Statin use and non-alcoholic steatohepatitis in at risk individuals

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.