Clinical Features and Hepatic Molecular Characteristics in NAFLD and NASH Patients Compared to Normal Weight Healthy Individuals

Abstract

The molecular events underlying the development and progression of nonalcoholic fatty liver disease (NAFLD), covering a wide spectrum from simple hepatic steatosis to the more aggressive inflammatory manifestation, nonalcoholic steatohepatitis (NASH), remain elusive. To promote the understanding of the pathophysiology behind this disease spectrum we characterized lean controls vs. individuals with simple NAFLD and NASH, respectively, by standard clinical measures, histopathology and global mRNA profiling of liver biopsies. The study included 11 patients with simple NAFLD, 11 patients with NASH (based on the FLIP/Bedossa score) and 15 lean healthy individuals. Liver biopsies from all subjects were evaluated using diagnostic histopathological scoring of steatosis, inflammation, fibrosis and ballooning degeneration of hepatocytes. Global mRNA quantification of liver biopsies was performed by RNA-sequencing. No steatosis was seen in the lean healthy individuals, whereas all patients with simple NAFLD and NASH displayed moderate steatosis, and to some degree inflammation and fibrosis. Only NASH patients had ballooning degeneration of hepatocytes. Several marker genes such as collagens and galectin-3 showed good correlation with disease severity being markedly upregulated in the NAFLD and NASH groups compared to healthy controls. However, the histopathological categorization of patient samples into NAFLD and NASH did not correlate well with gene expression levels. We here provide a unique characterization of a cohort of individuals covering the spectrum from healthy lean subjects over individuals with simple NAFLD to patients with NASH. Clinical markers as well as hepatic pathology and gene expression clearly discriminate NAFLD/NASH patients from healthy individuals, but NAFLD and NASH patients appear highly similar at all parameters, except for histopathological scoring of ballooning. Disclosure K. Rigbolt: Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. S. Veidal: None. S. Heebøll: None. M. Demant: None. J.I. Bagger: None. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. J. Jelsing: Stock/Shareholder; Self; Gubra. Research Support; Self; Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.