Nicolas Lanthier1, Laura Rubbia-Brandt2, Nathalie Lin-Marq2, Sophie Clément2, Jean-Louis Frossard3, Nicolas Goossens3, Antoine Hadengue3, Laurent Spahr4. 1. Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, Geneva, Switzerland; Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium. 2. Clinical Pathology, University Hospitals and Faculty of Medicine, Geneva, Switzerland. 3. Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, Geneva, Switzerland. 4. Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, Geneva, Switzerland. Electronic address: laurent.spahr@hcuge.ch.
Abstract
BACKGROUND & AIMS: The role of liver progenitor cell (LPC) expansion, known as a marker of disease severity, as well as the impact of macrophage activation on liver regeneration remains unclear in humans. We aimed to characterize the LPC and macrophage compartments in alcoholic hepatitis (AH), as well as gene expression patterns to identify predictors of a good prognosis in this setting. METHODS: Immunohistochemical studies for macrophages, proliferative hepatocytes, total and proliferative LPC, as well as whole liver microarray gene expression were performed on baseline liver biopsies of 58 AH patients early after admission. Abstinent cirrhotic patients were used as controls. Patients were qualified as "improvers" or "non-improvers" based on the change in MELD score three months after baseline. RESULTS: Compared to controls, AH patients demonstrated a significant expansion of macrophages, invasion of LPC and a higher number of proliferating hepatocytes and LPC. In AH patients, total LPC expansion (total Keratin7(+) cells) was associated with liver disease severity. The group of improvers (n=34) was characterized at baseline by a higher number of proliferating hepatocytes, proliferative LPC (double Keratin7(+)Ki67(+) cells) and liver macrophages as compared to non-improvers (n=24), despite similar clinical and biological variables. Upregulated genes in improvers were associated with cell cycle mitosis together with a major expression of SPINK1. CONCLUSIONS: Higher liver macrophage expansion, increased proliferative hepatocyte but also LPC number, as well as an upregulation of cell proliferation-related genes are associated with a favourable outcome. These new findings open novel therapeutic targets in AH.
BACKGROUND & AIMS: The role of liver progenitor cell (LPC) expansion, known as a marker of disease severity, as well as the impact of macrophage activation on liver regeneration remains unclear in humans. We aimed to characterize the LPC and macrophage compartments in alcoholic hepatitis (AH), as well as gene expression patterns to identify predictors of a good prognosis in this setting. METHODS: Immunohistochemical studies for macrophages, proliferative hepatocytes, total and proliferative LPC, as well as whole liver microarray gene expression were performed on baseline liver biopsies of 58 AHpatients early after admission. Abstinent cirrhoticpatients were used as controls. Patients were qualified as "improvers" or "non-improvers" based on the change in MELD score three months after baseline. RESULTS: Compared to controls, AHpatients demonstrated a significant expansion of macrophages, invasion of LPC and a higher number of proliferating hepatocytes and LPC. In AHpatients, total LPC expansion (total Keratin7(+) cells) was associated with liver disease severity. The group of improvers (n=34) was characterized at baseline by a higher number of proliferating hepatocytes, proliferative LPC (double Keratin7(+)Ki67(+) cells) and liver macrophages as compared to non-improvers (n=24), despite similar clinical and biological variables. Upregulated genes in improvers were associated with cell cycle mitosis together with a major expression of SPINK1. CONCLUSIONS: Higher liver macrophage expansion, increased proliferative hepatocyte but also LPC number, as well as an upregulation of cell proliferation-related genes are associated with a favourable outcome. These new findings open novel therapeutic targets in AH.
Authors: Beatriz Aguilar-Bravo; Daniel Rodrigo-Torres; Silvia Ariño; Mar Coll; Elisa Pose; Delia Blaya; Isabel Graupera; Luis Perea; Júlia Vallverdú; Teresa Rubio-Tomás; Laurent Dubuquoy; Carolina Armengol; Antonio Lo Nigro; Peter Stärkel; Philippe Mathurin; Ramon Bataller; Joan Caballería; Juan José Lozano; Pere Ginès; Pau Sancho-Bru Journal: Hepatology Date: 2019-03-12 Impact factor: 17.298
Authors: Eric Trépo; Nicolas Goossens; Naoto Fujiwara; Won-Min Song; Antonio Colaprico; Astrid Marot; Laurent Spahr; Pieter Demetter; Christine Sempoux; Gene Y Im; Joan Saldarriaga; Thierry Gustot; Jacques Devière; Swan N Thung; Charlotte Minsart; Thomas Sersté; Gianluca Bontempi; Karim Abdelrahman; Jean Henrion; Delphine Degré; Valerio Lucidi; Laura Rubbia-Brandt; Venugopalan D Nair; Christophe Moreno; Pierre Deltenre; Yujin Hoshida; Denis Franchimont Journal: Gastroenterology Date: 2017-11-20 Impact factor: 33.883