DOCSLIB.ORG

Cystic Fibrosis Liver Disease Clinical Research Workshop

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cystic Fibrosis Liver Disease Clinical Research Workshop Cystic Fibrosis Liver Disease Clinical Research Workshop JUNE 8 - 9, 2009 LISTER HILL AUDITORIUM NIH CAMPUS, BETHESDA, MD Organizing Committee Michael Narkewicz, M.D. University of Colorado Denver Michael Knowles, M.D. The University of North Carolina at Chapel Hill Patricia Robuck, Ph.D., M.P.H. National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Catherine McKeon, Ph.D. National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Jay H. Hoofnagle, M.D. National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bruce Marshall, M.D. Cystic Fibrosis Foundation Marilyn Siegel, M.D. Washington University Medical Center Edward Doo, M.D. National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health SPONSORS: The National Institute of Diabetes and Digestive and Kidney Diseases, the Office of Rare Diseases, and the Cystic Fibrosis Foundation. The lunch and poster session are sponsored by the Cystic Fibrosis Foundation. Cystic Fibrosis Liver Disease | Clinical Research Workshop iii Table of Contents Organizing Committee iii Agenda ix Speaker Abstracts Cystic Fibrosis Liver Disease: Clinical Features and Definitions Michael R. Narkewicz 3 Prevalence and Epidemiology of Cystic Fibrosis Liver Disease Jean Pappas Molleston 6 Cystic Fibrosis Liver Disease: Clinical Outcomes Peter Durie, Susanne Schibli, Rakesh Battacharjee, Mary Corey 8 Pathogenesis of Cystic Fibrosis Liver Disease Steven D. Freedman 10 The Pathology of Cystic Fibrosis Liver Disease David E. Kleiner 15 Genetic Modifiers of Cystic Fibrosis Liver Disease Michael R. Knowles for Jaclyn Bartlett, Peter Durie, and the Gene Modifier Study Group 17 Protein Folding Defects in Liver Disease: Alpha-1-antitrypsin Deficiency Jeffrey Teckman 19 Cystic Fibrosis Liver Disease: CFTR and the Liver Andrew P. Feranchak 21 The CFTR-/- Pig: Liver and Gallbladder Disease David K. Meyerholz, David A. Stoltz, Michael J. Welsh 24 Medical and Surgical Therapy of CF-associated Liver Disease Saul J. Karpen 25 Liver Transplantation in Children With Cystic Fibrosis: Status and Unanswered Questions George V. Mazariegos 27 Biomarkers as Tools for Early Disease Detection Nicole Mayer Hamblett 29 Cystic Fibrosis Liver Disease | Clinical Research Workshop v Table of Contents Emerging Techniques for Developing Novel Serum Biomarkers Keyur Patel 31 Biomarkers of Cystic Fibrosis Liver Disease Ross W. Shepherd, Grant Ramm, Peter Lewindon 33 Ultrasound and CT Imaging of Liver Fibrosis and Other Disease Marilyn J. Siegel 35 MRI Methods of Assessing Liver Fibrosis and Disease Claude B. Sirlin 37 Elastography to Assess Liver Fibrosis and Cirrhosis Detlef Schuppan 39 Agenda Poster Abstracts Long-term Effect of Simultaneous Liver-Pancreas Transplant on Hepatic, Pulmonary, and Pancreatic Function in Three Cystic Fibrosis Patients Molly Bozic, Jean Molleston, M. Howenstine, J. Fridell 43 Paracrine Induction of Sulfotransferase 1E1 in HepG2 Hepatocytes During Co-culture With CFTR-deficient MMNK-1 Cholangiocytes Charles N. Falany, Dongning He, Li Li, Teresa W. Wilborn, Melissa Runge-Morris 45 Quantitative Imaging of Biliary Fibrosis Progression Using a Small Molecule αv β6 Integrin Ligand With Nanomolar Affinity Yury Popov, Preeti Misra, Kumar Ranjan Bhushan, Deanna Y. Sverdlov, Nezam H. Afdhal, John V. Frangioni, Deflef Schuppan 46 Cystic Fibrosis Related Diabetes (CFRD) in CF Patients With Cirrhosis Kara Sullivan, A. Moran, B. Holm, S.J. Schwarzenberg 47 Design of a Pilot Study to Identify Optimum Markers of Liver Fibrosis in Children With Cystic Fibrosis Liver Disease (CFLD) Alexandra Vasilescu, Shruti Paranjape, Wikrom Karnsakul, Kathleen B. Schwarz 48 Participants List 51 Notes 65 vi Cystic Fibrosis Liver Disease | Clinical Research Workshop Agenda Monday, June 8, 2009 LISTER HILL AUDITORIUM NIH CAMPUS, BETHESDA, MD DAY ONE 8:00 a.m. – 8:30 a.m. Registration 8:30 a.m. – 8:40 a.m. Welcoming Remarks Jay Hoofnagle SESSION I. CLINICAL ASPECTS AND PREVALENCE OF CF LIVER DISEASE 8:40 a.m. – 9:00 a.m. Cystic Fibrosis Liver Disease: Clinical Features and Definitions Michael Narkewicz 9:00 a.m. – 9:20 a.m. Prevalence and Epidemiology of Cystic Fibrosis Liver Disease Jean Molleston 9:20 a.m. – 9:40 a.m. Cystic Fibrosis Liver Disease: Clinical Outcomes Peter Durie 9:40 a.m. – 10:10 a.m. Discussion 10:10 a.m. – 10:40 a.m. Break SESSION II. PATHOGENESIS OF CF LIVER DISEASE 10:40 a.m. – 11:00 a.m. Pathogenesis of CF Liver Disease Stephen Freedman 11:00 a.m. – 11:20 a.m. The Pathology of Cystic Fibrosis Liver Disease* David Kleiner 11:20 a.m. – 11:40 a.m. Genetic Modifiers of Cystic Fibrosis Liver Disease Michael Knowles * Results of a premeeting working group of clinicians and pathologists who will review pathology of CF liver disease and propose diagnostic criteria and staging and grading systems. Cystic Fibrosis Liver Disease | Clinical Research Workshop ix Agenda Agenda Monday, June 8, 2009 Tuesday, June 9, 2009 LISTER HILL AUDITORIUM CONTINUED NIH CAMPUS, BETHESDA, MD DAY TWO 11:40 a.m. – 12:00 p.m. Protein Folding Defects in Liver Disease: 8:00 a.m. – 8:10 a.m. Introduction to Day 2: Alpha-1-antitrypsin Deficiency Early Assessment and Identification Jeffrey Teckman Edward Doo 12:00 p.m. – 12:30 p.m. Discussion SESSION IV. NONINVASIVE ASSESSMENTS OF CF LIVER DISEASE 12:30 p.m. – 2:00 p.m. Lunch BIOMARKERS SESSION III. MODELS OF CF LIVER DISEASE AND THERAPEUTICS 8:10 a.m. – 8:30 a.m. Biomarkers as Tools for Early Disease Detection Nicole Hamblett 2:00 p.m. – 2:20 p.m. Cystic Fibrosis Liver Disease: CFTR and the Liver Andrew Feranchak 8:30 a.m. – 8:50 a.m. Emerging Techniques for Developing Novel Serum Biomarkers 2:20 p.m. – 2:40 p.m. The CFTR-/- Pig: Liver and Gallbladder Disease Keyur Patel David Meyerholz 8:50 a.m. – 9:10 a.m. Biomarkers of Cystic Fibrosis Liver Disease 2:40 p.m. – 3:00 p.m. Nodular Regenerative Hyperplasia: Ross Shepherd Clinical Features and Course Theo Heller 9:10 a.m. – 9:40 a.m. Discussion 3:00 p.m. – 3:20 p.m. Medical and Surgical Therapy of CF-associated 9:40 a.m. – 10:00 a.m. Break Liver Disease Saul Karpen IMAGING 3:20 p.m. – 3:40 p.m. Liver Transplantation in Children With Cystic Fibrosis: Status and Unanswered Questions 10:00 a.m. – 10:20 a.m. Ultrasound and CT Imaging of Liver Fibrosis and George Mazariegos Other Disease Marilyn Siegel 3:40 p.m. – 4:10 p.m. Discussion 10:20 a.m. – 10:40 a.m. MRI Methods of Assessing Liver 4:10 p.m. – 4:20 p.m. Break Fibrosis and Disease Claude Sirlin 4:20 p.m. – 5:30 p.m. Poster Session x Cystic Fibrosis Liver Disease | Clinical Research Workshop Cystic Fibrosis Liver Disease | Clinical Research Workshop xi Agenda Tuesday, June 9, 2009 CONTINUED IMAGING 10:40 a.m. – 11:00 a.m. Elastography to Assess Liver Fibrosis and Cirrhosis Detlef Schuppan 11:00 a.m. – 11:30 a.m. Discussion 11:30 a.m. – 12:30 p.m. Research Needs for the Future Michael Narkewicz Michael Knowles Patricia Robuck Catherine McKeon Speaker Abstracts Jay H. Hoofnagle Bruce Marshall Marilyn Siegel Edward Doo 12:30 p.m. Adjournment xii Cystic Fibrosis Liver Disease | Clinical Research Workshop Speaker Abstracts Cystic Fibrosis Liver Disease: Clinical Features and Definitions Michael R. Narkewicz, M.D. identified by 15 years of age, affecting up to 7 percent Hewit-Andrews Chair in Pediatric Liver Disease, Professor of patients. Risk factors for cirrhosis have included male of Pediatrics, University of Colorado Denver, School of sex, Hispanic ethnicity, and pancreatic insufficiency. Medicine, The Children’s Hospital, Aurora, CO There has not been any identified genotype/phenotype correlation with CFTR. The pathology is that of multi­ lobular cirrhosis, often with focal variation. Cystic Fibrosis (CF) is an autosomal recessive disorder that is the most common genetic disorder of Caucasian Other hepatic manifestations include: individuals, with a prevalence of 1 in 2,000 individuals of European descent. It is estimated to affect 30,000 Neonatal Cholestasis: This has been suggested to individuals in the United States. The disease is due to a occur in 1-2 percent of infants with CF. It is more defect in the cystic fibrosis transmembrane conductance common in infants with meconium ileus. In general, the regulator (CFTR). Although the lungs and pancreas cholestasis resolves. The subsequent risk for the develop­ are the pathopneumonic target organs in CF, many ment of cirrhosis is probably increased, but this remains other organs are affected. These include the small and unclear. large intestine, vas deferens, sinuses, and liver. In 2007, liver disease was the third leading cause of death in CF, Elevated AST, ALT, or GGT: Studies on subjects accounting for 2.3 percent of deaths. identified by newborn screening have shown that the prevalence of abnormal AST, ALT, or GGT is quite CFTR is expressed on the apical membrane of biliary frequent. By 20 years of age, 93 percent of patients have epithelium and not on the hepatocyte. The putative role had at least one abnormal ALT, with 50 percent hav­ of CFTR is to facilitate water and solute movement via ing at least one ALT greater than 1.5 times the upper chloride secretion and therefore promote bile flow. limit of normal (ULN) and 32 percent having an ALT greater than 2 times the ULN. Persistently abnormal Clinical Features of Liver Disease in CF: The ALT or AST is also quite frequent, with 42 percent of primary end result of liver disease in CF with the patients having a persistently abnormal ALT greater than most significant impact is the development of fibrosis 1.5 times the ULN by 20 years of age.
Load more

Recommended publications
  • Study Design to Validate Biomarkers of Therapeutic Response in NASH Due to Cirrhosis
    Study Design to Validate Biomarkers of Therapeutic Response in NASH Due to Cirrhosis Detlef Schuppan Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center Mainz, Germany Division of Gastroenterology, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, USA International Workshop on NASH Biomarkers, Washington, DC, May 18-19, 2018 HARVARD Research MEDICAL Center for SCHOOL Institute for Translational Immunology Immune Therapy No Conflict of Interest to Declare Related to this Presentation Fibrosis Progression and Reversal in NASH Inflammation, the reparative response and evolution of fibrosis/cirrhosis in NASH Fibrogenesis • is a waxing and waning process A • follows inflammation (reparative response) inflammation fibrosis Severity Time B Severity Time Antifibrotic therapy C cirrhosis Severity Time Schuppan et al, J Hepatol 2018 Fibrogenesis in NASH Ox. stress, ROS normal liver macrophage Insulin resistance, FFA Toxins repetitive damage MF Toxic bile salts (multiple hits) T (Auto-) Immunity HBV, HCV genetic Microbiome, nutrients quiescent predisposition stellate cell (lipoapoptotic) hepatocytes activated cholangiocytes endothelium fibrotic liver portal or collagen- Cirrhosis perivascular synthesis fibroblast organ MMP-1/3/13 failure activated matrix accumulation myofibroblast TIMP-1 Cirrhosis and HCC HSC TIMP-2 Schuppan and Afdhal, Lancet 2008 common pathways & Schuppan and Kim, JCI 2013 immune environment ! Inhibition of fibrogenesis - induction of fibrolysis normal
    [Show full text]
  • Outcome Measures in Coeliac Disease Trials
    Downloaded from http://gut.bmj.com/ on March 30, 2018 - Published by group.bmj.com Gut Online First, published on February 13, 2018 as 10.1136/gutjnl-2017-314853 Coeliac disease ORIGINAL ARTICLE Outcome measures in coeliac disease trials: the Tampere recommendations Jonas F Ludvigsson,1,2 Carolina Ciacci,3 Peter HR Green,4 Katri Kaukinen,5,6 Ilma R Korponay-Szabo,7,8 Kalle Kurppa,9,10 Joseph A Murray,11 Knut Erik Aslaksen Lundin,12,13 Markku J Maki,14,15 Alina Popp,16,17 Norelle R Reilly,18,19 Alfonso Rodriguez-Herrera,20 David S Sanders,21 Detlef Schuppan,22,23 Sarah Sleet,24 Juha Taavela,25 Kristin Voorhees,26 Marjorie M Walker,27 Daniel A Leffler28 ► Additional material is ABSTRact published online only. To view, Objective A gluten-free diet is the only treatment Significance of this study please visit the journal online option of coeliac disease, but recently an increasing (http:// dx. doi. org/ 10. 1136/ What is already known about this subject? gutjnl- 2017- 314853). number of trials have begun to explore alternative treatment strategies. We aimed to review the literature ► A gluten-free diet is the only treatment option For numbered affiliations see of coeliac disease, but recently an increasing end of article. on coeliac disease therapeutic trials and issue recommendations for outcome measures. number of trials have begun to explore alternative treatment strategies. Correspondence to Design Based on a literature review of 10 062 Dr Jonas F Ludvigsson, references, we (17 researchers and 2 patient ► A large number of trials of non-dietary Department of Medical representatives from 10 countries) reviewed the use treatments for coeliac disease are ongoing or Epidemiology and Biostatistics, and suitability of both clinical and non-clinical outcome under way.
    [Show full text]
  • A Common Dietary Component Wheat Amylase Trypsin Inhibitors As Drivers of Chronic Liver Disease in Pre-Clinical Models of NASH and Liver Fibrosis
    A Common Dietary Component Wheat Amylase Trypsin Inhibitors as Drivers of Chronic Liver Disease in Pre-Clinical Models of NASH and Liver Fibrosis Muhammad Ashfaq-Khan1, Misbah Aslam1,2, Muhammad Asif Qureshi3, Marcel Senkowski1, Shih Yen-Weng1, Yong Ook Kim1, Jörn M. Schattenberg4, Detlef Schuppan*1,4 1Institute of Translational Immunology, University Medical Center, Mainz, Germany 2 Shaheed Benazir Bhutto Women University, Peshawar, Pakistan 3 Dow University Medical Sciences, Karachi, Pakistan 4 Division of Gastroenterology, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, US. BACKGROUND & AIMS Proinflammatory gene expressions and immunohistochemistry of epididymal fat LFD HFD The gut-liver-axis has emerged an important Weight base indices driver of chronic liver disease. In line with this, specific food derived (non-tolerable) immunogenic Poster presented at: presented Poster HFD/G/ATI HFD/ATI signals from the gut are potentially the important CLSs CD68+ contributors in worsening obesity and non- alcoholic fatty liver disease (NAFLD) and liver fibrosis. A common immunogenic component in food staple (that resist to intestinal degradation) are wheat amylase trypsin inhibitors (ATI) that activate intestinal macrophages and dendritic cells via toll like receptor-4 migrate and propagate the inflammatory stimulus to the peripheral organs such as liver. We therefore studied how far nutritional ATI would affect NAFLD and liver Non alcoholic steatohepatitis (NAS) score fibrosis in preclinical models of NASH and liver A HFD HFD/G/ATI HFD/ATI fibrosis. LFD DOI: 10.3252/pso.eu.ILC2019.2019 METHOD 20x . Male C57BI/6J mice received a carbohydrate and protein 40x (zein) defined low fat or high fat diet (HFD), with or without 30% of the protein being replaced by wheat E B LFD HFD gluten (G, naturally containing 0.15g ATI per 10g), or 0.7% of the zein as purified ATI for 8 weeks.
    [Show full text]
  • Hedgehog Signaling Regulates Epithelial-Mesenchymal Transition During Biliary Fibrosis in Rodents and Humans
    Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans Alessia Omenetti, … , Detlef Schuppan, Anna Mae Diehl J Clin Invest. 2008;118(10):3331-3342. https://doi.org/10.1172/JCI35875. Research Article Epithelial-mesenchymal transitions (EMTs) play an important role in tissue construction during embryogenesis, and evidence suggests that this process may also help to remodel some adult tissues after injury. Activation of the hedgehog (Hh) signaling pathway regulates EMT during development. This pathway is also induced by chronic biliary injury, a condition in which EMT has been suggested to have a role. We evaluated the hypothesis that Hh signaling promotes EMT in adult bile ductular cells (cholangiocytes). In liver sections from patients with chronic biliary injury and in primary cholangiocytes isolated from rats that had undergone bile duct ligation (BDL), an experimental model of biliary fibrosis, EMT was localized to cholangiocytes with Hh pathway activity. Relief of ductal obstruction in BDL rats reduced Hh pathway activity, EMT, and biliary fibrosis. In mouse cholangiocytes, coculture with myofibroblastic hepatic stellate cells, a source of soluble Hh ligands, promoted EMT and cell migration. Addition of Hh-neutralizing antibodies to cocultures blocked these effects. Finally, we found that EMT responses to BDL were enhanced in patched-deficient mice, which display excessive activation of the Hh pathway. Together, these data suggest that activation of Hh signaling promotes EMT and contributes to the evolution of biliary fibrosis during chronic cholestasis. Find the latest version: https://jci.me/35875/pdf Related Commentary, page 3263 Research article Hedgehog signaling regulates epithelial- mesenchymal transition during biliary fibrosis in rodents and humans Alessia Omenetti,1 Alessandro Porrello,2 Youngmi Jung,1 Liu Yang,1 Yury Popov,3,4 Steve S.
    [Show full text]
  • Sensitivities to Wheat? Gluten Might Not Be to Blame
    Recently published research suggests that there may be a previously unknown protein in wheat which may be causing the symptoms we have associated with gluten in the past: Amylase- Trypsin Inhibitors (ATIs). Sensitivities to Wheat? Gluten Might Not Be to Blame What you've heard about gluten might be wrong. This article originally appeared on Medical Daily. Gluten may not be the culprit when it comes to wheat sensitivities, according to a new body of research presented at the United European Gastroenterology Week 2016. Instead, a team of scientists from Johannes Gutenberg University in Germany discovered a different protein in wheat known as amylase-trypsin inhibitors (ATIs), which may be what triggers stomach- sickening inflammation and other symptoms. The whole grains/gluten situation and its potential impact on health issues appears to be developing much more complexity than was previously understood: recent research in Australia identified dozens of proteins in wheat that have previously not been known, and many of these may in fact be more detrimental than those that are typically tested for (and there are currently no lab tests available for these proteins). (We were unable to locate the published research for this Australian paper by our publishing deadline, but we will continue to search for it and hopefully include it in a future newsletter). Biotics offers a number of formulations targeted towards the GI system: A.D.P. (Anti-Dysbiosis Product) 60T Berberine HCl May help activate AMPK Bio-HPF CANADA (H-Pylori Factor) May help activate AMPK BioDoph-7 Plus BioDophilus Caps BioDophilus-FOS Bromelain Plus CLA Caprin 100C FC-Cidal GamOctaPro (Powder) Gastrazyme HCL-Plus IAG Intenzyme Forte (Trypsin & Alpha Chymotrypsin) IPS Canada (Intestinal Permeability Support) L-Glutamine Caps L-Glutamine Powder Lactozyme Irrespective of the specific proteins in wheat and other grains that cause health issues, we all know that grains in general and some specific grains in particular (wheat, rye and barley).
    [Show full text]
  • Zedira Communication
    Press release __________________________________________________________________________ Zedira, Dr. Falk Pharma and the University of Mainz Hospital, which together comprise a flagship project of the Ci3 leading-edge cluster, are to receive additional subsidy funding for clinical development of a celiac disease drug. __________________________________________________________________________ Darmstadt, Freiburg, Mainz 20 October 2015 The consortium consisting of Zedira, Dr. Falk Pharma and Prof. Schuppan of the Institute of Translational Immunology and the Department of Medicine at the Johannes Gutenberg University in Mainz has announced that their collaboration on drug development of celiac disease is being further supported under the Ci3 excellence cluster of the German Federal Ministry for Education and Research (German abbreviation: BMBF). The project involves the clinical development of the ZED1227 drug candidate. ZED1227 is the first low-molecular tissue transglutaminase blocker in the clinics. The joint venture was started as a flagship project of the leading-edge cluster for individualized immuneintervention (Ci3). Celiac Disease is the most common chronic inflammation of the small intestine, with a worldwide prevalence around 1% in most countries. The autoimmune disease is triggered and maintained by alimentary gluten in genetically susceptible individuals. About Zedira: The Darmstadt-based biotech company focuses on celiac disease and consequently also on the transglutaminase family of enzymes. The Company develops, produces and markets products for research and development as well as for diagnostics. Based on its patented family of low-molecular transglutaminase blockers, Zedira is establishing an active ingredient pipeline covering the primary indication of celiac disease. As an area of secondary indication the company is working on new approaches to thrombosis prophylaxis. Further, Zedira is working on bioavailable tissue transglutaminase inhibitors to address fibrotic diseases, e.g.
    [Show full text]
  • The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): an Update
    nutrients Review The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): An Update Carlo Catassi 1, Armin Alaedini 2, Christian Bojarski 3, Bruno Bonaz 4, Gerd Bouma 5, Antonio Carroccio 6 ID , Gemma Castillejo 7 ID , Laura De Magistris 8, Walburga Dieterich 9, Diana Di Liberto 10, Luca Elli 11, Alessio Fasano 12, Marios Hadjivassiliou 13, Matthew Kurien 14 ID , Elena Lionetti 1, Chris J. Mulder 5, Kamran Rostami 15, Anna Sapone 12, Katharina Scherf 16, Detlef Schuppan 17, Nick Trott 14, Umberto Volta 18, Victor Zevallos 17, Yurdagül Zopf 9 and David S. Sanders 14,* 1 Department of Pediatrics, Marche Polytechnic University, 60121 Ancona, Italy; [email protected] (C.C.); [email protected] (E.L.) 2 Department of Medicine, Columbia University Medical Center, New York, NY 10027, USA; [email protected] 3 Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité, Campus Benjamin Franklin, 12203 Berlin, Germany; [email protected] 4 Department of Gastroenterology and Liver Diseases, CHU, 38043 Grenoble, France; [email protected] 5 Celiac Center Amsterdam, Department of Gastroenterology, VU University Medical Center, 1117 Amsterdam, The Netherlands; [email protected] (G.B.); [email protected] (C.J.M.) 6 Department of Internal Medicine, “Giovanni Paolo II” Hospital, Sciacca (AG) and University of Palermo, 92019 Sciacca, Italy; [email protected] 7 Paediatric Gastroenterology Unit, Sant Joan de Reus University Hospital. IISPV,
    [Show full text]
  • Liver Fibrosis in NASH: a Roadmap for Drug Discovery and Pharmacotherapy
    Liver fibrosis in NASH: A Roadmap for Drug Discovery and Pharmacotherapy Detlef Schuppan Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center Mainz, Germany Division of Gastroenterology, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, USA Liver Forum, EASL, Amsterdam, April 18, 2017 HARVARD Research MEDICAL Center for SCHOOL Institute for Translational Immunology Immune Therapy I have no conflicct of interest to declare Relevance of advanced liver fibrosis/cirrhosis as endpoint Noncirrhotic fibrosis Induction of reversal Decompensation Cirrhosis Liver related death HCC HCC Fibrogenesis is a Multicellular Process Toxins normal liver macrophage Toxic bile salts (Auto-) Immunity repetitive damage MF HBV, HCV (second hit) Ox. stress, ROS T Insulin resistance Microbiome, nutrients quiescent stellate cell genetic predisposition progenitor cell, cholangiocyte, hepatocyte endothelium fibrotic liver portal or collagen- Cirrhosis perivascular synthesis fibroblast organ MMP-1/3/13 failure activated matrix accumulation myofibroblast TIMP-1 Cirrhosis and HCC HSC TIMP-2 Schuppan and Afdhal, Lancet 2008 common pathways & Schuppan and Kim, JCI 2013 immune environment ! Reversibility of advanced fibrosis after removal/suppression of the primary causal hit Cirrhosis Regression with Longterm Tenofovir Treatment 1-5 yr extension of 48 week tenofovir trial (Marcellin P et al, NEJM 2008) 489/615 pts (76%) included 5 yr biopsy: 348/489 (71%) Baseline: no cirrhosis Better 105/252 Worse
    [Show full text]
  • Liver Forum 5 November 10, 2016 the Westin Copley Place Boston, MA
    Liver Forum 5 November 10, 2016 The Westin Copley Place Boston, MA 1:30 PM Welcome Coffee Reception & Check-in Moderators: Veronica Miller, Forum for Collaborative HIV Research 2:00 PM Session I: Introduction & Updates Arun Sanyal, Virginia Commonwealth University Medical Center David Shapiro, Intercept Pharmaceuticals Presenters: 2:00 PM Liver Forum Updates Arun Sanyal, Virginia Commonwealth University Medical Center Veronica Miller, Forum for Collaborative HIV Research Presenters: Lara Dimick-Santos, U.S. Food and Drug Administration 2:15 PM Regulatory Updates Elmer Schabel, Bundesinstitut für Arzneimittel und Medizinprodukte Presenters: Arun Sanyal, Virginia Commonwealth University Medical Center David Shapiro, Intercept Pharmaceuticals 2:45 PM Recognition for Outstanding Service Recipient: Captain Anissa Davis-Williams, U.S. Food and Drug Administration Moderators: 2:50 PM Session II: Focus on Biomarkers Veronica Miller, Forum for Collaborative HIV Research Quentin Anstee, Newcastle University Medical School FDA Biomarker Qualification in Drug Development Under Presenter: 2:50 PM IND or NDA/BLA Shashi Amur, U.S. Food and Drug Administration Presenter: 3:10 PM FNIH: NASH Biomarker Consortium Roberto Calle, on behalf of FNIH Presenter: 3:20 PM Liver Forum - FNIH Collaborations Arun Sanyal, co-chair FNIH Biomarker Consortium Presenter: 3:30 PM IMI: Accelerated Drug Portal Julia Brosnan, on behalf of IMI Moderators: 3:35 PM Session III: Definitions WG Update David Shapiro, Intercept Pharmaceuticals Stephen Harrison, University of Oxford
    [Show full text]
  • Prof. Dr. Dr. Detlef Schuppan
    Leitgremium des FZI Univ.-Prof. Dr. Dr. Detlef Schuppan * 9.8.1954 Professor für Molekulare and Translationale Medizin Professor of Medicine (Harvard Medical School) Leiter klinisches Zöliakie- und Fibrosezentrum I. Medizinische Klinik Universitätsmedizin der Johannes Gutenberg-Universität Mainz D-55131 Mainz, Langenbeckstr.1 Tel: +49-6131-17 7355/56, Fax: +49-6131-17 7357 [email protected] [email protected] www.unimedizin-mainz.de/tim/startseite.html Akademischer Werdegang 1973-79 Studium der Chemie an der Ludwig-Maximilians-Universität, München 1979-86 Studium der Humanmedizin in München (LMU), Marburg, Berlin (FU) 1979-82 Diplom- und Doktorarbeit in Biochemie am Max-Planck-Institut für Biochemie in Martinsried b. München (Thema: Strukturaufklärung von Basalmembran- kollagen; Abt. für Bindegewebsforschung; Mentor: Rupert Timpl) 1982 Dr.rer.nat. (Chemie) 1989 Dr.med. (Biochemie), Thema: Identifizierung und Charakterisierung von Undulin/Kollagen IV (summa cum laude) 1992 1. Habilitation in Chemie/Biochemie, FU Berlin 1996 2. Habilitation in Innerer Medizin Beruflicher Werdegang 1981-82 Wissenschaftlicher Assistent und Laborleiter Abt. für Gastroenterologie, Phillips-Universität, Marburg 1982-86 Wissenschaftlicher Assistent und Laborleiter, Abt. für Gastroenterologie, Hepatologie & Infektiologie, Klinikum Steglitz, FU Berlin; Beginn gentechnologischer Arbeiten (Generierung von cRNA für die in situ Hybridisierung) 1986 Approbation als Arzt 1986-93 Klinische Ausbildung zum Internisten, Abt. für Gastroenterologie,
    [Show full text]
  • Liver Forum 6
    Welcome and Introduction Presenter Katherine Greene, Forum for Collaborative Research www.forumresearch.org Time Topic Presenters 2:15 Session I: Project Overview 2:15 Welcome and Introduction Katherine Greene, Forum for Collaborative Research Lara Dimick-Santos, U.S. Food and Drug Administration Elmer Schabel, European Medicines Agency 14:25 Regulatory Perspective Updates and Remarks Irene Tebbs, U.S. Food and Drug Administration Daniel Krainak, U.S. Food and Drug Administration 3:10 Session II: Cirrhosis 3:10 Compensated Cirrhosis & Clinically Meaningful Benefit Naga Chalasani, Indiana University School of Medicine 3:25 Cirrhosis Endpoints: ACLF and MELD Rajiv Jalan, University College London Decompensated Cirrhosis: Experience from U.S. Pivotal 3:40 Arun Sanyal, Virginia Commonwealth University and Phase 2B Trials 3:55 Group Discussion 4:35 Break www.forumresearch.org Time Topic Presenters 5:00 Session III: U.S. Payer and Care Delivery Perspectives 5:00 Lessons Learned in HIV and HCV Carl Schmid, The AIDS Institute 5:10 Medicare Coverage: A Review Louis Jacques, ADVI Louis Jacques, ADVI 5:40 Panel Discussion Heather Patton, Kaiser Permanente Hal Yee, LA County Department of Health Services 6:30 Session IV: Working Groups Sophie Megnien, Genfit 6:30 Case Definitions Working Group Brent Tetri, Saint Louis University 6:40 Pediatric Issues Working Group Miriam Vos, Emory University 6:50 Placebo Arm Data Working Group Eric Lefebvre, Allergan Manal Abdelmalek, Duke University 7:00 Standard of Care Working Group Sven Francque, Antwerp University
    [Show full text]
  • Updates from Biomarker Consortia Fibrosis Markers
    Liver Investigation: Testing Marker Utility in Steatohepatitis Updates from Biomarker Consortia Fibrosis markers Detlef Schuppan University Medical Center, Mainz, Germany Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 1 Noncirrhotic fibrosis (F1-F2) Induction of reversal Decompensation Cirrhosis Liver related death HCC HCC Collagen and Noncollagen Serum Fibrosis Markers (UMCM, NB, SOMA) Aim: Development of serum/plasma fibrosis markers to • Identify patients with advanced fibrosis (>F2; >F1) with highest sensitivity and specificity • Identify patients with high fibrogenic (fibrolytic) activity (dynamic markers) • Permit noninvasive selection and stratification of patients in need for treatment • Permit noninvasive monitoring of treatment efficacy (antifibrotic effect) on a regular basis • Allow short-term POC studies with novel drugs • Allow a personalized (antifibrotic) therapy 3 Fibrogenesis A • is a waxing and waning process • follows inflammation (reparative response) inflammation fibrosis Severity Time B Severity Time C cirrhosis Severity Time Schuppan et al, J Hepatol 2018 Strategy and current state Establishment and validation of a panel of (fibrosis) protein biomarkers using cross-sectional and follow-up patient cohorts: • Noncollagen ECM-markers (via proteomics and rational design, UMCM) • Collagen ECM-markers (protease ‚fingerprint‘ epitopes, NB) • These are largely dynamic markers of the fibrotic ECM in liver • Establishment of marker panel of disease severity and progression on DNA- aptamer based platform
    [Show full text]