Paola Dongiovanni1, Salvatore Petta2, Ville Mannisto3, Rosellina Margherita Mancina4, Rosaria Pipitone2, Vesa Karja5, Marco Maggioni6, Pirjo Kakela7, Olov Wiklund4, Enrico Mozzi8, Stefania Grimaudo2, Dorota Kaminska9, Raffaela Rametta10, Antonio Craxi2, Silvia Fargion11, Valerio Nobili12, Stefano Romeo13, Jussi Pihlajamaki14, Luca Valenti15. 1. Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy. 2. Department of Gastroenterology, Università di Palermo, Palermo, Italy. 3. Clinical Nutrition and Obesity Center (V.M., J.P.), Kuopio University Hospital, Kuopio, Finland. 4. Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. 5. Department of Pathology, University of Eastern Finland and Kuopio University Hospital, Finland, Kuopio, Finland. 6. Department of Pathology, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy. 7. Department of Surgery (P.K.), University of Eastern Finland and Kuopio University Hospital, Finland, Kuopio, Finland. 8. Department of Surgery, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy. 9. Department of Public Health and Clinical Nutrition (D.K., J.P.), University of Eastern Finland, Kuopio, Finland. 10. Department of Pathophysiology and Transplantation (R.R., S.F., L.V.), Università degli Studi di Milano, Milan, Italy. 11. 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. 12. Hepato-Metabolic Unit (V.N.), Ospedale Bambin Gesù, Roma, Italy. 13. 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. 14. 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. 15. 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.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: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, PNPLA3I148M risk alleles, TM6SF2E167K 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 I148MPNPLA3 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 I148MPNPLA3 risk variant limited this beneficial effect.