Statine als Therapie bei Lebererkrankungen?

Abstract

Statins have proven effects in the primary and secondary prevention of coronary disease. Besides lowering LDL-cholesterol beneficial pleiotropic consequences of statin therapy are increasingly discussed. Retrospective analyses of large cohort studies have shown favorable effects on the sequels of chronic viral induced liver disease and of non alcoholic fatty liver disease. These findings are substantiated by experimental work showing that statins reduce inflammation, fibrosis and proliferation in the diseased liver. Prospective controlled trials are necessary to elucidate whether, when and where statins have a role in the therapeutic armamentarium for liver disease.

Statine vermindern die Cholesterinkonzentration im Plasma und senken damit das Risiko der koronaren Herzerkrankung. Darüber hinaus haben sie weitere sogenannte pleiotrope Effekte. Es gibt Hinweise, dass sich dies bei verschiedenen Lebererkrankungen positiv auswirken könnte.

Schlüsselwörter

Statine - chronische Lebererkrankungen - Leberzirrhose - Therapie

Key words

statins - chronic liver disease - liver cirrhosis - therapy

• Literatur

• 1 Schwabe U, Paffrath D. Arzneiverordnungs-Report 2016. Springer-Verlag; 2016
• 2 Vaughan CJ, Gotto AM, Basson CT. The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol 2000; 35: 1-10
• 3 Kohl NE, Mosser SD, deSolms SJ. et al. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science 1993; 260: 1934-1937
• 4 Oesterle A, Laufs U, Liao JK. Pleiotropic Effects of Statins on the Cardiovascular System. Circ Res 2017; 120: 229-243
• 5 Russo MW, Hoofnagle JH, Gu J. et al. The Spectrum of Statin Hepatotoxicity: Experience of the Drug Induced Liver Injury Network. Hepatology 2014; 60: 679-686
• 6 Chalasani N, Aljadhey H, Kesterson J. et al. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004; 126: 1287-1292
• 7 Clarke AT, Mills PR. Atorvastatin associated liver disease. Dig Liver Dis 2006; 38: 772-777
• 8 Athyros VG, Tziomalos K, Gossios TD. et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010; 376: 1916-1922
• 9 Kargiotis K, Athyros VG, Giouleme O. et al. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome. World J Gastroenterol 2015; 21: 7860-7868
• 10 Dongiovanni P, Petta S, Mannisto V. et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. Journal of Hepatology 2015; 63: 705-712
• 11 Nascimbeni F, Aron-Wisnewsky J, Pais R. et al. Statins, antidiabetic medications and liver histology in patients with diabetes with non-alcoholic fatty liver disease. BMJ Open Gastroenterol 2016; 3: e000075
• 12 Huang YW, Lee CL, Yang SS. et al. Statins Reduce the Risk of Cirrhosis and Its Decompensation in Chronic Hepatitis B Patients: A Nationwide Cohort Study. Am J Gastroenterol 2016; 111: 976-985
• 13 Chang FM, Wang YP, Lang HC. et al. Statins decrease the risk of decompensation in HBV- and HCV-related cirrhosis: A population-based study. Hepatology 2017;
• 14 Simon TG, Bonilla H, Yan P. et al. Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: Results from ERCHIVES. Hepatology 2016; 64: 47-57
• 15 Mohanty A, Tate JP, Garcia-Tsao G. Statins Are Associated With a Decreased Risk of Decompensation and Death in Veterans With Hepatitis C-Related Compensated Cirrhosis. Gastroenterology 2016; 150: 430-440
• 16 Oliver NT, Hartman CM, Kramer JR. et al. Statin drugs decrease progression to cirrhosis in HIV/HCV co-infected individuals. AIDS 2016 in press
• 17 van der Meer AJ, Veldt BJ, Feld JJ. et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012; 308: 2584-2593
• 18 Trebicka J, Hennenberg M, Laleman W. et al. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology 2007; 46: 242-253
• 19 Uschner FE, Ranabhat G, Choi SS. et al. Statins activate the canonical hedgehog-signaling and aggravate non-cirrhotic portal hypertension, but inhibit the non-canonical hedgehog signaling and cirrhotic portal hypertension. Sci Rep 2015; 5: 14573
• 20 Zafra C, Abraldes JG, Turnes J. et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology 2004; 126: 749-755
• 21 Abraldes JG, Albillos A, Bañares R. et al. Simvastatin Lowers Portal Pressure in Patients With Cirrhosis and Portal Hypertension: A Randomized Controlled Trial. Gastroenterology 2009; 136: 1651-1658
• 22 Pollo-Flores P, Soldan M, Santos UC. et al. Three months of simvastatin therapy vs. placebo for severe portal hypertension in cirrhosis: A randomized controlled trial. Dig Liver Dis 2015; 47: 957-963
• 23 Abraldes JG, Villanueva C, Aracil C. et al. Addition of Simvastatin to Standard Therapy for the Prevention of Variceal Rebleeding Does Not Reduce Rebleeding but Increases Survival in Patients With Cirrhosis. Gastroenterology 2016; 150: 1160-1170
• 24 du Souich P, Roederer G, Dufour R. Myotoxicity of statins: Mechanism of action. Pharmacol Ther 2017; 175: 1-16
• 25 Rodríguez S, Raurell I, Torres-Arauz M. et al. A Nitric Oxide-Donating Statin Decreases Portal Pressure with a Better Toxicity Profile than Conventional Statins in Cirrhotic Rats. Sci Rep 2017; 7
• 26 Hsiang JC, Wong GLH, Tse YK. et al. Statin and the risk of hepatocellular carcinoma and death in a hospital-based hepatitis B-infected population: A propensity score landmark analysis. J Hepatol 2015; 63: 1190-1197
• 27 Singh S, Singh PP, Singh AG. et al. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 2013; 144: 323-332
• 28 Graf H, Jüngst C, Straub G. et al. Chemoembolization combined with pravastatin improves survival in patients with hepatocellular carcinoma. Digestion 2008; 78: 34-38
• 29 Kawata S, Yamasaki E, Nagase T. et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer 2001; 84: 886-891
• 30 Higashi T, Hayashi H, Kitano Y. et al. Statin attenuates cell proliferative ability via TAZ (WWTR1) in hepatocellular carcinoma. Med Oncol 2016; 33: 123
• 31 Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med 2012; 367: 1792-1802
• 32 Emberson JR, Kearney PM. Cholesterol Treatment Trialists’ (CTT) Collaboration. et al. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175000 people in 27 randomised trials of statin therapy. PLoS ONE. 2012 7. e29849
• 33 Ray KK, Seshasai SRK, Erqou S. et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65229 participants. Arch Intern Med 2010; 170: 1024-1031
• 34 Trebicka J, Hennenberg M, Odenthal M. et al. Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. J Hepatol 2010; 53: 702-712
• 35 Klein S, Klösel J, Schierwagen R. et al. Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats. Lab Invest 2012; 92: 1440-1450
• 36 Schierwagen R, Maybüchen L, Hittatiya K. et al. Statins improve NASH via inhibition of RhoA and Ras. Am J Physiol Gastrointest Liver Physiol 2016; 311 (04) G724-G733
• 37 Sutter AP, Maaser K, Höpfner M. et al. Cell cycle arrest and apoptosis induction in hepatocellular carcinoma cells by HMG-CoA reductase inhibitors. Synergistic antiproliferative action with ligands of the peripheral benzodiazepine receptor. J Hepatol 2005; 43: 808-816
• 38 Marrone G, Maeso-Díaz R, García-Cardena G. et al. KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut 2015; 64: 1434-1443
• 39 Zhou YY, Zhu GQ, Wang Y. et al. Systematic review with network meta-analysis: statins and risk of hepatocellular carcinoma. Oncotarget 2016; 7: 21753-21762