Generic placeholder image

Current Vascular Pharmacology

Editor-in-Chief

ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Research Article

Prevalence, Diagnosis, and Treatment with 3 Different Statins of Non-alcoholic Fatty Liver Disease/Non-alcoholic Steatohepatitis in Military Personnel. Do Genetics Play a Role?

Author(s): Georgios Sfikas*, Michael Psallas, Charalambos Koumaras, Konstantinos Imprialos, Evangelos Perdikakis, Michael Doumas, Olga Giouleme, Asterios Karagiannis and Vasilios G. Athyros

Volume 19, Issue 5, 2021

Published on: 15 October, 2020

Page: [572 - 581] Pages: 10

DOI: 10.2174/1570161118666201015152921

Price: $65

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) and its severe form, non-alcoholic steatohepatitis (NASH), are major health problems worldwide. Genetics may play a role in the pathogenesis of NAFLD/NASH.

Aims: To investigate the prevalence of NAFLD/NASH in 5,400 military personnel and evaluate the effect of treatment with 3 statins on NAFLD/NASH using 2 non-invasive scores [NAFLD Activity Score (NAS); Fibrosis-4 score (FIB-4)].

Methods: During the mandatory annual medical check-up, military personnel underwent a clinical and laboratory evaluation. Participants with NAFLD/NASH were randomized into 4 groups (n=151 each): diet-exercise, atorvastatin, rosuvastatin, or pitavastatin for 1 year (i.e., until the next routine evaluation).

Results: From all the participants, 613 had NAFLD/NASH (prevalence 11.3 vs 39.8% in the general population, p<0.001), and a total of 604 consented to participate in the study. After a year of treatment, the diet-exercise group showed no significant changes in both scores (NAS 4.98 baseline vs. 5.62, p=0.07; FIB-4 3.42 vs. 3.52, p=0.7). For the atorvastatin group, both scores were reduced (NAS 4.97 vs 1.95, p<0.001, FIB-4 3.56 vs 0.83, p<0.001), for rosuvastatin (NAS 5.55 vs 1.81, p<0.001, FIB-4 3.61 vs 0.79, p<0.001), and for pitavastatin (NAS 4.89 vs 1.99, p<0.001, FIB-4 3.78 vs 0.87, p<0.001).

Conclusion: Atorvastatin, rosuvastatin, and pitavastatin have a beneficial and safe effect in NAFLD/NASH patients as recorded by the improvement in the NAS (representing NAFLD activity) and FIB-4 (representing liver fibrosis) scores. Since both those with and without NAFLD/- NASH shared several baseline characteristics, genetics may play a role in the pathogenesis of NAFLD/NASH and its treatment with statins.

Keywords: Non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, diet, atorvastatin, rosuvastatin, pitavastatin.

[1]
Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346(16): 1221-31.
[http://dx.doi.org/10.1056/NEJMra011775] [PMID: 11961152]
[2]
Davison BA, Harrison SA, Cotter G, et al. Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials 2020; 73(6): 1322-32.
[http://dx.doi.org/10.1016/j.jhep.2020.06.025]
[3]
Seeff LB, Everson GT, Morgan TR, et al. HALT–C Trial Group. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol 2010; 8(10): 877-83.
[http://dx.doi.org/10.1016/j.cgh.2010.03.025] [PMID: 20362695]
[4]
Ratziu V, Charlotte F, Heurtier A, et al. LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005; 128(7): 1898-906.
[http://dx.doi.org/10.1053/j.gastro.2005.03.084] [PMID: 15940625]
[5]
Younossi Z, Stepanova M, Ong JP, et al. Global Nonalcoholic Steatohepatitis Council. Nonalcoholic Steatohepatitis Is the Fastest Growing Cause of Hepatocellular Carcinoma in Liver Transplant Candidates. Clin Gastroenterol Hepatol 2019; 17(4): 748-55.
[http://dx.doi.org/10.1016/j.cgh.2018.05.057] [PMID: 29908364]
[6]
Kleiner DE, Brunt EM, Van Natta M, et al. Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41(6): 1313-21.
[http://dx.doi.org/10.1002/hep.20701] [PMID: 15915461]
[7]
Vilar-Gomez E, Chalasani N. Non-invasive assessment of non-alcoholic fatty liver disease: Clinical prediction rules and blood-based biomarkers. J Hepatol 2018; 68(2): 305-15.
[http://dx.doi.org/10.1016/j.jhep.2017.11.013] [PMID: 29154965]
[8]
Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007; 45(4): 846-54.
[http://dx.doi.org/10.1002/hep.21496] [PMID: 17393509]
[9]
Mohammadi A, Bazazi A, Maleki-Miyandoab T, Ghasemi-Rad M. Evaluation of relationship between grading of fatty liver and severity of atherosclerotic finding. Int J Clin Exp Med 2012; 5(3): 251-6.
[PMID: 22837800]
[10]
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): 1916-22.
[http://dx.doi.org/10.1016/S0140-6736(10)61272-X] [PMID: 21109302]
[11]
Tikkanen MJ, Fayyad R, Faergeman O, et al. IDEAL Investigators. Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels. Int J Cardiol 2013; 168(4): 3846-52.
[http://dx.doi.org/10.1016/j.ijcard.2013.06.024] [PMID: 24001698]
[12]
Kargiotis K, Katsiki N, Athyros VG, et al. Effect of rosuvastatin on non-alcoholic steatohepatitis in patients with metabolic syndrome and hypercholesterolaemia: a preliminary report. Curr Vasc Pharmacol 2014; 12(3): 505-11.
[http://dx.doi.org/10.2174/15701611113119990009] [PMID: 24805248]
[14]
Kleiner DE, Brunt EM, Wilson LA, et al. Nonalcoholic Steatohepatitis Clinical Research Network. Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease. JAMA Netw Open 2019; 2(10): e1912565.
[http://dx.doi.org/10.1001/jamanetworkopen.2019.12565] [PMID: 31584681]
[15]
Sterling RK, Lissen E, Clumeck N, et al. APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006; 43(6): 1317-25.
[http://dx.doi.org/10.1002/hep.21178] [PMID: 16729309]
[16]
Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. Hyperuricaemia and non-alcoholic fatty liver disease (NAFLD): a relationship with implications for vascular risk? Curr Vasc Pharmacol 2011; 9(6): 698-705.
[http://dx.doi.org/10.2174/157016111797484152] [PMID: 21388346]
[17]
Zois CD, Baltayiannis GH, Bekiari A, et al. Steatosis and steatohepatitis in postmortem material from Northwestern Greece. World J Gastroenterol 2010; 16(31): 3944-9.
[http://dx.doi.org/10.3748/wjg.v16.i31.3944] [PMID: 20712056]
[18]
Chen LZ, Xin YN, Geng N, Jiang M, Zhang DD, Xuan SY. PNPLA3 I148M variant in nonalcoholic fatty liver disease: demographic and ethnic characteristics and the role of the variant in nonalcoholic fatty liver fibrosis. World J Gastroenterol 2015; 21(3): 794-802.
[http://dx.doi.org/10.3748/wjg.v21.i3.794] [PMID: 25624712]
[20]
Athyros VG, Bouloukos VI, Pehlivanidis AN, et al. MetS-Greece Collaborative Group. The prevalence of the metabolic syndrome in Greece: the MetS-Greece Multicentre Study. Diabetes Obes Metab 2005; 7(4): 397-405.
[http://dx.doi.org/10.1111/j.1463-1326.2004.00409.x] [PMID: 15955126]
[21]
Schulz LO, Bennett PH, Ravussin E, et al. Effects of traditional and western environments on prevalence of type 2 diabetes in Pima Indians in Mexico and the U.S. Diabetes Care 2006; 29(8): 1866-71.
[http://dx.doi.org/10.2337/dc06-0138] [PMID: 16873794]
[22]
Bloom K, Mohsen AW, Karunanidhi A, et al. Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus. J Inherit Metab Dis 2018; 41(1): 49-57.
[http://dx.doi.org/10.1007/s10545-017-0013-y] [PMID: 28120165]
[23]
Zhang X, Zhang J, Sun H, et al. Defective Phosphatidylglycerol Remodeling Causes Hepatopathy, Linking Mitochondrial Dysfunction to Hepatosteatosis. Cell Mol Gastroenterol Hepatol 2019; 7(4): 763-81.
[http://dx.doi.org/10.1016/j.jcmgh.2019.02.002] [PMID: 30831319]
[24]
Wang JZ, Cao HX, Chen JN, Pan Q. PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease. World J Clin Cases 2018; 6(8): 167-75.
[http://dx.doi.org/10.12998/wjcc.v6.i8.167] [PMID: 30148144]
[25]
Traussnigg S, Kienbacher C, Halilbasic E, et al. Challenges and Management of Liver Cirrhosis: Practical Issues in the Therapy of Patients with Cirrhosis due to NAFLD and NASH. Dig Dis 2015; 33(4): 598-607.
[http://dx.doi.org/10.1159/000375353] [PMID: 26159280]
[26]
Zhang W, Yang X, Chen Y, et al. Activation of hepatic Nogo-B receptor expression-A new anti-liver steatosis mechanism of statins. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863(2): 177-90.
[http://dx.doi.org/10.1016/j.bbalip.2017.12.002] [PMID: 29217477]
[27]
Hu W, Zhang W, Chen Y, et al. Nogo-B receptor deficiency increases liver X receptor alpha nuclear translocation and hepatic lipogenesis through an adenosine monophosphate-activated protein kinase alpha-dependent pathway. Hepatology 2016; 64(5): 1559-76.
[http://dx.doi.org/10.1002/hep.28747] [PMID: 27480224]
[28]
Leisegang MS, Bibli SI, Günther S, et al. Pleiotropic effects of laminar flow and statins depend on the Krüppel-like factor-induced lncRNA MANTIS. Eur Heart J 2019; 40(30): 2523-33.
[http://dx.doi.org/10.1093/eurheartj/ehz393] [PMID: 31222221]
[29]
Lin S, Nascimento EM, Gajera CR, et al. Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury. Nature 2018; 556(7700): 244-8.
[http://dx.doi.org/10.1038/s41586-018-0004-7] [PMID: 29618815]
[30]
Overi D, Carpino G, Franchitto A, Onori P, Gaudio E. Hepatocyte Injury and Hepatic Stem Cell Niche in the Progression of Non-Alcoholic Steatohepatitis. Cells 2020; 9(3): 590.
[http://dx.doi.org/10.3390/cells9030590] [PMID: 32131439]
[31]
Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52(5): 1836-46.
[http://dx.doi.org/10.1002/hep.24001] [PMID: 21038418]
[32]
Liu Z, Zhang Y, Graham S, et al. Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping. J Hepatol 2020; 73(2): 263-76.
[http://dx.doi.org/10.1016/j.jhep.2020.03.006] [PMID: 32165250]
[33]
Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus ‘usual’ care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin 2002; 18(4): 220-8.
[http://dx.doi.org/10.1185/030079902125000787] [PMID: 12201623]
[34]
Mearns BM. Pharmacotherapy: Statins are safe in NAFLD. Nat Rev Cardiol 2011; 8(2): 65.
[http://dx.doi.org/10.1038/nrcardio.2010.219] [PMID: 21348145]
[35]
Athyros VG, Katsiki N, Mikhailidis DP. Statins and non-alcoholic steatohepatitis. Metabolism 2017; 66: e1-2.
[http://dx.doi.org/10.1016/j.metabol.2016.10.006] [PMID: 27836113]
[36]
Athyros VG, Katsiki N, Karagiannis A, Mikhailidis DP. Are statins ‘IDEAL’ for non-alcoholic fatty liver disease? Curr Med Res Opin 2014; 30(2): 229-31.
[http://dx.doi.org/10.1185/03007995.2013.855192] [PMID: 24127654]
[37]
Athyros VG, Ganotakis E, Kolovou GD, et al. Assessing The Treatment Effect in Metabolic Syndrome Without Perceptible Diabetes (ATTEMPT) Collaborative. Assessing the treatment effect in metabolic syndrome without perceptible diabetes (ATTEMPT): a prospective-randomized study in middle aged men and women. Curr Vasc Pharmacol 2011; 9(6): 647-57.
[http://dx.doi.org/10.2174/157016111797484080] [PMID: 21476961]
[38]
Athyros VG, Katsiki N, Mikhailidis DP. Letter to the editor: Treating nonalcoholic fatty liver disease with statins. Are all statins equal?Am J Physiol Gastrointest Liver Physiol 2017; 312(6): 681-2.
[http://dx.doi.org/10.1152/ajpgi.00101.2017]
[39]
Yokohama K, Fukunishi S, Ii M, et al. Rosuvastatin as a potential preventive drug for the development of hepatocellular carcinoma associated with non-alcoholic fatty liver disease in mice. Int J Mol Med 2016; 38(5): 1499-506.
[http://dx.doi.org/10.3892/ijmm.2016.2766] [PMID: 28025996]
[40]
Dongiovanni P, Petta S, Mannisto V, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol 2015; 63(3): 705-12.
[http://dx.doi.org/10.1016/j.jhep.2015.05.006] [PMID: 25980762]
[41]
Nascimbeni F, Aron-Wisnewsky J, Pais R, et al. LIDO study Group. Statins, antidiabetic medications and liver histology in patients with diabetes with non-alcoholic fatty liver disease. BMJ Open Gastroenterol 2016; 3(1): e000075.
[http://dx.doi.org/10.1136/bmjgast-2015-000075] [PMID: 27110380]
[42]
Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363(14): 1341-50.
[http://dx.doi.org/10.1056/NEJMra0912063] [PMID: 20879883]
[43]
Del Ben M, Baratta F, Polimeni L, et al. Under-prescription of statins in patients with non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2017; 27(2): 161-7.
[http://dx.doi.org/10.1016/j.numecd.2016.09.011] [PMID: 27914698]
[44]
Cho Y, Lee H, Park HK, et al. Differential Diabetogenic Effect of Pitavastatin and Rosuvastatin, in vitro and in vivo. J Atheroscler Thromb 2020; 27(5): 429-40.
[http://dx.doi.org/10.5551/jat.50039] [PMID: 31527323]
[45]
Ott-Fontes PR, Diedrich Neto JA, Goldoni MB. Comparison of the severity of non-alcoholic fatty liver disease in diabetic and non-diabetic obese patients. Rev Col Bras Cir 2020; 47: e20202485.
[http://dx.doi.org/10.1590/0100-6991e-20202485] [PMID: 32638913]
[46]
Park H, Shima T, Yamaguchi K, et al. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol 2011; 46(1): 101-7.
[http://dx.doi.org/10.1007/s00535-010-0291-8] [PMID: 20658156]
[47]
Wierzbicki AS, Oben J. Nonalcoholic fatty liver disease and lipids. Curr Opin Lipidol 2012; 23(4): 345-52.
[http://dx.doi.org/10.1097/MOL.0b013e3283541cfc] [PMID: 22617751]
[48]
Takeshita Y, Takamura T, Honda M, et al. The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia 2014; 57(5): 878-90.
[http://dx.doi.org/10.1007/s00125-013-3149-9] [PMID: 24407920]
[49]
Husain NE, Hassan AT, Elmadhoun WM, Ahmed MH. Evaluating the safety of Liptruzet (ezetimibe and atorvastatin): what are the potential benefits beyond low-density lipoprotein cholesterol-lowering effect? Expert Opin Drug Saf 2015; 14(9): 1445-55.
[http://dx.doi.org/10.1517/14740338.2015.1063613] [PMID: 26134926]
[50]
Simon TG, Corey KE, Cannon CP, et al. The nonalcoholic fatty liver disease (NAFLD) fibrosis score, cardiovascular risk stratification and a strategy for secondary prevention with ezetimibe. Int J Cardiol 2018; 270: 245-52.
[http://dx.doi.org/10.1016/j.ijcard.2018.05.087] [PMID: 29903515]
[51]
Doumas M, Imprialos Κ, Stavropoulos K, Reklou A, Sachinidis A, Athyros VG. Combination of SGLT-2 Inhibitors and GLP-1 Receptor Agonists: Potential Benefits in Surrogate and Hard Endpoints. Curr Pharm Des 2018; 24(17): 1879-86.
[http://dx.doi.org/10.2174/1381612824666180604113653] [PMID: 29865997]
[52]
Athyros VG, Katsiki N, Karagiannis A. Editorial: Can Glucagon Like Peptide 1 (GLP1) Agonists or Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors Ameliorate Non-Alcoholic Steatohepatitis in People with or without Diabetes? Curr Vasc Pharmacol 2016; 14(6): 494-7.
[http://dx.doi.org/10.2174/1570161114666160909161811] [PMID: 27633289]
[53]
Dougherty JA, Guirguis E, Thornby KA. A Systematic Review of Newer Antidiabetic Agents in the Treatment of Nonalcoholic Fatty Liver Disease. Ann Pharmacother 2021; 55(1): 65-79.
[PMID: 32571083]
[54]
EASL-EASD-EASO clinical practice guidelines for the management of non alcoholic fatty liver disease. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). J Hepatol 2016; 64: 1388-402.
[http://dx.doi.org/10.1016/j.jhep.2015.11.004]
[55]
Doumas M, Imprialos K, Stavropoulos K, Athyros VG. What Does the Future Hold for Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis? Curr Vasc Pharmacol 2019; 17(5): 425-8.
[http://dx.doi.org/10.2174/157016111705190703102816] [PMID: 31418344]
[56]
Sumida Y, Yoneda M, Hyogo H, et al. Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD). Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol 2012; 12: 2.
[http://dx.doi.org/10.1186/1471-230X-12-2] [PMID: 22221544]
[57]
Baratta F, Pastori D, Angelico F, et al. Nonalcoholic Fatty Liver Disease and Fibrosis Associated With Increased Risk of Cardiovascular Events in a Prospective Study. Clin Gastroenterol Hepatol 2020; 18(10): 2324-31.
[http://dx.doi.org/10.1016/j.cgh.2019.12.026]
[58]
Athyros VG, Mikhailidis DP, Liberopoulos EN, et al. Effect of statin treatment on renal function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syndrome: a subgroup analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. Nephrol Dial Transplant 2007; 22(1): 118-27.
[http://dx.doi.org/10.1093/ndt/gfl538] [PMID: 16998214]
[59]
Athyros VG, Kakafika AI, Papageorgiou AA, et al. Effects of statin treatment in men and women with stable coronary heart disease: a subgroup analysis of the GREACE Study. Curr Med Res Opin 2008; 24(6): 1593-9.
[http://dx.doi.org/10.1185/03007990802069563] [PMID: 18430270]
[60]
Athyros VG, Alexandrides TK, Bilianou H, et al. The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement. Metabolism 2017; 71: 17-32.
[http://dx.doi.org/10.1016/j.metabol.2017.02.014] [PMID: 28521870]
[61]
Arnaboldi L, Corsini A. Could changes in adiponectin drive the effect of statins on the risk of new-onset diabetes? The case of pitavastatin. Atheroscler Suppl 2015; 16: 1-27.
[http://dx.doi.org/10.1016/S1567-5688(14)70002-9] [PMID: 25575403]
[62]
Brouwers MCGJ, Simons N, Stehouwer CDA, Isaacs A. Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality. Diabetologia 2020; 63(2): 253-60.
[http://dx.doi.org/10.1007/s00125-019-05024-3] [PMID: 31713012]
[63]
Tavaglione F, Targher G, Valenti L, et al. Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum. Endocrinol Diab Metab 2020; 3(4): e00179.
[http://dx.doi.org/10.1002/edm2.179]
[64]
Mahjoubin-Tehran M, De Vincentis A, Mikhailidis DP, et al. Non-alcoholic fatty liver disease and steatohepatitis: State of the art on effective therapeutics based on the gold standard method for diagnosis. Mol Metab 2021; 101049.
[http://dx.doi.org/10.1016/j.molmet.2020.101049] [PMID: 32673798]
[65]
Athyros VG, Katsiki N, Mikhailidis DP. NAFLD and Statins. Dig Dis Sci 2020; 65(10): 3052-3.
[http://dx.doi.org/10.1007/s10620-020-06505-x] [PMID: 32797344]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy