Subscribe to RSS
DOI: 10.1055/s-0039-1679956
Prevention of Hepatocellular Carcinoma by Statins: Clinical Evidence and Plausible Mechanisms
FundingThe study was funded by the Bio & Medical Technology Development Program of the NRF, Korea, MSIP (2016R1A2B4013029 to E.S. Kang).Publication History
Publication Date:
25 March 2019 (online)
Abstract
Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are widely used to treat hypercholesterolemia for primary and secondary prevention of cardiovascular disease. Statins inhibit HMG-CoA reductase, the rate-limiting step in cholesterol synthesis, and modulate the downstream signaling of the mevalonate pathway. In addition to the primary effect, the antitumor effect of statins can be associated with mevalonate pathway-mediated and nonmevalonate pathway-mediated mechanisms, which improve endothelial function and lead to proapoptotic, antiproliferative, antiinflammatory, and antifibrotic properties. Statins are implicated in the improvement of metabolic status. Statins are orally available and safely and widely used for long-term treatment; they represent a novel approach for the prevention and treatment for hepatocellular carcinoma (HCC). Although several observational studies and experimental studies have revealed the preventive and therapeutic potential of statins for HCC treatment, further prospective interventional studies and randomized control trials are warranted to confirm these observations.
-
References
- 1 Blaha MJ, Martin SS. How do statins work? Changing paradigms with implications for statin allocation. J Am Coll Cardiol 2013; 62 (25) 2392-2394
- 2 Baigent C, Blackwell L, Emberson J. , et al; Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376 (9753): 1670-1681
- 3 Iannelli F, Lombardi R, Milone MR. , et al. Targeting mevalonate pathway in cancer treatment: repurposing of statins. Recent Patents Anticancer Drug Discov 2018; 13 (02) 184-200
- 4 Demierre MF, Higgins PD, Gruber SB, Hawk E, Lippman SM. Statins and cancer prevention. Nat Rev Cancer 2005; 5 (12) 930-942
- 5 Mullen PJ, Yu R, Longo J, Archer MC, Penn LZ. The interplay between cell signalling and the mevalonate pathway in cancer. Nat Rev Cancer 2016; 16 (11) 718-731
- 6 Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127 (12) 2893-2917
- 7 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61 (02) 69-90
- 8 El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132 (07) 2557-2576
- 9 Bosetti C, Turati F, La Vecchia C. Hepatocellular carcinoma epidemiology. Best Pract Res Clin Gastroenterol 2014; 28 (05) 753-770
- 10 Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol 2018; 68 (03) 526-549
- 11 Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64 (01) 73-84
- 12 Bosch FX, Ribes J, Díaz M, Cléries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004; 127 (05) (Suppl. 01) S5-S16
- 13 El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006; 4 (03) 369-380
- 14 Piscaglia F, Svegliati-Baroni G, Barchetti A. , et al; HCC-NAFLD Italian Study Group. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology 2016; 63 (03) 827-838
- 15 Bosetti C, Levi F, Boffetta P, Lucchini F, Negri E, La Vecchia C. Trends in mortality from hepatocellular carcinoma in Europe, 1980-2004. Hepatology 2008; 48 (01) 137-145
- 16 Qiu D, Katanoda K, Marugame T, Sobue T. A Joinpoint regression analysis of long-term trends in cancer mortality in Japan (1958-2004). Int J Cancer 2009; 124 (02) 443-448
- 17 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010; 138 (02) 513-521 , 521.e1–521.e6
- 18 Goldberg D, Ditah IC, Saeian K. , et al. Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterology 2017; 152 (05) 1090-1099.e1
- 19 Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology 2014; 59 (06) 2188-2195
- 20 Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology 2008; 48 (06) 2047-2063
- 21 Aravalli RN, Cressman EN, Steer CJ. Cellular and molecular mechanisms of hepatocellular carcinoma: an update. Arch Toxicol 2013; 87 (02) 227-247
- 22 Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 2007; 27 (01) 55-76
- 23 Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006; 6 (09) 674-687
- 24 Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018; 391 (10127): 1301-1314
- 25 Stegh AH. Targeting the p53 signaling pathway in cancer therapy - the promises, challenges and perils. Expert Opin Ther Targets 2012; 16 (01) 67-83
- 26 Feitelson MA, Sun B, Satiroglu Tufan NL, Liu J, Pan J, Lian Z. Genetic mechanisms of hepatocarcinogenesis. Oncogene 2002; 21 (16) 2593-2604
- 27 de La Coste A, Romagnolo B, Billuart P. , et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A 1998; 95 (15) 8847-8851
- 28 Anson M, Crain-Denoyelle AM, Baud V. , et al. Oncogenic β-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice. J Clin Invest 2012; 122 (02) 586-599
- 29 Luedde T, Schwabe RF. NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011; 8 (02) 108-118
- 30 Elsharkawy AM, Mann DA. Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis. Hepatology 2007; 46 (02) 590-597
- 31 Ito Y, Takeda T, Sakon M. , et al. Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer 2001; 84 (10) 1377-1383
- 32 Daveau M, Scotte M, François A. , et al. Hepatocyte growth factor, transforming growth factor alpha, and their receptors as combined markers of prognosis in hepatocellular carcinoma. Mol Carcinog 2003; 36 (03) 130-141
- 33 Lee S, Lee HJ, Kim JH, Lee HS, Jang JJ, Kang GH. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol 2003; 163 (04) 1371-1378
- 34 Liew CT, Li HM, Lo KW. , et al. High frequency of p16INK4A gene alterations in hepatocellular carcinoma. Oncogene 1999; 18 (03) 789-795
- 35 Murata H, Tsuji S, Tsujii M. , et al. Promoter hypermethylation silences cyclooxygenase-2 (Cox-2) and regulates growth of human hepatocellular carcinoma cells. Lab Invest 2004; 84 (08) 1050-1059
- 36 Wong CM, Lee JM, Ching YP, Jin DY, Ng IO. Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. Cancer Res 2003; 63 (22) 7646-7651
- 37 Yu J, Zhang HY, Ma ZZ, Lu W, Wang YF, Zhu JD. Methylation profiling of twenty four genes and the concordant methylation behaviours of nineteen genes that may contribute to hepatocellular carcinogenesis. Cell Res 2003; 13 (05) 319-333
- 38 Ji J, Shi J, Budhu A. , et al. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 2009; 361 (15) 1437-1447
- 39 Jopling C. Liver-specific microRNA-122: biogenesis and function. RNA Biol 2012; 9 (02) 137-142
- 40 Hu TH, Huang CC, Lin PR. , et al. Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma. Cancer 2003; 97 (08) 1929-1940
- 41 Ohlsson C, Mohan S, Sjögren K. , et al. The role of liver-derived insulin-like growth factor-I. Endocr Rev 2009; 30 (05) 494-535
- 42 Bhat M, Sonenberg N, Gores GJ. The mTOR pathway in hepatic malignancies. Hepatology 2013; 58 (02) 810-818
- 43 Shachaf CM, Kopelman AM, Arvanitis C. , et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature 2004; 431 (7012): 1112-1117
- 44 Wang BB, Cheng JY, Gao HH, Zhang Y, Chen ZN, Bian H. Hepatic stellate cells in inflammation-fibrosis-carcinoma axis. Anat Rec (Hoboken) 2010; 293 (09) 1492-1496
- 45 Ding YF, Wu ZH, Wei YJ, Shu L, Peng YR. Hepatic inflammation-fibrosis-cancer axis in the rat hepatocellular carcinoma induced by diethylnitrosamine. J Cancer Res Clin Oncol 2017; 143 (05) 821-834
- 46 Calvisi DF, Ladu S, Gorden A. , et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 2006; 130 (04) 1117-1128
- 47 Park EJ, Lee JH, Yu GY. , et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140 (02) 197-208
- 48 Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J. Angiogenesis in liver disease. J Hepatol 2009; 50 (03) 604-620
- 49 Gazzerro P, Proto MC, Gangemi G. , et al. Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev 2012; 64 (01) 102-146
- 50 Hanai J, Doro N, Sasaki AT. , et al. Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways. J Cell Physiol 2012; 227 (04) 1709-1720
- 51 Rao S, Porter DC, Chen X, Herliczek T, Lowe M, Keyomarsi K. Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. Proc Natl Acad Sci U S A 1999; 96 (14) 7797-7802
- 52 Relja B, Meder F, Wilhelm K, Henrich D, Marzi I, Lehnert M. Simvastatin inhibits cell growth and induces apoptosis and G0/G1 cell cycle arrest in hepatic cancer cells. Int J Mol Med 2010; 26 (05) 735-741
- 53 Cao Z, Fan-Minogue H, Bellovin DI. , et al. MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase. Cancer Res 2011; 71 (06) 2286-2297
- 54 Zhang W, Wu J, Zhou L, Xie HY, Zheng SS. Fluvastatin, a lipophilic statin, induces apoptosis in human hepatocellular carcinoma cells through mitochondria-operated pathway. Indian J Exp Biol 2010; 48 (12) 1167-1174
- 55 Montero J, Morales A, Llacuna L. , et al. Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. Cancer Res 2008; 68 (13) 5246-5256
- 56 Docrat TF, Nagiah S, Krishnan A, Naidoo DB, Chuturgoon AA. Atorvastatin induces MicroRNA-145 expression in HEPG2 cells via regulation of the PI3K/AKT signalling pathway. Chem Biol Interact 2018; 287: 32-40
- 57 Dulak J, Józkowicz A. Anti-angiogenic and anti-inflammatory effects of statins: relevance to anti-cancer therapy. Curr Cancer Drug Targets 2005; 5 (08) 579-594
- 58 Hoshida Y, Fuchs BC, Tanabe KK. Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges. Curr Cancer Drug Targets 2012; 12 (09) 1129-1159
- 59 Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev 2017; 121: 27-42
- 60 Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6 (12) 1399-1402
- 61 Okada Y, Yamaguchi K, Nakajima T. , et al. Rosuvastatin ameliorates high-fat and high-cholesterol diet-induced nonalcoholic steatohepatitis in rats. Liver Int 2013; 33 (02) 301-311
- 62 Chong LW, Hsu YC, Lee TF. , et al. Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells. BMC Gastroenterol 2015; 15: 22
- 63 Ma FX, Han ZC. Statins, nitric oxide and neovascularization. Cardiovasc Drug Rev 2005; 23 (04) 281-292
- 64 Ray K. Liver: sussing out statins in cirrhosis--KLF2 is the key. Nat Rev Gastroenterol Hepatol 2015; 12 (02) 64
- 65 Atkins GB, Jain MK. Role of Krüppel-like transcription factors in endothelial biology. Circ Res 2007; 100 (12) 1686-1695
- 66 Gracia-Sancho J, Russo L, García-Calderó H, García-Pagán JC, García-Cardeña G, Bosch J. Endothelial expression of transcription factor Kruppel-like factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver. Gut 2011; 60 (04) 517-524
- 67 Marrone G, Russo L, Rosado E. , et al. The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins. J Hepatol 2013; 58 (01) 98-103
- 68 Sweet DR, Fan L, Hsieh PN, Jain MK. Krüppel-like factors in vascular inflammation: mechanistic insights and therapeutic potential. Front Cardiovasc Med 2018; 5: 6
- 69 Jha P, Das H. KLF2 in regulation of NF-κB-mediated immune cell function and inflammation. Int J Mol Sci 2017; 18 (11) E2383
- 70 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 (09) 1434-1443
- 71 Mallat A, Preaux AM, Blazejewski S, Dhumeaux D, Rosenbaum J, Mavier P. Effect of simvastatin, an inhibitor of hydroxy-methylglutaryl coenzyme A reductase, on the growth of human Ito cells. Hepatology 1994; 20 (06) 1589-1594
- 72 Chang FM, Wang YP, Lang HC. , et al. Statins decrease the risk of decompensation in hepatitis B virus- and hepatitis C virus-related cirrhosis: a population-based study. Hepatology 2017; 66 (03) 896-907
- 73 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 (07) 976-985
- 74 Simon TG, King LY, Zheng H, Chung RT. Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C. J Hepatol 2015; 62 (01) 18-23
- 75 Kim RG, Loomba R, Prokop LJ, Singh S. Statin use and risk of cirrhosis and related complications in patients with chronic liver diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2017; 15 (10) 1521-1530.e8
- 76 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
- 77 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 (03) 749-755
- 78 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 (11) 957-963
- 79 Abraldes JG, Villanueva C, Aracil C. , et al; BLEPS Study Group. 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 (05) 1160-1170.e3
- 80 Villa E, Cammà C, Marietta M. , et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012; 143 (05) 1253-1260.e4
- 81 Anstee QM, Wright M, Goldin R, Thursz MR. Parenchymal extinction: coagulation and hepatic fibrogenesis. Clin Liver Dis 2009; 13 (01) 117-126
- 82 Bitto N, Salerno F, Tripodi A, La Mura V. Coagulation and fibrosis: a potential non-negligible target of statins in chronic hepatitis. J Hepatol 2015; 63 (01) 277-278
- 83 Undas A, Brummel-Ziedins KE, Mann KG. Anticoagulant effects of statins and their clinical implications. Thromb Haemost 2014; 111 (03) 392-400
- 84 Lötsch F, Königsbrügge O, Posch F, Zielinski C, Pabinger I, Ay C. Statins are associated with low risk of venous thromboembolism in patients with cancer: a prospective and observational cohort study. Thromb Res 2014; 134 (05) 1008-1013
- 85 Hametner S, Ferlitsch A, Ferlitsch M. , et al. The VITRO Score (von Willebrand factor antigen/thrombocyte ratio) as a new marker for clinically significant portal hypertension in comparison to other non-invasive parameters of fibrosis including ELF test. PLoS One 2016; 11 (02) e0149230
- 86 Kumar S, Grace ND, Qamar AA. Statin use in patients with cirrhosis: a retrospective cohort study. Dig Dis Sci 2014; 59 (08) 1958-1965
- 87 Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol 2014; 6 (01) a009191
- 88 Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 2015; 161 (01) 161-172
- 89 Schierwagen R, Uschner FE, Magdaleno F, Klein S, Trebicka J. Rationale for the use of statins in liver disease. Am J Physiol Gastrointest Liver Physiol 2017; 312 (05) G407-G412
- 90 Park HS, Jang JE, Ko MS. , et al. Statins increase mitochondrial and peroxisomal fatty acid oxidation in the liver and prevent non-alcoholic steatohepatitis in mice. Diabetes Metab J 2016; 40 (05) 376-385
- 91 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
- 92 Ekstedt M, Franzén LE, Mathiesen UL, Holmqvist M, Bodemar G, Kechagias S. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol 2007; 47 (01) 135-141
- 93 Athyros VG, Tziomalos K, Gossios TD. , et al; GREACE Study Collaborative Group. 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 (9756): 1916-1922
- 94 de Keyser CE, Koehler EM, Schouten JN. , et al. Statin therapy is associated with a reduced risk of non-alcoholic fatty liver in overweight individuals. Dig Liver Dis 2014; 46 (08) 720-725
- 95 Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis?. Nat Rev Cancer 2004; 4 (11) 891-899
- 96 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144 (05) 646-674
- 97 Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324 (5930): 1029-1033
- 98 Dang CV. Links between metabolism and cancer. Genes Dev 2012; 26 (09) 877-890
- 99 Ma R, Zhang W, Tang K. , et al. Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma. Nat Commun 2013; 4: 2508
- 100 Wang HJ, Park JY, Kwon O. , et al. Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction. Autophagy 2015; 11 (11) 2089-2101
- 101 Friis S, Poulsen AH, Johnsen SP. , et al. Cancer risk among statin users: a population-based cohort study. Int J Cancer 2005; 114 (04) 643-647
- 102 El-Serag HB, Johnson ML, Hachem C, Morgana RO. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology 2009; 136 (05) 1601-1608
- 103 Chiu HF, Ho SC, Chen CC, Yang CY. Statin use and the risk of liver cancer: a population-based case–control study. Am J Gastroenterol 2011; 106 (05) 894-898
- 104 Tsan YT, Lee CH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol 2012; 30 (06) 623-630
- 105 Lai SW, Liao KF, Lai HC, Muo CH, Sung FC, Chen PC. Statin use and risk of hepatocellular carcinoma. Eur J Epidemiol 2013; 28 (06) 485-492
- 106 Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 2013; 144 (02) 323-332
- 107 Tsan YT, Lee CH, Ho WC, Lin MH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection. J Clin Oncol 2013; 31 (12) 1514-1521
- 108 McGlynn KA, Divine GW, Sahasrabuddhe VV. , et al. Statin use and risk of hepatocellular carcinoma in a U.S. population. Cancer Epidemiol 2014; 38 (05) 523-527
- 109 Shi M, Zheng H, Nie B, Gong W, Cui X. Statin use and risk of liver cancer: an update meta-analysis. BMJ Open 2014; 4 (09) e005399
- 110 McGlynn KA, Hagberg K, Chen J. , et al. Statin use and risk of primary liver cancer in the Clinical Practice Research Datalink. J Natl Cancer Inst 2015; 107 (04) djv009
- 111 Zhou YY, Zhu GQ, Wang Y. , et al. Systematic review with network meta-analysis: statins and risk of hepatocellular carcinoma. Oncotarget 2016; 7 (16) 21753-21762
- 112 Kim G, Jang SY, Han E. , et al. Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: a nationwide nested case-control study. Int J Cancer 2017; 140 (04) 798-806
- 113 Kim G, Jang SY, Nam CM, Kang ES. Statin use and the risk of hepatocellular carcinoma in patients at high risk: a nationwide nested case-control study. J Hepatol 2018; 68 (03) 476-484
- 114 Simon TG, Bonilla H, Yan P, Chung RT, Butt AA. 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 (01) 47-57
- 115 Kamal S, Khan MA, Seth A. , et al. Beneficial effects of statins on the rates of hepatic fibrosis, hepatic decompensation, and mortality in chronic liver disease: a systematic review and meta-analysis. Am J Gastroenterol 2017; 112 (10) 1495-1505
- 116 Emberson JR, Kearney PM, Blackwell L. , et al; Cholesterol Treatment Trialists' (CTT) Collaboration. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One 2012; 7 (01) e29849
- 117 Weis M, Heeschen C, Glassford AJ, Cooke JP. Statins have biphasic effects on angiogenesis. Circulation 2002; 105 (06) 739-745
- 118 Demyen M, Alkhalloufi K, Pyrsopoulos NT. Lipid-lowering agents and hepatotoxicity. Clin Liver Dis 2013; 17 (04) 699-714 , x x
- 119 Vargas JI, Arrese M, Shah VH, Arab JP. Use of statins in patients with chronic liver disease and cirrhosis: current views and prospects. Curr Gastroenterol Rep 2017; 19 (09) 43
- 120 Henninger C, Huelsenbeck J, Huelsenbeck S. , et al. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity. Toxicol Appl Pharmacol 2012; 261 (01) 66-73
- 121 Björnsson E, Jacobsen EI, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol 2012; 56 (02) 374-380
- 122 Chalasani N, Bonkovsky HL, Fontana R. , et al; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology 2015; 148 (07) 1340-52.e7
- 123 Bays H, Cohen DE, Chalasani N, Harrison SA. ; The National Lipid Association's Statin Safety Task Force. An assessment by the Statin Liver Safety Task Force: 2014 update. J Clin Lipidol 2014; 8 (3, Suppl): S47-S57
- 124 Bader T. Yes! Statins can be given to liver patients. J Hepatol 2012; 56 (02) 305-307
- 125 Shimizu M, Yasuda Y, Sakai H. , et al. Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice. BMC Cancer 2011; 11: 281