title: Statin use and non-alcoholic steatohepatitis in at risk individuals.
abstract: OBJECTIVE
  Excess hepatic free cholesterol contributes to the pathogenesis of non-alcoholic steatohepatitis, and statins reduce cholesterol synthesis. Aim of this study was to assess whether statin use is associated with histological liver damage related to steatohepatitis.
  
  
  METHODS
  The relationship between statin use, genetic risk factors, and liver damage was assessed in a multi-center cohort of 1201 European individuals, who underwent liver biopsy for suspected non-alcoholic steatohepatitis.
  
  
  RESULTS
  Statin use was recorded in 107 subjects, and was associated with protection from steatosis, NASH, and fibrosis stage F2-F4, in a dose-dependent manner (adjusted p<0.05 for all). In 100 treated patients matched 1:1 for modality of recruitment, gender, presence of IFG or type 2 diabetes, PNPLA3 I148M risk alleles, TM6SF2 E167K variant, age, and BMI, statin use remained associated with protection from steatosis (OR 0.09, 95% C.I. 0.01-0.32; p=0.004), steatohepatitis (OR 0.25, 95% C.I. 0.13-0.47; p<0.001), and fibrosis stage F2-F4 (OR 0.42, 95% C.I. 0.20-0.8; p=0.017). Results were confirmed in a second analysis, where individuals were matched within recruitment center (p<0.05 for all). The protective effect of statins on steatohepatitis was stronger in subjects not carrying the I148M PNPLA3 risk variant (p=0.02 for interaction), as statins were negatively associated with steatohepatitis in patients negative (p<0.001), but not in those positive for the I148M variant (p=n.s.).
  
  
  CONCLUSIONS
  Statin use was associated with protection towards the full spectrum of liver damage in individuals at risk of non-alcoholic steatohepatitis. However, the I148M PNPLA3 risk variant limited this beneficial effect.
authors.affiliation: Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.affiliation: Department of Gastroenterology, Università di Palermo, Palermo, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Petta
authors.affiliation: Clinical Nutrition and Obesity Center (V.M., J.P.), Kuopio University Hospital, Kuopio, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Mannisto
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Rosellina Margherita
authors.initials: RM
authors.lastname: Mancina
authors.affiliation: Department of Gastroenterology, Università di Palermo, Palermo, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Pipitone
authors.affiliation: Department of Pathology, University of Eastern Finland and Kuopio University Hospital, Finland, Kuopio, Finland.
authors.forename: Vesa
authors.initials: V
authors.lastname: Karja
authors.affiliation: Department of Pathology, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.affiliation: Department of Surgery (P.K.), University of Eastern Finland and Kuopio University Hospital, Finland, Kuopio, Finland.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Kakela
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Olov
authors.initials: O
authors.lastname: Wiklund
authors.affiliation: Department of Surgery, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Mozzi
authors.affiliation: Department of Gastroenterology, Università di Palermo, Palermo, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Grimaudo
authors.affiliation: Department of Public Health and Clinical Nutrition (D.K., J.P.), University of Eastern Finland, Kuopio, Finland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kaminska
authors.affiliation: Department of Pathophysiology and Transplantation (R.R., S.F., L.V.), Università degli Studi di Milano, Milan, Italy.
authors.forename: Raffaela
authors.initials: R
authors.lastname: Rametta
authors.affiliation: Department of Gastroenterology, Università di Palermo, Palermo, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Craxi
authors.affiliation: Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy; Department of Pathophysiology and Transplantation (R.R., S.F., L.V.), Università degli Studi di Milano, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.affiliation: Hepato-Metabolic Unit (V.N.), Ospedale Bambin Gesù, Roma, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Nobili
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Clinical Nutrition Unit (S.R.), Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy; Clinical Nutrition Unit (S.R.), Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy. Electronic address: stefano.romeo@wlab.gu.se.
authors.forename: Stefano
authors.initials: S
authors.lastname: Romeo
authors.affiliation: Clinical Nutrition and Obesity Center (V.M., J.P.), Kuopio University Hospital, Kuopio, Finland; Department of Public Health and Clinical Nutrition (D.K., J.P.), University of Eastern Finland, Kuopio, Finland. Electronic address: jussi.pihlajamaki@uef.fi.
authors.forename: Jussi
authors.initials: J
authors.lastname: Pihlajamaki
authors.affiliation: Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy; Department of Pathophysiology and Transplantation (R.R., S.F., L.V.), Università degli Studi di Milano, Milan, Italy. Electronic address: luca.valenti@unimi.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D008049:Lipase / Q000235:genetics; D008099:Liver / Q000473:pathology; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced* / Q000473:pathology; D012306:Risk; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008049:Lipase; D008565:Membrane Proteins; C419195:TM6SF2 protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: Cholesterol; NASH; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; PNPLA3; Statin; Steatosis