumstances, such as ALF in pregnancy or ischemic hepatitis. Ultimately, maintaining a wide differential diagnosis in patients with ALF is essential to identifying the proper treatment and prognosis.
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Affiliation(s)
- Russell Rosenblatt
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA.
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44
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Mieli-Vergani G, Vergani D, Czaja AJ, Manns MP, Krawitt EL, Vierling JM, Lohse AW, Montano-Loza AJ. Autoimmune hepatitis. Nat Rev Dis Primers 2018; 4:18017. [PMID: 29644994 DOI: 10.1038/nrdp.2018.17] [Citation(s) in RCA: 272] [Impact Index Per Article: 38.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis (AIH) is a severe liver disease that affects children and adults worldwide. The diagnosis of AIH relies on increased serum transaminase and immunoglobulin G levels, presence of autoantibodies and interface hepatitis on liver histology. AIH arises in genetically predisposed individuals when a trigger, such as exposure to a virus, leads to a T cell-mediated autoimmune response directed against liver autoantigens; this immune response is permitted by inadequate regulatory immune control leading to a loss of tolerance. AIH responds favourably to immunosuppressive treatment, which should be started as soon as the diagnosis is made. Standard regimens include fairly high initial doses of corticosteroids (prednisone or prednisolone), which are tapered gradually as azathioprine is introduced. For those patients who do not respond to standard treatment, second-line drugs should be considered, including mycophenolate mofetil, calcineurin inhibitors, mechanistic target of rapamycin (mTOR) inhibitors and biologic agents, which should be administered only in specialized hepatology centres. Liver transplantation is a life-saving option for those who progress to end-stage liver disease, although AIH can recur or develop de novo after transplantation. In-depth investigation of immune pathways and analysis of changes to the intestinal microbiota should advance our knowledge of the pathogenesis of AIH and lead to novel, tailored and better tolerated therapies.
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Affiliation(s)
- Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, SE5 9RS London, UK
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, SE5 9RS London, UK
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Edward L Krawitt
- Department of Medicine, University of Vermont, Burlington, VT, USA.,Department of Medicine, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA
| | - John M Vierling
- Division of Abdominal Transplantation and Section of Gastroenterology and Hepatology, Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Ansgar W Lohse
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
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45
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Luan J, Zhang X, Wang S, Li Y, Fan J, Chen W, Zai W, Wang S, Wang Y, Chen M, Meng G, Ju D. NOD-Like Receptor Protein 3 Inflammasome-Dependent IL-1β Accelerated ConA-Induced Hepatitis. Front Immunol 2018; 9:758. [PMID: 29692782 PMCID: PMC5902503 DOI: 10.3389/fimmu.2018.00758] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 03/27/2018] [Indexed: 12/20/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a progressive inflammatory disorders of unknown etiology, characterized by immune-mediated destruction of hepatocytes and massive production of cytokines. Interleukin-1β is a pleiotropic proinflammatory cytokine and well known to be critical in a variety of autoimmune diseases. However, the role of interleukin-1β (IL-1β) in AIH is still indistinct. Here, we first investigated the significance of NOD-like receptor protein 3 (NLRP3) inflammasome-dependent IL-1β in the pathogenesis of AIH with a murine model of immune-mediated hepatitis induced by Concanavalin A (ConA). In ConA-treated mice, pathogenic elevated NLRP3, Cleaved caspase-1 and IL-1β levels, as well as an inflammatory cell death known as pyroptosis predominantly occurred in the livers. Strikingly, NLRP3−/− and caspase-1−/− mice were broadly protected from hepatitis as determined by decreased histological liver injury, serum aminotransferase (ALT)/aspartate transaminase levels, and pyroptosis. In vivo intervention with recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) strongly suppressed ConA-induced hepatitis by decreasing tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17) secretion, and inflammatory cell infiltration into livers. Additionally, rhIL-1Ra-pretreated mice developed significantly reduced NLRP3 inflammasome activation and reactive oxygen species (ROS) generation. Scavenging of ROS by N-acetyl-cysteine also attenuated NLRP3 inflammasome activation and liver inflammation, indicating that the essential role of ROS in mediating NLRP3 inflammasome activation in ConA-induced hepatitis. In conclusion, our results demonstrated that NLRP3 inflammasome-dependent IL-1β production was crucial in the pathogenesis of ConA-induced hepatitis, which shed light on the development of promising therapeutic strategies for AIH by blocking NLRP3 inflammasome and IL-1β.
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Affiliation(s)
- Jingyun Luan
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Xuyao Zhang
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Shaofei Wang
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Yubin Li
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Jiajun Fan
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Wei Chen
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Wenjing Zai
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Sijia Wang
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Yichen Wang
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Mingkuan Chen
- Unit of Innate Immunity, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Guangxun Meng
- Unit of Innate Immunity, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Dianwen Ju
- Department of Microbiological and Biochemical Pharmacy, The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
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46
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Clinical and Pathological Characteristics of Autoimmune Hepatitis with Acute Presentation. Can J Gastroenterol Hepatol 2018; 2018:3513206. [PMID: 29744332 PMCID: PMC5878912 DOI: 10.1155/2018/3513206] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 12/27/2017] [Accepted: 01/08/2018] [Indexed: 02/05/2023] Open
Abstract
Aim. To study the differences between acute presentation-autoimmune hepatitis (A-AIH) and chronic autoimmune hepatitis (C-AIH). Methods. Through long-term follow-up, 80 patients were included in our study by using the revised international autoimmune hepatitis group (IAIHG) score and were divided into acute and chronic groups for comparison. Results. No significant difference was found in the gender, age, IAIHG score (pretreatment/posttreatment), definite diagnosis rate, extrahepatic autoimmune disease, onset time, or treatment before biopsy between the acute and chronic groups. In terms of clinical symptoms, A-AIH patients were more prone to jaundice, anorexia, yellow urine, and detesting oil than C-AIH patients, but melena only occurred in chronic group (P < 0.05). The acute group exhibited more severe injury upon histological evaluation, with lobular inflammation and bile duct injury, especially central necrosis of the lobule, more pronounced in this group (P < 0.05). Conclusion. A-AIH had manifestations of acute hepatitis and presented cholestasis. Serum indicators could preliminarily distinguish A-AIH and C-AIH. Histologically, the primary manifestation of A-AIH was lobular inflammation, which was usually accompanied by lobular central necrosis. For the diagnosis of A-AIH, more attention should be paid to long-term follow-up. This study was registered at ClinicalTrials.gov (identifier: NCT02994537).
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47
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Abstract
Autoimmune hepatitis occurs in genetically susceptible individuals as a result of loss of immunological tolerance to hepatic autoantigens that can be precipitated by environmental triggers. The clinical manifestation is usually insidious but can be also acute with liver failure. The diagnosis is made on the basis of antibody positivity, elevated immunoglobulin G levels and interface hepatitis on liver histology. Induction of remission is achieved with high-dose steroids in the majority of cases, and maintenance of remission with azathioprine. Treatment withdrawal is achievable only in a small proportion of patients. Patients with acute liver failure unresponsive to steroids or those with end-stage liver failure or hepatocellular carcinoma may require liver transplantation. Variant forms of overlapping autoimmune hepatitis with either primary biliary cholangitis or sclerosing cholangitis are associated with worse outcomes. New insights into the pathophysiology of the disease may provide novel therapeutic targets and a more individualized approach to treatment of autoimmune hepatitis.
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Affiliation(s)
- Eleni Theocharidou
- Senior Clinical Fellow, Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London
| | - Michael A Heneghan
- Consultant Hepatologist, Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London SE5 9RS
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48
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Fujiwara K, Fukuda Y, Seza K, Saito M, Yasui S, Nakano M, Yokosuka O, Kato N. Long-term observation of acute-onset autoimmune hepatitis presenting clinically and radiologically as acute hepatitis. Hepatol Int 2018; 12:191-199. [DOI: 10.1007/s12072-018-9848-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 01/29/2018] [Indexed: 01/15/2023]
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49
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Dohmen K, Tanaka H, Haruno M, Aishima S. Immunoserological and histological differences between autoimmune hepatitis with acute presentation and chronic autoimmune hepatitis. Hepatol Res 2017; 47:1375-1382. [PMID: 28219122 DOI: 10.1111/hepr.12875] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Revised: 02/01/2017] [Accepted: 02/16/2017] [Indexed: 12/12/2022]
Abstract
AIM The histological features of clinically chronic autoimmune hepatitis (AIH) have been well established, with interface hepatitis and plasma cell infiltration as hallmark lesions, however, the immunoserological and histological features of recent-onset and acute AIH remain undefined. The goal of this study was to define the immunoserological and histological differences between AIH with acute presentation and chronic AIH. METHODS Thirty-two consecutive patients with well-characterized AIH who had undergone a liver biopsy were identified at our institution. These patients were divided into two groups. Sixteen patients whose liver dysfunction had persisted for at least 12 months were defined as chronic AIH (C-AIH) patients, and 16 patients whose liver dysfunction had been within normal limits for >12 months previously, and had only recently been found to have abnormal function for the first time, were defined as AIH with acute presentation (AIH-a) patients. Various biological and histological characteristics were compared between these two patient groups. RESULTS No significant differences were found between the groups for age, body mass index, serum levels of total bilirubin, transaminase, alkaline phosphatase, prothrombin activity, immunoglobulin, titers of antinuclear antibody, or diagnostic scores between the groups. Histologically, there was no significant difference in the degree of interface hepatitis, plasma cell infiltration, or centrilobular necrosis between AIH-a and C-AIH patients. However, histological active findings such as activity, lobular inflammation, rosette formation, spotty necrosis, seroid-laden macrophages, and single cell necrosis were significantly more frequent in AIH-a patients, whereas portal fibrosis was significantly more frequent in C-AIH patients. Only one case among the 16 AIH-a patients was confirmed as acute AIH, showing massive centrilobular necrosis with a mild degree of portal inflammation and interface hepatitis. All patients with AIH-a and C-AIH responded well to corticosteroid or ursodeoxycholic acid treatment. CONCLUSIONS Patients with AIH-a could not be distinguished from C-AIH patients clinically or immunoserologically. Based on the histopathological findings of the liver, almost all cases of AIH-a might be exacerbations of non-symptomatic pre-existing C-AIH.
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50
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Harada K, Hiep NC, Ohira H. Challenges and difficulties in pathological diagnosis of autoimmune hepatitis. Hepatol Res 2017; 47:963-971. [PMID: 28675685 DOI: 10.1111/hepr.12931] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 06/19/2017] [Accepted: 06/23/2017] [Indexed: 02/08/2023]
Abstract
Autoimmune hepatitis (AIH) with acute presentation is widely recognized as a distinct clinical entity, and its clinicopathology has been extensively studied. In most cases, AIH with acute presentation is merely acute exacerbation of classical chronic AIH, but pure acute-onset AIH without previous symptoms of chronic liver disease is also encountered. Rapid diagnosis and initiation of immunosuppressive treatment are necessary for both acute exacerbation and acute-onset to prevent fatal liver failure. The diagnostic criteria commonly used for classical AIH are generally applicable to acute exacerbation, but acute-onset AIH may present with additional pathological features. These features include an acute hepatitis phase characterized by centrilobular necrosis. However, centrilobular necrosis is also a feature of drug-induced liver injury, and there are no known histological characteristics exclusive to acute-onset AIH. Moreover, the possibilities of drug-induced AIH and immune-mediated drug-induced liver injury make diagnosis even more difficult. At present, liver biopsy is mandatory for the diagnosis of AIH with acute presentation, but careful consideration of all clinicopathological signs is necessary for differential diagnosis.
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Affiliation(s)
- Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Nguyen Canh Hiep
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
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