title: Hepatic cell proliferation plays a pivotal role in the prognosis of alcoholic hepatitis.
abstract: OBJECTIVE
  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.
authors: 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.
authors: Nicolas
authors: N
authors: Lanthier
authors: Clinical Pathology, University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors: Laura
authors: L
authors: Rubbia-Brandt
authors: Clinical Pathology, University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors: Nathalie
authors: N
authors: Lin-Marq
authors: Clinical Pathology, University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors: Sophie
authors: S
authors: Clément
authors: Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors: Jean-Louis
authors: JL
authors: Frossard
authors: Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors: Nicolas
authors: N
authors: Goossens
authors: Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, Geneva, Switzerland.
authors: Antoine
authors: A
authors: Hadengue
authors: Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, Geneva, Switzerland. Electronic address: laurent.spahr@hcuge.ch.
authors: Laurent
authors: L
authors: Spahr
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D049109:Cell Proliferation; D006519:Hepatitis, Alcoholic / Q000473:pathology*; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D053552:Keratin-7 / Q000032:analysis; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011379:Prognosis; D013234:Stem Cells / Q000502:physiology*; D014158:Transcription, Genetic; D014359:Trypsin Inhibitor, Kazal Pancreatic
chemical_list: D002352:Carrier Proteins; D053552:Keratin-7; C486642:SPINK1 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic
keywords: Alcoholic hepatitis; Liver biopsy; Liver progenitor cell; Macrophage; Regeneration; SPINK1