title: Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology.
abstract: OBJECTIVE
  The recently developed histological scoring system for non-alcoholic fatty liver disease (NAFLD) by the NASH Clinical Research Network (NASH-CRN) has been widely used in clinical settings, but is increasingly employed in preclinical research as well. However, it has not been systematically analyzed whether the human scoring system can directly be converted to preclinical rodent models. To analyze this, we systematically compared human NAFLD liver pathology, using human liver biopsies, with liver pathology of several NAFLD mouse models. Based upon the features pertaining to mouse NAFLD, we aimed at establishing a modified generic scoring system that is applicable to broad spectrum of rodent models.
  
  
  METHODS
  The histopathology of NAFLD was analyzed in several different mouse models of NAFLD to define generic criteria for histological assessment (preclinical scoring system). For validation of this scoring system, 36 slides of mouse livers, covering the whole spectrum of NAFLD, were blindly analyzed by ten observers. Additionally, the livers were blindly scored by one observer during two separate assessments longer than 3 months apart.
  
  
  RESULTS
  The criteria macrovesicular steatosis, microvesicular steatosis, hepatocellular hypertrophy, inflammation and fibrosis were generally applicable to rodent NAFLD. The inter-observer reproducibility (evaluated using the Intraclass Correlation Coefficient) between the ten observers was high for the analysis of macrovesicular steatosis and microvesicular steatosis (ICC = 0.784 and 0.776, all p<0.001, respectively) and moderate for the analysis of hypertrophy and inflammation (ICC = 0.685 and 0.650, all p<0.001, respectively). The intra-observer reproducibility between the different observations of one observer was high for the analysis of macrovesicular steatosis, microvesicular steatosis and hypertrophy (ICC = 0.871, 0.871 and 0.896, all p<0.001, respectively) and very high for the analysis of inflammation (ICC = 0.931, p<0.001).
  
  
  CONCLUSIONS
  We established a simple NAFLD scoring system with high reproducibility that is applicable for different rodent models and for all stages of NAFLD etiology.
authors.affiliation: Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands; Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Wen
authors.initials: W
authors.lastname: Liang
authors.affiliation: TNO-Triskelion, Zeist, The Netherlands.
authors.forename: Aswin L
authors.initials: AL
authors.lastname: Menke
authors.affiliation: Department of Pathology, University Hospital Antwerp, University of Antwerp, Edegem, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Driessen
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University Medical Center Maastricht, Maastricht, The Netherlands.
authors.forename: Ger H
authors.initials: GH
authors.lastname: Koek
authors.affiliation: Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Lindeman
authors.affiliation: Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
authors.forename: Reinout
authors.initials: R
authors.lastname: Stoop
authors.affiliation: Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands; Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.affiliation: Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleemann
authors.affiliation: Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
authors.forename: Anita M
authors.initials: AM
authors.lastname: van den Hoek
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006529:Hepatomegaly / Q000473:pathology; D006652:Histological Techniques; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008099:Liver / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology*; D015203:Reproducibility of Results; D012720:Severity of Illness Index