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?
Tóm tắt
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.
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)].
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).
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).
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.
Từ khóa
Tài liệu tham khảo
Davison BA; Harrison SA; Cotter G; Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials 2020,73(6),1322-1332
Seeff L.B.; Everson G.T.; Morgan T.R.; Curto T.M.; Lee W.M.; Ghany M.G.; Shiffman M.L.; Fontana R.J.; Di Bisceglie A.M.; Bonkovsky H.L.; Dienstag J.L.; Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol HALT–C Trial Group2010,8(10),877-883
Ratziu V.; Charlotte F.; Heurtier A.; Gombert S.; Giral P.; Bruckert E.; Grimaldi A.; Capron F.; Poynard T.; Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology LIDO Study Group2005,128(7),1898-1906
Younossi Z.; Stepanova M.; Ong J.P.; Jacobson I.M.; Bugianesi E.; Duseja A.; Eguchi Y.; Wong V.W.; Negro F.; Yilmaz Y.; Romero-Gomez M.; George J.; Ahmed A.; Wong R.; Younossi I.; Ziayee M.; Afendy A.; Nonalcoholic Steatohepatitis Is the Fastest Growing Cause of Hepatocellular Carcinoma in Liver Transplant Candidates. Clin Gastroenterol Hepatol Global Nonalcoholic Steatohepatitis Council2019,17(4),748-755
Kleiner D.E.; Brunt E.M.; Van Natta M.; Behling C.; Contos M.J.; Cummings O.W.; Ferrell L.D.; Liu Y.C.; Torbenson M.S.; Unalp-Arida A.; Yeh M.; McCullough A.J.; Sanyal A.J.; Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology Nonalcoholic Steatohepatitis Clinical Research Network2005,41(6),1313-1321
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),305-315
Angulo P.; Hui J.M.; Marchesini G.; Bugianesi E.; George J.; Farrell G.C.; Enders F.; Saksena S.; Burt A.D.; Bida J.P.; Lindor K.; Sanderson S.O.; Lenzi M.; Adams L.A.; Kench J.; Therneau T.M.; Day C.P.; The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007,45(4),846-854
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),251-256
Athyros V.G.; Tziomalos K.; Gossios T.D.; Griva T.; Anagnostis P.; Kargiotis K.; Pagourelias E.D.; Theocharidou E.; Karagiannis A.; Mikhailidis D.P.; 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 GREACE Study Collaborative Group2010,376(9756),1916-1922
Tikkanen M.J.; Fayyad R.; Faergeman O.; Olsson A.G.; Wun C.C.; Laskey R.; Kastelein J.J.; Holme I.; Pedersen T.R.; 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 IDEAL Investigators2013,168(4),3846-3852
Kargiotis K.; Katsiki N.; Athyros V.G.; Giouleme O.; Patsiaoura K.; Katsiki E.; Mikhailidis D.P.; Karagiannis A.; Effect of rosuvastatin on non-alcoholic steatohepatitis in patients with metabolic syndrome and hypercholesterolaemia: a preliminary report. Curr Vasc Pharmacol 2014,12(3),505-511
US medicine. The voice of federal medicine. Available at:
Kleiner D.E.; Brunt E.M.; Wilson L.A.; Behling C.; Guy C.; Contos M.; Cummings O.; Yeh M.; Gill R.; Chalasani N.; Neuschwander-Tetri B.A.; Diehl A.M.; Dasarathy S.; Terrault N.; Kowdley K.; Loomba R.; Belt P.; Tonascia J.; Lavine J.E.; Sanyal A.J.; Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease. JAMA Netw Open Nonalcoholic Steatohepatitis Clinical Research Network2019,2(10),e1912565
Sterling R.K.; Lissen E.; Clumeck N.; Sola R.; Correa M.C.; Montaner J.; S Sulkowski M.; Torriani F.J.; Dieterich D.T.; Thomas D.L.; Messinger D.; Nelson M.; Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology APRICOT Clinical Investigators2006,43(6),1317-1325
Katsiki N.; Athyros V.G.; Karagiannis A.; Mikhailidis D.P.; Hyperuricaemia and non-alcoholic fatty liver disease (NAFLD): a relationship with implications for vascular risk? Curr Vasc Pharmacol 2011,9(6),698-705
Zois C.D.; Baltayiannis G.H.; Bekiari A.; Goussia A.; Karayiannis P.; Doukas M.; Demopoulos D.; Mitsellou A.; Vougiouklakis T.; Mitsi V.; Tsianos E.V.; Steatosis and steatohepatitis in postmortem material from Northwestern Greece. World J Gastroenterol 2010,16(31),3944-3949
Chen L.Z.; Xin Y.N.; Geng N.; Jiang M.; Zhang D.D.; Xuan S.Y.; 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
Clinical Trials .gov. Available at:
Athyros V.G.; Bouloukos V.I.; Pehlivanidis A.N.; Papageorgiou A.A.; Dionysopoulou S.G.; Symeonidis A.N.; Petridis D.I.; Kapousouzi M.I.; Satsoglou E.A.; Mikhailidis D.P.; The prevalence of the metabolic syndrome in Greece: the MetS-Greece Multicentre Study. Diabetes Obes Metab MetS-Greece Collaborative Group2005,7(4),397-405
Schulz L.O.; Bennett P.H.; Ravussin E.; Kidd J.R.; Kidd K.K.; Esparza J.; Valencia M.E.; 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),1866-1871
Bloom K.; Mohsen A.W.; Karunanidhi A.; El Demellawy D.; Reyes-Múgica M.; Wang Y.; Ghaloul-Gonzalez L.; Otsubo C.; Tobita K.; Muzumdar R.; Gong Z.; Tas E.; Basu S.; Chen J.; Bennett M.; Hoppel C.; Vockley J.; Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus. J Inherit Metab Dis 2018,41(1),49-57
Zhang X.; Zhang J.; Sun H.; Liu X.; Zheng Y.; Xu D.; Wang J.; Jia D.; Han X.; Liu F.; Nie J.; Shi Y.; Defective Phosphatidylglycerol Remodeling Causes Hepatopathy, Linking Mitochondrial Dysfunction to Hepatosteatosis. Cell Mol Gastroenterol Hepatol 2019,7(4),763-781
Wang J.Z.; Cao H.X.; Chen J.N.; Pan Q.; PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease. World J Clin Cases 2018,6(8),167-175
Traussnigg S.; Kienbacher C.; Halilbasic E.; Rechling C.; Kazemi-Shirazi L.; Hofer H.; Munda P.; Trauner M.; 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
Zhang W.; Yang X.; Chen Y.; Hu W.; Liu L.; Zhang X.; Liu M.; Sun L.; Liu Y.; Yu M.; Li X.; Li L.; Zhu Y.; Miao Q.R.; Han J.; Duan Y.; 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),177-190
Hu W.; Zhang W.; Chen Y.; Rana U.; Teng R.J.; Duan Y.; Liu Z.; Zhao B.; Foeckler J.; Weiler H.; Kallinger R.E.; Thomas M.J.; Zhang K.; Han J.; Miao Q.R.; 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),1559-1576
Leisegang M.S.; Bibli S.I.; Günther S.; Pflüger-Müller B.; Oo J.A.; Höper C.; Seredinski S.; Yekelchyk M.; Schmitz-Rixen T.; Schürmann C.; Hu J.; Looso M.; Sigala F.; Boon R.A.; Fleming I.; Brandes R.P.; Pleiotropic effects of laminar flow and statins depend on the Krüppel-like factor-induced lncRNA MANTIS. Eur Heart J 2019,40(30),2523-2533
Lin S.; Nascimento E.M.; Gajera C.R.; Chen L.; Neuhöfer P.; Garbuzov A.; Wang S.; Artandi S.E.; Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury. Nature 2018,556(7700),244-248
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
Tilg H.; Moschen A.R.; Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010,52(5),1836-1846
Liu Z.; Zhang Y.; Graham S.; Wang X.; Cai D.; Huang M.; Pique-Regi R.; Dong X.C.; Chen Y.E.; Willer C.; Liu W.; Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping. J Hepatol 2020,73(2),263-276
Athyros V.G.; Papageorgiou A.A.; Mercouris B.R.; Athyrou V.V.; Symeonidis A.N.; Basayannis E.O.; Demitriadis D.S.; Kontopoulos A.G.; 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),220-228
Athyros V.G.; Katsiki N.; Mikhailidis D.P.; Statins and non-alcoholic steatohepatitis. Metabolism 2017,66,e1-e2
Athyros V.G.; Katsiki N.; Karagiannis A.; Mikhailidis D.P.; Are statins ‘IDEAL’ for non-alcoholic fatty liver disease? Curr Med Res Opin 2014,30(2),229-231
Athyros V.G.; Ganotakis E.; Kolovou G.D.; Nicolaou V.; Achimastos A.; Bilianou E.; Alexandrides T.; Karagiannis A.; Paletas K.; Liberopoulos E.N.; Tziomalos K.; Petridis D.; Kakafika A.; Elisaf M.S.; Mikhailidis D.P.; Assessing the treatment effect in metabolic syndrome without perceptible diabetes (ATTEMPT): a prospective-randomized study in middle aged men and women. Curr Vasc Pharmacol Assessing The Treatment Effect in Metabolic Syndrome Without Perceptible Diabetes (ATTEMPT) Collaborative2011,9(6),647-657
Athyros V.G.; Katsiki N.; Mikhailidis D.P.; Am J Physiol Gastrointest Liver Physiol 2017,312(6),681-682
Yokohama K.; Fukunishi S.; Ii M.; Nakamura K.; Ohama H.; Tsuchimoto Y.; Asai A.; Tsuda Y.; Higuchi K.; 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),1499-1506
Dongiovanni P.; Petta S.; Mannisto V.; Mancina R.M.; Pipitone R.; Karja V.; Maggioni M.; Kakela P.; Wiklund O.; Mozzi E.; Grimaudo S.; Kaminska D.; Rametta R.; Craxi A.; Fargion S.; Nobili V.; Romeo S.; Pihlajamaki J.; Valenti L.; Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol 2015,63(3),705-712
Nascimbeni F.; Aron-Wisnewsky J.; Pais R.; Tordjman J.; Poitou C.; Charlotte F.; Bedossa P.; Poynard T.; Clément K.; Ratziu V.; Statins, antidiabetic medications and liver histology in patients with diabetes with non-alcoholic fatty liver disease. BMJ Open Gastroenterol LIDO study Group2016,3(1),e000075
Targher G.; Day C.P.; Bonora E.; Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010,363(14),1341-1350
Del Ben M.; Baratta F.; Polimeni L.; Pastori D.; Loffredo L.; Averna M.; Violi F.; Angelico F.; Under-prescription of statins in patients with non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2017,27(2),161-167
Cho Y.; Lee H.; Park H.K.; Choe E.Y.; Wang H.J.; Kim R.H.; Kim Y.; Kang E.S.; Differential Diabetogenic Effect of Pitavastatin and Rosuvastatin, in vitro and in vivo. J Atheroscler Thromb 2020,27(5),429-440
Ott-Fontes P.R.; Diedrich Neto J.A.; Goldoni M.B.; Comparison of the severity of non-alcoholic fatty liver disease in diabetic and non-diabetic obese patients. Rev Col Bras Cir 2020,47,e20202485
Park H.; Shima T.; Yamaguchi K.; Mitsuyoshi H.; Minami M.; Yasui K.; Itoh Y.; Yoshikawa T.; Fukui M.; Hasegawa G.; Nakamura N.; Ohta M.; Obayashi H.; Okanoue T.; Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol 2011,46(1),101-107
Wierzbicki A.S.; Oben J.; Nonalcoholic fatty liver disease and lipids. Curr Opin Lipidol 2012,23(4),345-352
Takeshita Y.; Takamura T.; Honda M.; Kita Y.; Zen Y.; Kato K.; Misu H.; Ota T.; Nakamura M.; Yamada K.; Sunagozaka H.; Arai K.; Yamashita T.; Mizukoshi E.; Kaneko S.; The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia 2014,57(5),878-890
Husain N.E.; Hassan A.T.; Elmadhoun W.M.; Ahmed M.H.; 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),1445-1455
Simon T.G.; Corey K.E.; Cannon C.P.; Blazing M.; Park J.G.; O’Donoghue M.L.; Chung R.T.; Giugliano R.P.; The nonalcoholic fatty liver disease (NAFLD) fibrosis score, cardiovascular risk stratification and a strategy for secondary prevention with ezetimibe. Int J Cardiol 2018,270,245-252
Doumas M.; Imprialos Κ.; Stavropoulos K.; Reklou A.; Sachinidis A.; Athyros V.G.; Combination of SGLT-2 Inhibitors and GLP-1 Receptor Agonists: Potential Benefits in Surrogate and Hard Endpoints. Curr Pharm Des 2018,24(17),1879-1886
Athyros V.G.; 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),494-497
Dougherty J.A.; Guirguis E.; Thornby K.A.; A Systematic Review of Newer Antidiabetic Agents in the Treatment of Nonalcoholic Fatty Liver Disease. Ann Pharmacother 2021,55(1),65-79
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 2016,64,1388-1402
Doumas M.; Imprialos K.; Stavropoulos K.; Athyros V.G.; What Does the Future Hold for Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis? Curr Vasc Pharmacol 2019,17(5),425-428
Sumida Y.; Yoneda M.; Hyogo H.; Itoh Y.; Ono M.; Fujii H.; Eguchi Y.; Suzuki Y.; Aoki N.; Kanemasa K.; Fujita K.; Chayama K.; Saibara T.; Kawada N.; Fujimoto K.; Kohgo Y.; Yoshikawa T.; Okanoue T.; Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD)2012,12,2
Baratta F; Pastori D; Angelico F; Nonalcoholic Fatty Liver Disease and Fibrosis Associated With Increased Risk of Cardiovascular Events in a Prospective Study. Clin Gastroenterol Hepatol 2020,18(10),2324-2331
Athyros V.G.; Mikhailidis D.P.; Liberopoulos E.N.; Kakafika A.I.; Karagiannis A.; Papageorgiou A.A.; Tziomalos K.; Ganotakis E.S.; Elisaf M.; 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),118-127
Athyros V.G.; Kakafika A.I.; Papageorgiou A.A.; Paraskevas K.I.; Tziomalos K.; Anagnostis P.; Pagourelias E.; Koumaras C.; Karagiannis A.; Mikhailidis D.P.; 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),1593-1599
Athyros V.G.; Alexandrides T.K.; Bilianou H.; Cholongitas E.; Doumas M.; Ganotakis E.S.; Goudevenos J.; Elisaf M.S.; Germanidis G.; Giouleme O.; Karagiannis A.; Karvounis C.; Katsiki N.; Kotsis V.; Kountouras J.; Liberopoulos E.; Pitsavos C.; Polyzos S.; Rallidis L.S.; Richter D.; Tsapas A.G.; Tselepis A.D.; Tsioufis K.; Tziomalos K.; Tzotzas T.; Vasiliadis T.G.; Vlachopoulos C.; Mikhailidis D.P.; Mantzoros C.; 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
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
Brouwers M.C.G.J.; Simons N.; Stehouwer C.D.A.; Isaacs A.; Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality. Diabetologia 2020,63(2),253-260
Tavaglione F; Targher G; Valenti L; Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum. Endocrinol Diab Metab 2020,3(4),e00179
Mahjoubin-Tehran M.; De Vincentis A.; Mikhailidis D.P.; Atkin S.L.; Mantzoros C.S.; Jamialahmadi T.; Sahebkar A.; 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