1
|
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.
Collapse
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
| |
Collapse
|
2
|
Jiao J, Zhang X. Steatotic Liver Disease: Navigating Pathologic Features, Diagnostic Challenges, and Emerging Insights. Adv Anat Pathol 2025:00125480-990000000-00135. [PMID: 39895389 DOI: 10.1097/pap.0000000000000483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Steatotic liver disease (SLD) is now used as an overarching category encompassing five subcategories: metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic and alcohol related/associated liver disease (MetALD), alcohol-related/associated liver disease (ALD), SLD with specific etiology, and cryptogenic SLD. This review summarizes foundational and recent advances in the histologic evaluation of SLD, including common pathologic features across all subcategories, distinctions associated with different etiologies, scoring and grading systems, and the evolution of digital pathology techniques for SLD assessment.
Collapse
Affiliation(s)
- Jingjing Jiao
- Department of Pathology, Yale University School of Medicine, New Haven, CT
| | | |
Collapse
|
3
|
Zhu YJ, Zhang Y, Rao Y, Jiang Y, Liu YG, Li JZ, Yuan JQ, Zhao Y, Zheng WW, Ma L, Wang CY, Li J. Evaluation of autoimmune phenomena in patients with nonalcoholic fatty liver disease on the basis of liver pathology. World J Hepatol 2024; 16:1407-1416. [DOI: 10.4254/wjh.v16.i12.1407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/14/2024] [Accepted: 10/29/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Autoimmune phenomena can be used in some patients with nonalcoholic fatty liver disease (NAFLD) in the clinic, but these patients are not autoimmune hepatitis patients.
AIM To determine whether autoimmunity is present in patients with NAFLD, this study was performed.
METHODS A total of 104 patients with NAFLD diagnosed by liver biopsy at Tianjin Second People’s Hospital between 2019 and 2023 were enrolled. The patients were divided into three groups according to their biopsy results: The NAFL (n = 36), nonalcoholic steatohepatitis (n = 51), and liver cirrhosis groups (n = 17).
RESULTS The differences in IgA, an immune marker, among the three groups of patients were statistically significant (P = 0.025). In all NAFLD patients, antinuclear antibody and anti-smooth muscle antibody were the most common autoantibodies. The antinuclear antibody detection rate was the highest at 48.1%. The cirrhosis group had the highest autoantibody positivity rate (64.7%). Portal enlargement is also common in NAFLD patients. The rates of positivity for portal lymphoplasmacytic infiltration, small bile duct hyperplasia and interfacial hepatitis were highest in the cirrhosis group; the differences between the cirrhosis group and the other two groups were significant (P < 0.05). Hepatocellular rosettes were identified only in the cirrhosis group (11.8%).
CONCLUSION Autoimmune phenomena occur in NAFLD patients, especially in patients with NAFLD-related cirrhosis, in whom this phenomenon may be more pronounced.
Collapse
Affiliation(s)
- Yu-Jin Zhu
- Department of Infectious Diseases, Xi’an No. 3 Hospital, the Affiliated Hospital of Northwest University, Xi’an 710018, Shaanxi Province, China
| | - Yan Zhang
- Department of Epidemiology, Tianjin Medical University, Tianjin 300070, China
| | - Yao Rao
- Department of Gastroenterology, Clinical School of the Second People's Hospital, Tianjin 300110, China
| | - Yong Jiang
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Yong-Gang Liu
- Department of Pathology, Clinical School of the Second People's Hospital, Tianjin 300110, China
| | - Jian-Zhou Li
- Department of Gastro-Enterologie, Xining Second People's Hospital, Xining 810003, Qinghai Province, China
| | - Jia-Qi Yuan
- Department of Gastro-Enterologie, Xining Second People's Hospital, Xining 810003, Qinghai Province, China
| | - Ying Zhao
- Department of Epidemiology, Tianjin Medical University, Tianjin 300070, China
| | - Wen-Wen Zheng
- Department of Epidemiology, Tianjin Medical University, Tianjin 300070, China
| | - Lin Ma
- Department of Epidemiology, Tianjin Medical University, Tianjin 300070, China
| | - Chun-Yan Wang
- Department of Gastroenterology, Clinical School of the Second People's Hospital, Tianjin 300110, China
| | - Jia Li
- Department of Gastroenterology, Clinical School of the Second People's Hospital, Tianjin 300110, China
| |
Collapse
|
4
|
Pericàs JM, Anstee QM, Augustin S, Bataller R, Berzigotti A, Ciudin A, Francque S, Abraldes JG, Hernández-Gea V, Pons M, Reiberger T, Rowe IA, Rydqvist P, Schabel E, Tacke F, Tsochatzis EA, Genescà J. A roadmap for clinical trials in MASH-related compensated cirrhosis. Nat Rev Gastroenterol Hepatol 2024; 21:809-823. [PMID: 39020089 DOI: 10.1038/s41575-024-00955-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/03/2024] [Indexed: 07/19/2024]
Abstract
Although metabolic dysfunction-associated steatohepatitis (MASH) is rapidly becoming a leading cause of cirrhosis worldwide, therapeutic options are limited and the number of clinical trials in MASH-related compensated cirrhosis is low as compared to those conducted in earlier disease stages. Moreover, designing clinical trials in MASH cirrhosis presents a series of challenges regarding the understanding and conceptualization of the natural history, regulatory considerations, inclusion criteria, recruitment, end points and trial duration, among others. The first international workshop on the state of the art and future direction of clinical trials in MASH-related compensated cirrhosis was held in April 2023 at Vall d'Hebron University Hospital in Barcelona (Spain) and was attended by a group of international experts on clinical trials from academia, regulatory agencies and industry, encompassing expertise in MASH, cirrhosis, portal hypertension, and regulatory affairs. The presented Roadmap summarizes important content of the workshop on current status, regulatory requirements and end points in MASH-related compensated cirrhosis clinical trials, exploring alternative study designs and highlighting the challenges that should be considered for upcoming studies on MASH cirrhosis.
Collapse
Affiliation(s)
- Juan M Pericàs
- Liver Unit, Division of Digestive Diseases, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain.
- Centros de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
| | - Quentin M Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Newcastle NIHR Biomedical Research Center, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | | | - Ramón Bataller
- Liver Unit, Hospital Clinic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat Barcelona, Barcelona, Spain
| | - Annalisa Berzigotti
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Andreea Ciudin
- Endocrinology and Nutrition Department, Morbid Obesity Unit Coordinator, Vall d'Hebron University Hospital, Barcelona, Spain
- Centros de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Juan G Abraldes
- Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada
| | - Virginia Hernández-Gea
- Centros de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Unit, Hospital Clinic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat Barcelona, Barcelona, Spain
| | - Mònica Pons
- Liver Unit, Division of Digestive Diseases, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Ian A Rowe
- Leeds Institute for Medical Research, University of Leeds, Leeds, UK
| | - Peter Rydqvist
- Medical Department, Madrigal Pharmaceuticals, West Conshohocken, PA, USA
| | - Elmer Schabel
- Federal Institute for Drugs and Medical Devices, Bonn, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Emmanuel A Tsochatzis
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK
| | - Joan Genescà
- Liver Unit, Division of Digestive Diseases, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain
- Centros de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
5
|
Mohammad N, Oshins R, Gu T, Clark V, Lascano J, Assarzadegan N, Marek G, Brantly M, Khodayari N. Liver Characterization of a Cohort of Alpha-1 Antitrypsin Deficiency Patients with and without Lung Disease. J Clin Transl Hepatol 2024; 12:845-856. [PMID: 39440224 PMCID: PMC11491504 DOI: 10.14218/jcth.2024.00201] [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: 06/17/2024] [Revised: 08/20/2024] [Accepted: 08/25/2024] [Indexed: 10/25/2024] Open
Abstract
Background and Aims Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder characterized by the misfolding and accumulation of the mutant variant of alpha-1 antitrypsin (AAT) within hepatocytes, which limits its access to the circulation and exposes the lungs to protease-mediated tissue damage. This results in progressive liver disease secondary to AAT polymerization and accumulation, and chronic obstructive pulmonary disease (COPD) due to deficient levels of AAT within the lungs. Our goal was to characterize the unique effects of COPD secondary to AATD on liver disease and gene expression. Methods A subcohort of AATD individuals with COPD (n = 33) and AATD individuals without COPD (n = 14) were evaluated in this study from our previously reported cross-sectional cohort. We used immunohistochemistry to assess the AATD liver phenotype, and RNA sequencing to explore liver transcriptomics. We observed a distinct transcriptomic profile in liver tissues from AATD individuals with COPD compared to those without. Results A total of 339 genes were differentially expressed. Canonical pathways related to fibrosis, extracellular matrix remodeling, collagen deposition, hepatocellular damage, and inflammation were significantly upregulated in the livers of AATD individuals with COPD. Histopathological analysis also revealed higher levels of fibrosis and hepatocellular damage in these individuals. Conclusions Our data supports a relationship between the development of COPD and liver disease in AATD and introduces genes and pathways that may play a role in AATD liver disease when COPD is present. We believe addressing lung impairment and airway inflammation may be an approach to managing AATD-related liver disease.
Collapse
Affiliation(s)
- Naweed Mohammad
- Division of Pulmonary, Critical Care and Sleep Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Regina Oshins
- Division of Pulmonary, Critical Care and Sleep Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Tongjun Gu
- Interdisciplinary Center for Biotechnology Research, Bioinformatics Core, University of Florida, Gainesville, FL, USA
| | - Virginia Clark
- Division of Gastroenterology, Hepatology and Nutrition, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Jorge Lascano
- Division of Pulmonary, Critical Care and Sleep Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Naziheh Assarzadegan
- Division of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - George Marek
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Mark Brantly
- Division of Pulmonary, Critical Care and Sleep Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Nazli Khodayari
- Division of Pulmonary, Critical Care and Sleep Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| |
Collapse
|
6
|
Solleiro-Villavicencio H, Méndez-García LA, Ocampo-Aguilera NA, Baltazar-Pérez I, Arreola-Miranda JA, Aguayo-Guerrero JA, Alfaro-Cruz A, González-Chávez A, Fonseca-Sánchez MA, Fragoso JM, Escobedo G. Decreased Hepatic and Serum Levels of IL-10 Concur with Increased Lobular Inflammation in Morbidly Obese Patients. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:862. [PMID: 38929479 PMCID: PMC11205754 DOI: 10.3390/medicina60060862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/22/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024]
Abstract
Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. Accumulating evidence in animal models suggests that loss of interleukin-10 (IL-10) anti-inflammatory actions might contribute to lobular inflammation, considered one of the first steps toward NASH development. However, the role of IL-10 in lobular inflammation remains poorly explored in humans. We examined mRNA and protein levels of IL-10 in liver biopsies and serum samples from morbidly obese patients, investigating the relationship between IL-10 and lobular inflammation degree. Materials and Methods: We prospectively enrolled morbidly obese patients of both sexes, assessing the lobular inflammation grade by the Brunt scoring system to categorize participants into mild (n = 7), moderate (n = 19), or severe (n = 13) lobular inflammation groups. We quantified the hepatic mRNA expression of IL-10 by quantitative polymerase chain reaction and protein IL-10 levels in liver and serum samples by Luminex Assay. We estimated statistical differences by one-way analysis of variance (ANOVA) and Tukey's multiple comparison test. Results: The hepatic expression of IL-10 significantly diminished in patients with severe lobular inflammation compared with the moderate lobular inflammation group (p = 0.01). The hepatic IL-10 protein levels decreased in patients with moderate or severe lobular inflammation compared with the mild lobular inflammation group (p = 0.008 and p = 0.0008, respectively). In circulation, IL-10 also significantly decreased in subjects with moderate or severe lobular inflammation compared with the mild lobular inflammation group (p = 0.005 and p < 0.0001, respectively). Conclusions: In liver biopsies and serum samples of morbidly obese patients, the protein levels of IL-10 progressively decrease as lobular inflammation increases, supporting the hypothesis that lobular inflammation develops because of the loss of the IL-10-mediated anti-inflammatory counterbalance.
Collapse
Affiliation(s)
| | - Lucía Angélica Méndez-García
- Laboratory of Immunometabolism, Research Division, General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06726, Mexico; (L.A.M.-G.); (N.A.O.-A.); (I.B.-P.); (J.A.A.-M.); (J.A.A.-G.)
| | - Nydia A. Ocampo-Aguilera
- Laboratory of Immunometabolism, Research Division, General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06726, Mexico; (L.A.M.-G.); (N.A.O.-A.); (I.B.-P.); (J.A.A.-M.); (J.A.A.-G.)
| | - Itzel Baltazar-Pérez
- Laboratory of Immunometabolism, Research Division, General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06726, Mexico; (L.A.M.-G.); (N.A.O.-A.); (I.B.-P.); (J.A.A.-M.); (J.A.A.-G.)
| | - José A. Arreola-Miranda
- Laboratory of Immunometabolism, Research Division, General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06726, Mexico; (L.A.M.-G.); (N.A.O.-A.); (I.B.-P.); (J.A.A.-M.); (J.A.A.-G.)
| | - José A. Aguayo-Guerrero
- Laboratory of Immunometabolism, Research Division, General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06726, Mexico; (L.A.M.-G.); (N.A.O.-A.); (I.B.-P.); (J.A.A.-M.); (J.A.A.-G.)
| | - Ana Alfaro-Cruz
- Pathological Anatomy Department, General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06726, Mexico;
| | - Antonio González-Chávez
- Clínica de Atención Integral para Pacientes con Diabetes y Obesidad (CAIDO), General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06726, Mexico;
| | | | - José Manuel Fragoso
- Department of Molecular Biology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico;
| | - Galileo Escobedo
- Laboratory of Immunometabolism, Research Division, General Hospital of Mexico “Dr. Eduardo Liceaga”, Mexico City 06726, Mexico; (L.A.M.-G.); (N.A.O.-A.); (I.B.-P.); (J.A.A.-M.); (J.A.A.-G.)
| |
Collapse
|
7
|
Zhang C, Xu Q, Xu C, Yang K, Xia T, Hasi W, Hao M, Kuang H. Sex Differences in the Association Between AST/ALT and Incidence of Type 2 Diabetes in Japanese Patients with Nonalcoholic Fatty Liver Disease: A Retrospective Cohort Study. Endocr Res 2024; 49:1-11. [PMID: 37752709 DOI: 10.1080/07435800.2023.2262034] [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: 12/22/2022] [Accepted: 09/16/2023] [Indexed: 09/28/2023]
Abstract
OBJECTIVES/INTRODUCTION The purpose of the current study was to investigate the association between Aspartate Transaminase (AST)/Alanine transaminase(ALT) and type 2 diabetes (T2DM) in nonalcoholic fatty liver disease (NAFLD) patients and to determine whether there were sex differences. METHODS In the retrospective study, we collected data on NAFLD patients (1, 896 men and 465 women) at Murakami Memorial Hospital from 2004 to 2015. Data were stratified by sex to investigate the association between AST/ALT and T2DM incidence by sex. Multiple regression analysis, smooth curve fitting model and subgroup analysis were used to determine the correlation, non-linear relationship and threshold effect between AST/ALT and T2DM. RESULTS In our study, 157 men and 40 women developed T2DM at follow-up. After adjusting for risk factors, AST/ALT was significantly associated with T2DM in men with NAFLD but not in women with NAFLD. The risk of T2DM increased as the AST/ALT ratio decreased. Besides, in male NAFLD patients, AST/ALT showed a non-linear relationship with T2DM, with an inflection point value of 0.964. When the AST to ALT ratio was below the threshold (AST/ALT <0.964), AST/ALT was significantly negatively associated with T2DM (HR = 0.177, 95% CI 0.055-0.568; P = 0.0036). In contrast, when AST/ALT >0.964, no significant association was found (HR = 3.174, 95% CI 0.345-29.167; P = 0.3074). Moreover, subgroup analysis showed that GGT could alter the relationship between AST/ALT and T2DM. In the group with GGT ≤ 40, AST/ALT was strongly associated with T2DM (HR = 0.24, 95% CI 0.09-0.66; P = 0.0059). CONCLUSIONS These results suggested that there were sex differences in the association between AST/ALT and T2DM in NAFLD participants. A non-linear association between AST/ALT and T2DM was observed in males. AST/ALT in the normal GGT group (GGT ≤40) might better facilitate the early screening of T2DM.
Collapse
Affiliation(s)
- Cong Zhang
- Department of Endocrinology, The First Clinical Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Qian Xu
- Department of Endocrinology, The First Clinical Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Chengye Xu
- Department of Endocrinology, The First Clinical Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Kun Yang
- Department of Endocrinology, The First Clinical Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Tian Xia
- Department of Endocrinology, The First Clinical Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Wuying Hasi
- Department of Endocrinology, The First Clinical Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ming Hao
- Department of Endocrinology, The First Clinical Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Hongyu Kuang
- Department of Endocrinology, The First Clinical Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| |
Collapse
|
8
|
Sanyal AJ, Jha P, Kleiner DE. Digital pathology for nonalcoholic steatohepatitis assessment. Nat Rev Gastroenterol Hepatol 2024; 21:57-69. [PMID: 37789057 DOI: 10.1038/s41575-023-00843-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/23/2023] [Indexed: 10/05/2023]
Abstract
Histological assessment of nonalcoholic fatty liver disease (NAFLD) has anchored knowledge development about the phenotypes of the condition, their natural history and their clinical course. This fact has led to the use of histological assessment as a reference standard for the evaluation of efficacy of drug interventions for nonalcoholic steatohepatitis (NASH) - the more histologically active form of NAFLD. However, certain limitations of conventional histological assessment systems pose challenges in drug development. These limitations have spurred intense scientific and commercial development of machine learning and digital approaches towards the assessment of liver histology in patients with NAFLD. This research field remains an area in rapid evolution. In this Perspective article, we summarize the current conventional assessment of NASH and its limitations, the use of specific digital approaches for histological assessment, and their application to the study of NASH and its response to therapy. Although this is not a comprehensive review, the leading tools currently used to assess therapeutic efficacy in drug development are specifically discussed. The potential translation of these approaches to support routine clinical assessment of NAFLD and an agenda for future research are also discussed.
Collapse
Affiliation(s)
- Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
| | - Prakash Jha
- Food and Drug Administration, Silver Spring, MD, USA
| | - David E Kleiner
- Post-Mortem Section Laboratory of Pathology Center for Cancer Research National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
9
|
Palmer M, Kleiner DE, Goodman Z, Brunt E, Avigan MI, Regev A, Hayashi PH, Lewis JH, Mehta R, Harrison SA, Siciliano M, McWherter CA, Vuppalanchi R, Behling C, Miller V, Chalasani N, Sanyal AJ. Liver biopsy for assessment of suspected drug-induced liver injury in metabolic dysfunction-associated steatohepatitis clinical trials: Expert consensus from the Liver Forum. Aliment Pharmacol Ther 2024; 59:201-216. [PMID: 37877759 DOI: 10.1111/apt.17762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 05/25/2023] [Accepted: 10/03/2023] [Indexed: 10/26/2023]
Abstract
BACKGROUND Causality assessment of suspected drug-induced liver injury (DILI) during metabolic dysfunction-associated steatohepatitis (MASH) clinical trials can be challenging, and liver biopsies are not routinely performed as part of this evaluation. While the field is moving away from liver biopsy as a diagnostic and prognostic tool, information not identified by non-invasive testing may be provided on histology. AIM To address the appropriate utilisation of liver biopsy as part of DILI causality assessment in this setting. METHODS From 2020 to 2022, the Liver Forum convened a series of webinars on issues pertaining to liver biopsy during MASH trials. The Histology Working Group was formed to generate a series of consensus documents addressing these challenges. This manuscript focuses on liver biopsy as part of DILI causality assessment. RESULTS Expert opinion, guidance and recommendations on the role of liver biopsy as part of causality assessment of suspected DILI occurring during clinical trials for a drug(s) being developed for MASH are provided. Lessons learned from prior MASH programs are reviewed and gaps identified. CONCLUSIONS Although there are no pathognomonic features, histologic evaluation of suspected DILI during MASH clinical trials may alter patient management, define the pattern and severity of injury, detect findings that favour a diagnosis of DILI versus MASH progression, identify prognostic features, characterise the clinicopathological phenotype of DILI, and/or define lesions that influence decisions about trial discontinuation and further development of the drug.
Collapse
Affiliation(s)
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA
| | - Zachary Goodman
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Elizabeth Brunt
- Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA
| | - Mark I Avigan
- Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA
| | | | - Paul H Hayashi
- Division of Hepatology and Nutrition, Food and Drug Administration, Silver Spring, Maryland, USA
| | - James H Lewis
- Division of Gastroenterology, Georgetown University Hospital, Washington, District of Columbia, USA
| | - Ruby Mehta
- Center for Drug Evaluation and Research Office of New Drugs, Office of Inflammation and Immunity, Division of Hepatology and Nutrition, US Food and Drug Administration, Silver Spring, Maryland, USA
| | | | - Massimo Siciliano
- Fatebenefratelli Gemelli Isola - Rome, Sacred Heart Catholic Univesity, Rome, Italy
| | - Charles A McWherter
- Research and Development, CymaBay Therapeutics, Inc., Newark, California, USA
| | - Raj Vuppalanchi
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | | | - Veronica Miller
- University of California Berkeley, School of Public Health, Forum for Collaborative Research, Washington, District of Columbia, USA
| | - Naga Chalasani
- Indiana University School of Medicine, Indiana University Health, Indianapolis, Indiana, USA
| | - Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
- Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| |
Collapse
|
10
|
Romano-Munive AF, Moctezuma-Velázquez C, Sauma-Rodríguez J, Ramos-Martínez P, Torre-Delgadillo A. CD138 immunohistochemistry identifies more plasma cells compared with hematoxylin and eosin staining in autoimmune hepatitis. An observational study. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2024; 89:52-56. [PMID: 36973120 DOI: 10.1016/j.rgmxen.2022.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 08/25/2022] [Indexed: 03/29/2023]
Abstract
INTRODUCTION Autoimmune hepatitis (AIH) is associated with periportal infiltration by plasma cells. Plasma cell detection is routinely performed through hematoxylin and eosin (H&E) staining. The present study aimed to assess the utility of CD138, an immunohistochemical plasma cell marker, in the evaluation of AIH. MATERIALS AND METHODS A retrospective study was conducted, in which cases consistent with AIH, within the time frame of 2001 and 2011, were collected. Routine H&E-stained sections were used for evaluation. CD138 immunohistochemistry (IHC) was performed to detect plasma cells. RESULTS Sixty biopsies were included. In the H&E group, the median and interquartile range (IQR) was 6 (4-9) plasma cells/high power field (HPF) and was 10 (IQR 6-20) plasma cells/HPF in the CD138 group (p < 0.001). There was a significant correlation between the number of plasma cells determined by H&E and CD138 (p = 0.31, p = 0.01). No significant correlation was found between the number of plasma cells determined by CD138 and IgG level (p = 0.21, p = 0.09) or stage of fibrosis (p = 0.12, p = 0.35), or between IgG level and stage of fibrosis (p = 0.17, p = 0.17). No significant correlation was found between the treatment response and the number of plasma cells determined by H&E (p = 0.11, p = 0.38), CD138 (p = 0.07, p = 0.55), or stage of fibrosis (p = 0.16, p = 0.20). CD138 expression was different between the treatment response groups (p = 0.04). CONCLUSION CD138 increased the detection of plasma cells in liver biopsies of patients with AIH, when compared with routine H&E staining. However, there was no correlation between the number of plasma cells determined by CD138 and serum IgG levels, stage of fibrosis, or response to treatment.
Collapse
Affiliation(s)
- A F Romano-Munive
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Tlalpan, Mexico City, Mexico.
| | - C Moctezuma-Velázquez
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Tlalpan, Mexico City, Mexico
| | | | - P Ramos-Martínez
- Departamento de Patología, INCMNSZ, Tlalpan, Mexico City, Mexico
| | - A Torre-Delgadillo
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Tlalpan, Mexico City, Mexico
| |
Collapse
|
11
|
Hirschfield GM, Shiffman ML, Gulamhusein A, Kowdley KV, Vierling JM, Levy C, Kremer AE, Zigmond E, Andreone P, Gordon SC, Bowlus CL, Lawitz EJ, Aspinall RJ, Pratt DS, Raikhelson K, Gonzalez-Huezo MS, Heneghan MA, Jeong SH, Ladrón de Guevara AL, Mayo MJ, Dalekos GN, Drenth JP, Janczewska E, Leggett BA, Nevens F, Vargas V, Zuckerman E, Corpechot C, Fassio E, Hinrichsen H, Invernizzi P, Trivedi PJ, Forman L, Jones DE, Ryder SD, Swain MG, Steinberg A, Boudes PF, Choi YJ, McWherter CA. Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study. Hepatology 2023; 78:397-415. [PMID: 37386786 PMCID: PMC10344437 DOI: 10.1097/hep.0000000000000395] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/21/2023] [Accepted: 02/25/2023] [Indexed: 07/01/2023]
Abstract
BACKGROUND AND AIMS ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). APPROACH AND RESULTS Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events. CONCLUSIONS Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.
Collapse
Affiliation(s)
- Gideon M. Hirschfield
- University Health Network and Division of Gastroenterology and Hepatology, Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | - Mitchell L. Shiffman
- Liver Institute of Virginia, Bon Secours Mercy Health, Bon Secours Liver Institute of Richmond, Richmond, Virginia, USA
- Bon Secours Liver Institute of Hampton Roads, Newport News, Virginia, USA
| | - Aliya Gulamhusein
- University Health Network and Department of Medicine, Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada
| | | | - John M. Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - Cynthia Levy
- Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Andreas E. Kremer
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Ehud Zigmond
- Center for Autoimmune Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Pietro Andreone
- Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, Modena, Italy
- Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, Italy
| | - Stuart C. Gordon
- Division of Hepatology, Henry Ford Hospital, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Christopher L. Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California, USA
| | - Eric J. Lawitz
- Texas Liver Institute, University of Texas Health San Antonio, San Antonio, Texas, USA
| | - Richard J. Aspinall
- Department of Hepatology, Portsmouth Liver Centre, Portsmouth Hospitals National Health Service Trust, Queen Alexandra Hospital, Portsmouth, UK
| | - Daniel S. Pratt
- Autoimmune and Cholestatic Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Karina Raikhelson
- Saint Petersburg State University, St. Petersburg, Russia
- City Hospital 31, St. Petersburg, Russia
| | | | - Michael A. Heneghan
- King’s College Hospital National Health Service Foundation Trust, London, UK
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | | | - Marlyn J. Mayo
- Division of Digestive and Liver Diseases, University of Texas Southwestern, Dallas, Texas, USA
| | - George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Joost P.H. Drenth
- Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, The Netherlands
| | - Ewa Janczewska
- Department of Basic Medical Sciences, Faculty of Health Sciences in Bytom, Medical University of Silesia, Katowice, Poland
- ID Clinic, Myslowice, Poland
| | - Barbara A. Leggett
- School of Medicine, University of Queensland, Herston, Queensland, Australia
| | - Frederik Nevens
- University Hospitals KU Leuven, Belgium
- Center of European Reference Network (ERN) RARE-LIVER, Leuven, Belgium
| | - Victor Vargas
- Liver Unit, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Bellaterra, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Eli Zuckerman
- Liver Unit, Carmel Medical Center, Technion, Faculty of Medicine, Israeli Association for the Study of the Liver, Haifa, Israel
| | - Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology and Gastroenterology Department (MIVB-H), Filière Maladies Rares: Maladies Rares du Foie de l’Adulte et de l’Enfant (FILFOIE), European Reference Network (ERN) RARE-LIVER, Inserm, Centre de Recherche Saint-Antoine (CRSA), Assistance Publique-Hopitaux of Paris (AP-HP), Saint-Antoine Hospital, Sorbonne Universités, Paris, France
| | - Eduardo Fassio
- DIM Clínica Privada, Ramos Mejía, Buenos Aires province, Argentina
| | | | - Pietro Invernizzi
- Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Italy
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori & European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Monza, Italy
| | - Palak J. Trivedi
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, UK
- Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, UK
- Institute of Applied Health Research, University of Birmingham, UK
| | - Lisa Forman
- University of Colorado, Aurora, Colorado, USA
| | - David E.J. Jones
- Institute of Cellular Medicine and National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK
| | - Stephen D. Ryder
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at Nottingham University Hospitals National Health Service (NHS) Trust and the University of Nottingham, Queens Medical Centre, Nottingham, UK
| | - Mark G. Swain
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | | | | | | |
Collapse
|