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Статины, печень и гепатотоксичность: доказательства против домыслов
Статины, печень и гепатотоксичность: доказательства против домыслов
Бубнова М.Г., Парнес Л.Е. Статины, печень и гепатотоксичность: доказательства против домыслов. CardioСоматика. 2019; 10 (3): 42–49. DOI: 10.26442/22217185.2019.3.190470
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Аннотация
Цель. Осветить современные представления о переносимости и безопасности терапии статинами у пациентов с хроническими заболеваниями печени.
Материалы и методы. Рассмотрены данные 66 научных источников, опубликованных в российской и зарубежной печати в 1988–2019 гг.
Результаты. Общепризнанно, что статины – препараты 1-й линии терапии для лечения атерогенной дислипидемии. Одно из наиболее часто обсуждаемых побочных явлений статинов – это гепатотоксический эффект, ограничивающий их применение в клинической практике, особенно при назначении в режиме высоких доз и у пациентов с хроническими заболеваниями печени. Механизм повышения активности печеночных трансаминаз неясен. Представлены результаты клинических и экспериментальных исследований, метаанализов, в которых обсуждаются возможности назначения статинов при разных хронических заболеваниях печени и эффекты их воздействия на биохимические параметры и гистологию печени. Рассматриваются перспективы применения в комплексе с терапией статинами комбинированного гепатопротектора у пациентов с хроническими заболеваниями печени (в первую очередь с неалкогольной жировой болезнью печени) для коррекции липидных нарушений, нормализации ферментов и функции печени, снижения сердечно-сосудистого риска.
Заключение. В целом статины имеют хороший профиль переносимости и могут рассматриваться к назначению у пациентов с хроническими заболеваниями печени.
Ключевые слова: статины, хронические заболевания печени, печеночная дисфункция, гепатопротекторы.
Materials and methods. The data of 66 scientific sources published in the Russian and foreign press in 1988–2019 are considered.
Results. It is generally accepted that statins are the drugs of the 1st line of therapy for the treatment of atherogenic dyslipidemia. One of the most commonly discussed side effects of statins is the hepatotoxic effect, which limits their use in clinical practice, especially when administered in high-dose regimen and in patients with chronic liver diseases. The mechanism of increased liver transaminase activity is unclear. Presents the results of clinical and experimental studies, meta-analyzes, which discuss the possibility of prescribing statins in various chronic liver diseases and the effects of their effects on biochemical parameters and histology of the liver. Prospects for use in combination with statin therapy combined hepatoprotector in patients with chronic liver diseases (primarily with nonalcoholic fatty liver disease) for correcting lipid disorders, normalizing enzymes and liver function, reducing cardiovascular risk are considered.
Conclusion. In general, statins have a good tolerability profile and can be considered for administration in patients with chronic liver diseases.
Key words: statins, chronic liver diseases, hepatic dysfunction, hepatoprotectors.
Материалы и методы. Рассмотрены данные 66 научных источников, опубликованных в российской и зарубежной печати в 1988–2019 гг.
Результаты. Общепризнанно, что статины – препараты 1-й линии терапии для лечения атерогенной дислипидемии. Одно из наиболее часто обсуждаемых побочных явлений статинов – это гепатотоксический эффект, ограничивающий их применение в клинической практике, особенно при назначении в режиме высоких доз и у пациентов с хроническими заболеваниями печени. Механизм повышения активности печеночных трансаминаз неясен. Представлены результаты клинических и экспериментальных исследований, метаанализов, в которых обсуждаются возможности назначения статинов при разных хронических заболеваниях печени и эффекты их воздействия на биохимические параметры и гистологию печени. Рассматриваются перспективы применения в комплексе с терапией статинами комбинированного гепатопротектора у пациентов с хроническими заболеваниями печени (в первую очередь с неалкогольной жировой болезнью печени) для коррекции липидных нарушений, нормализации ферментов и функции печени, снижения сердечно-сосудистого риска.
Заключение. В целом статины имеют хороший профиль переносимости и могут рассматриваться к назначению у пациентов с хроническими заболеваниями печени.
Ключевые слова: статины, хронические заболевания печени, печеночная дисфункция, гепатопротекторы.
________________________________________________
Materials and methods. The data of 66 scientific sources published in the Russian and foreign press in 1988–2019 are considered.
Results. It is generally accepted that statins are the drugs of the 1st line of therapy for the treatment of atherogenic dyslipidemia. One of the most commonly discussed side effects of statins is the hepatotoxic effect, which limits their use in clinical practice, especially when administered in high-dose regimen and in patients with chronic liver diseases. The mechanism of increased liver transaminase activity is unclear. Presents the results of clinical and experimental studies, meta-analyzes, which discuss the possibility of prescribing statins in various chronic liver diseases and the effects of their effects on biochemical parameters and histology of the liver. Prospects for use in combination with statin therapy combined hepatoprotector in patients with chronic liver diseases (primarily with nonalcoholic fatty liver disease) for correcting lipid disorders, normalizing enzymes and liver function, reducing cardiovascular risk are considered.
Conclusion. In general, statins have a good tolerability profile and can be considered for administration in patients with chronic liver diseases.
Key words: statins, chronic liver diseases, hepatic dysfunction, hepatoprotectors.
Полный текст
Список литературы
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2. Aronov D.M., Bubnova M.G. Pleiotropnye effekty statinov na sovremennom etape ikh izucheniia (fokus na atorvastatin). Chast' 1. Cardiosomatics. 2012; 3 (3): 55–64 (in Russian).
3. Aronov D.M. Kaskad terapevticheskikh effektov statinov. Kardiologiia. 2004; 10: 85–94 (in Russian).
4. Tandon V, Bano G, Khajuria V et al. Pleiotropic effects of statins. Indian J Pharmacol 2005; 37: 77–85.
5. Buhaescu I, Izzedine H. Mevalonate pathway: a review of clinical and therapeutical implications. Clin Biochem 2007; 40: 575–84. DOI: 10.1016/j.clinbiochem.
6. Ward NC, Watts GF, Eckel RH. Statin Toxicity Mechanistic Insights and Clinical Implications. Сirc Res 2019; 124: 328–50. DOI: 10.1161/CIRCRESAHA.118.312782
7. Newman CB, Preiss D, Tobert JА et al. Statin Safety and Associated Adverse Events A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol 2018; 38: e00–e00. DOI: 10.1161/ATV.0000000000000073
8. Calderon RM, Cubeddu LX, Goldberg RB, Schiff ER. Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma. Mayo Clin Proc 2010; 85 (4): 349–56.
9. Lazebnik L.B., Zvenigorodskaia L.A., Samsonova N.G. et al. Gipolipidemicheskaia terapiia u bol'nykh s nealkogol'noi zhirovoi bolezn'iu pecheni. Cardiosomatics. 2010; 1: 38–45 (in Russian).
10. Thapar M, Russo M, Bonkovsky HL. Statins and liver injury. J Gastroenterology and Hepatology 2013; 9 (9): 605–6.
11. Dale KM, White CM, Henyan NN et al. Impact of statin dosing intensity on transaminase and creatine kinase. Am J Med 2007; 120: 706–12.
12. Mach F, Ray KK, Wiklund O et al. European Atherosclerosis Society Consensus Panel. Adverse effects of statin therapy: perception vs. the evidence – focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract. Eur Heart J 2018; 39: 2526–39. DOI:10.1093/eurheartj/ehy182
13. Jose J. Statins and its hepatic effects: Newer data, implications, and changing recommendations. J Pharmacy Bioallied Sci 2016; 8 (1): 23–8.
14. Björnsson ES. Hepatotoxicity of statins and other lipid-lowering agents. Liver Int 2017; 37: 173–8. DOI: 10.1111/liv.13308
15. Gluba-Brzozka A, Franczyk B, Toth PP et al. Molecular mechanisms of statin intolerance. Arch Med Sci 2016; 12: 645–58. DOI: 10.5114/aoms.2016.59938
16. Kostapanos MS, Milionis HJ, Elisaf MS. Rosuvastatin-associated adverse effects and drug-drug interactions in the clinical setting of dyslipidemia. Am J Cardiovasc Drugs 2010; 10 (1): 11–28.
17. Catapano AL, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J 2016; 37: 2999–3058.
18. Magan-Fernandez A, Rizzo M, Montalto G, Marchesini G. Statins in liver disease: not only prevention of cardiovascular events. Expt Rev Gastroenterol Hepatol 2018; DOI: 10.1080/17474124.2018.1477588
19. Younossi Z, Anstee QM, Marietti M et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018; 15 (1): 11–20.
20. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol 2012; 107: 811–26. DOI: 10.1038/ ajg.2012.128
21. 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. Digestive and liver disease. Liver 2014; 46: 720–25.
22. Browning JD. Statins and hepatic steatosis: perspectives from the Dallas heart study. Hepatology 2006; 44: 466–71.
23. Pastori D, Polimeni L, Baratta F et al. The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis 2015; 47: 4–11.
24. European association for the study of the L., European association for the study of D., European association for the study of O. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64: 1388–1402.
25. Athyros VG, Tziomalos K, Gossios TD et al. for the 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: 1916–22.
26. 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.
27. 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: 878–90.
28. Loomba R, Sirlin CB, Ang B et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 2015; 61:1239–50.
29. Chan DC, Watts GF, Gan SK et al. Effect of ezetimibe on hepatic fat, inflammatory markers, and apolipoprotein B-100 kinetics in insulin-resistant obese subjects on a weight loss diet. Diabetes Care 2010; 33: 1134–9.
30. 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: 7860–8. DOI: 10.3748/wjg.v21.i25.7860
31. Hyogo H, Ikegami T, Tokushige K et al. Efficacy of pitavastatin for the treatmentof non-alcoholic steatohepatitis with dyslipidemia: an open-label, pilot study. Hepatol Res 2011; 41: 1057–65.
32. Kimura Y, Hyogo H, Yamagishi S et al. Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH. J Gastroenterol 2010; 45: 750–7. DOI: 10.1007/s00535-010-0203-y
33. Gómez-Domínguez E, Gisbert JP, Moreno-Monteagudo JA et al. A pilot study of atorvastatin treatment in dyslipemid, non alcoholic fatty liver patients. Aliment Pharmacol Ther 2006; 23: 1643–7.
34. 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: 1521–30.
35. Nascimbeni F, Pellegrini E, Lugari S et al. Statins and nonalcoholic fatty liver disease in the era of precision medicine: More friends than foes. Atherosclerosis 2019; 284: 66–74. https://doi.org/10.1016/j.atherosclerosis. 2019.02.028
36. Bishnu S, Ahammed SM, Sarkar A et al. Effects of atorvastatin on portal hemodynamics and clinical outcomes in patients with cirrhosis with portal hypertension: a proof of concept study. Eur J Gastroenterol Hepatol 2018; 30: 54–9.
37. 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: 18–23. DOI: 10.1016/j.jhep.2014.08.013
38. 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: 430–40. e1. DOI: 10.1053/j.gastro.2015.10.007
39. Ambrosino P, Lupoli R, Di Minno A et al. The risk of coronary artery disease and cerebrovascular disease in patients with hepatitis C: a systematic review and meta-analysis. Int J Cardiol 2016; 221: 746–54. DOI: 10.1016/j.ijcard.2016.06.337
40. 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 [published correction appears in Am J Gastroenterol 2018; 113: 447]. Am J Gastroenterol 2016; 111: 976–85. DOI: 10.1038/ajg.2016.179
41. Tsan Y-T, Lee Ch-Hg, Wang J-D et al. Statins and the Risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol 2012; 30: 623–30.
42. Motamed N et al. Non-alcoholic fatty liver disease (NAFLD) and 10-year risk of cardiovascular diseases. Clin Res Hepatol Gastroenterol 2017; 41: 31–8.
43. Del Ben M, Baratta F, Polimeni L et al. Under-prescription of statins in patients with non-alcoholic fatty liver disease. Nutr Metabol Cardiovasc Dis 2017; 27: 161–7.
44. Blais P, Lin M, Kramer JR et al. Statins are underutilized in patients with nonalcoholic fatty liver disease and dyslipidemia. Dig Dis Sci 2016; 61: 1714–20.
45. Labenz C, Huber Y, Kalliga E et al. Predictors of advanced fibrosis in non-cirrhotic non-alcoholic fatty liver disease in Germany. Aliment Pharmacol Ther 2018; 48: 1109–16.
46. Rzouq FS, Volk ML, Hatoum HH et al. Hepatotoxicity fears contribute to under-utilization of statin medications by primary care physicians. Am J Med Sci 2010; 340: 89–93.
47. Ekstedt M, Franzen LE, Mathiesen UL et al. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol 2007; 47 (1): 135–41.
48. Kiderman A, Ben-Dov IZ, Glikberg F, Ackerman Z. Declining frequency of liver enzyme abnormalities with statins: experience from general practice in Jerusalem. Eur J Gastroenterol Hepatol 2008; 20 (10): 1002–5.
49. Ivashkin V.T., Maevskaia M.V., Pavlov Ch.S. et al. Klinicheskie rekomendatsii po diagnostike i lecheniiu nealkogol'noi zhirovoi bolezni pecheni Rossiiskogo obshchestva po izucheniiu pecheni i Rossiiskoi gastroenterologicheskoi assotsiatsii. Ros. zhurn. gastroenterologii, gepatologii i koloproktologii. 2016; 2: 24–42 (in Russian).
50. Zhuravleva M.V. Primenenie Eslidina u bol'nykh sakharnym diabetom tipa 2. Cardiosomatics. 2011; 2 (2): 75–81. (in Russian).
51. Gonciarz Z, Besser P, Lelek E et al. Randomised placebo-controlled doubleblind trial on essential phospholipids in the treatment of fatty liver associated with diabetes. Med Chir Dig 1988; 17 (1): 61–5.
52. Sas E, Grinevich V, Efimov O et al Beneficial influence of polyunsaturated Phosphatidylcholine enhances functional liver condition and liver structure in patients with Nonalcoholic steatohepatitis. Results of prolonged randomized blinded prospective clinical study. J Hepatol 2013; 58: S549.
53. Un C, Zheng X, Tan Z et al. Clinical Observation on Polyene Phosphatidyl Choline and Metformin in the Treatment of Type 2 Diabetes and Non-alcoholic Fatty Liver Disease. Clin Focus 2008; 23 (17): 1272–3.
54. Yin Kong. Observation for curative effect of Essentiale in treatment of fatty liver caused by diabetes mellitus. Med J Qilu 2000; 15: 277–8.
55. Ivashkin V.T., Maevskaia M.V., Shirokova E.N., Morozova M.A. Opyt primeneniia preparata Eslidin u patsientov s nealkogol'noi zhirovoi bolezn'iu pecheni v praktike vracha ambulatornogo zvena (Global Observation of Liver Disease treatment with Eslidin®, "GOLD"). RMZh. 2015; 21: 1272–7 (in Russian).
56. Finkelstein JD, Martin JJ. Methionine metabolism in mammals. Distribution of homocysteine between competing pathways. J Biol Chem 1984; 259: 9508–13.
57. Fernandez A, Matías N, Martínez L et al. Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-l-methionine and glutathione. J Biol Chem 2010; 285: 18528–36.
58. Moundras C, Rémésy C, Levrat MA, Demigné C. Methionine deficiency in rats fed soy protein induces hypercholesterolemia and potentiates lipoprotein susceptibility to peroxidation. Metabolism 1995; 44: 1146–52.
59. Dhar I, Lysne V, Seifert R et al. Plasma methionine and risk of acute myocardial infarction: Effect modification by established risk factors. Atherosclerosis 2018; 272: 175–81. https://doi.org/10.1016/j.atherosclerosis. 2018.03.038
60. Bubnova M.G., Aronov D.M., Evdakov V.A. Gipolipidemicheskaia i gepatoprotektornaia effektivnost' fiksirovannoi kombinatsii essentsial'nykh fosfolipidov s metioninom na fone terapii atorvastatinom u bol'nykh s serdechno-sosudistymi zabolevaniiami i sakharnym diabetom 2 tipa, stradaiushchikh giperlipidemiei (issledovanie OLIMP, chast' I). Cardiosomatics. 2012; 3 (3): 82–93 (in Russian).
61. Bubnova M.G., Aronov D.M., Evdakov V.A., Vygodin V.A. Vliianie atorvastatina pri monoterapii i v kombinatsii s essentsial'nymi fosfolipidami na pokazateli uglevodnogo obmena, funktsiiu endoteliia i markery vospaleniia u bol'nykh s serdechno-sosudistymi zabolevaniiami i sakharnym diabetom tipa 2 v sochetanii s giperlipidemiei (issledovanie OLIMP, chast' II). Cardiosomatics. 2012; 3 (4): 28–37 (in Russian).
62. Younossi Z, Anstee QM, Marietti M et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018; 15 (1): 11–20.
63. Trombetta M, Spiazzi G, Zoppini G, Muggeo M. Review article: type 2 diabetes and chronic liver disease in the Verona diabetes study. Aliment Pharmacol Ther 2005; 22 (Suppl. 2): 24–7.
64. Biddinger SB, Hernandez-Onj A, Rask-Madsen C et al. Hepatic insulin resistance to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab 2008; 7: 125–34.
65. Ioannou GN, Weiss NS, Boyko EJ et al. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology 2006; 43: 1145–51.
66. Lee D-H, Silventoinen K, Hu G et al. Serum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28 838 middle-aged men and women. Eur Heart J 2006; 27: 2170–6.
2. Аронов Д.М., Бубнова М.Г. Плейотропные эффекты статинов на современном этапе их изучения (фокус на аторвастатин). Часть 1. CardioСоматика. 2012; 3 (3): 55–64.
[Aronov D.M., Bubnova M.G. Pleiotropnye effekty statinov na sovremennom etape ikh izucheniia (fokus na atorvastatin). Chast' 1. Cardiosomatics. 2012; 3 (3): 55–64 (in Russian).]
3. Аронов Д.М. Каскад терапевтических эффектов статинов. Кардиология. 2004; 10: 85–94.
[Aronov D.M. Kaskad terapevticheskikh effektov statinov. Kardiologiia. 2004; 10: 85–94 (in Russian).]
4. Tandon V, Bano G, Khajuria V et al. Pleiotropic effects of statins. Indian J Pharmacol 2005; 37: 77–85.
5. Buhaescu I, Izzedine H. Mevalonate pathway: a review of clinical and therapeutical implications. Clin Biochem 2007; 40: 575–84. DOI: 10.1016/j.clinbiochem.
6. Ward NC, Watts GF, Eckel RH. Statin Toxicity Mechanistic Insights and Clinical Implications. Сirc Res 2019; 124: 328–50. DOI: 10.1161/CIRCRESAHA.118.312782
7. Newman CB, Preiss D, Tobert JА et al. Statin Safety and Associated Adverse Events A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol 2018; 38: e00–e00. DOI: 10.1161/ATV.0000000000000073
8. Calderon RM, Cubeddu LX, Goldberg RB, Schiff ER. Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma. Mayo Clin Proc 2010; 85 (4): 349–56.
9. Лазебник Л.Б., Звенигородская Л.А., Самсонова Н.Г. и др. Гиполипидемическая терапия у больных с неалкогольной жировой болезнью печени. CardioСоматика. 2010; 1: 38–45.
[Lazebnik L.B., Zvenigorodskaia L.A., Samsonova N.G. et al. Gipolipidemicheskaia terapiia u bol'nykh s nealkogol'noi zhirovoi bolezn'iu pecheni. Cardiosomatics. 2010; 1: 38–45 (in Russian).]
10. Thapar M, Russo M, Bonkovsky HL. Statins and liver injury. J Gastroenterology and Hepatology 2013; 9 (9): 605–6.
11. Dale KM, White CM, Henyan NN et al. Impact of statin dosing intensity on transaminase and creatine kinase. Am J Med 2007; 120: 706–12.
12. Mach F, Ray KK, Wiklund O et al. European Atherosclerosis Society Consensus Panel. Adverse effects of statin therapy: perception vs. the evidence – focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract. Eur Heart J 2018; 39: 2526–39. DOI:10.1093/eurheartj/ehy182
13. Jose J. Statins and its hepatic effects: Newer data, implications, and changing recommendations. J Pharmacy Bioallied Sci 2016; 8 (1): 23–8.
14. Björnsson ES. Hepatotoxicity of statins and other lipid-lowering agents. Liver Int 2017; 37: 173–8. DOI: 10.1111/liv.13308
15. Gluba-Brzozka A, Franczyk B, Toth PP et al. Molecular mechanisms of statin intolerance. Arch Med Sci 2016; 12: 645–58. DOI: 10.5114/aoms.2016.59938
16. Kostapanos MS, Milionis HJ, Elisaf MS. Rosuvastatin-associated adverse effects and drug-drug interactions in the clinical setting of dyslipidemia. Am J Cardiovasc Drugs 2010; 10 (1): 11–28.
17. Catapano AL, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J 2016; 37: 2999–3058.
18. Magan-Fernandez A, Rizzo M, Montalto G, Marchesini G. Statins in liver disease: not only prevention of cardiovascular events. Expt Rev Gastroenterol Hepatol 2018; DOI: 10.1080/17474124.2018.1477588
19. Younossi Z, Anstee QM, Marietti M et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018; 15 (1): 11–20.
20. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol 2012; 107: 811–26. DOI: 10.1038/ ajg.2012.128
21. 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. Digestive and liver disease. Liver 2014; 46: 720–25.
22. Browning JD. Statins and hepatic steatosis: perspectives from the Dallas heart study. Hepatology 2006; 44: 466–71.
23. Pastori D, Polimeni L, Baratta F et al. The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis 2015; 47: 4–11.
24. European association for the study of the L., European association for the study of D., European association for the study of O. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64: 1388–1402.
25. Athyros VG, Tziomalos K, Gossios TD et al. for the 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: 1916–22.
26. 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.
27. 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: 878–90.
28. Loomba R, Sirlin CB, Ang B et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 2015; 61:1239–50.
29. Chan DC, Watts GF, Gan SK et al. Effect of ezetimibe on hepatic fat, inflammatory markers, and apolipoprotein B-100 kinetics in insulin-resistant obese subjects on a weight loss diet. Diabetes Care 2010; 33: 1134–9.
30. 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: 7860–8. DOI: 10.3748/wjg.v21.i25.7860
31. Hyogo H, Ikegami T, Tokushige K et al. Efficacy of pitavastatin for the treatmentof non-alcoholic steatohepatitis with dyslipidemia: an open-label, pilot study. Hepatol Res 2011; 41: 1057–65.
32. Kimura Y, Hyogo H, Yamagishi S et al. Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH. J Gastroenterol 2010; 45: 750–7. DOI: 10.1007/s00535-010-0203-y
33. Gómez-Domínguez E, Gisbert JP, Moreno-Monteagudo JA et al. A pilot study of atorvastatin treatment in dyslipemid, non alcoholic fatty liver patients. Aliment Pharmacol Ther 2006; 23: 1643–7.
34. 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: 1521–30.
35. Nascimbeni F, Pellegrini E, Lugari S et al. Statins and nonalcoholic fatty liver disease in the era of precision medicine: More friends than foes. Atherosclerosis 2019; 284: 66–74. https://doi.org/10.1016/j.atherosclerosis. 2019.02.028
36. Bishnu S, Ahammed SM, Sarkar A et al. Effects of atorvastatin on portal hemodynamics and clinical outcomes in patients with cirrhosis with portal hypertension: a proof of concept study. Eur J Gastroenterol Hepatol 2018; 30: 54–9.
37. 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: 18–23. DOI: 10.1016/j.jhep.2014.08.013
38. 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: 430–40. e1. DOI: 10.1053/j.gastro.2015.10.007
39. Ambrosino P, Lupoli R, Di Minno A et al. The risk of coronary artery disease and cerebrovascular disease in patients with hepatitis C: a systematic review and meta-analysis. Int J Cardiol 2016; 221: 746–54. DOI: 10.1016/j.ijcard.2016.06.337
40. 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 [published correction appears in Am J Gastroenterol 2018; 113: 447]. Am J Gastroenterol 2016; 111: 976–85. DOI: 10.1038/ajg.2016.179
41. Tsan Y-T, Lee Ch-Hg, Wang J-D et al. Statins and the Risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol 2012; 30: 623–30.
42. Motamed N et al. Non-alcoholic fatty liver disease (NAFLD) and 10-year risk of cardiovascular diseases. Clin Res Hepatol Gastroenterol 2017; 41: 31–8.
43. Del Ben M, Baratta F, Polimeni L et al. Under-prescription of statins in patients with non-alcoholic fatty liver disease. Nutr Metabol Cardiovasc Dis 2017; 27: 161–7.
44. Blais P, Lin M, Kramer JR et al. Statins are underutilized in patients with nonalcoholic fatty liver disease and dyslipidemia. Dig Dis Sci 2016; 61: 1714–20.
45. Labenz C, Huber Y, Kalliga E et al. Predictors of advanced fibrosis in non-cirrhotic non-alcoholic fatty liver disease in Germany. Aliment Pharmacol Ther 2018; 48: 1109–16.
46. Rzouq FS, Volk ML, Hatoum HH et al. Hepatotoxicity fears contribute to under-utilization of statin medications by primary care physicians. Am J Med Sci 2010; 340: 89–93.
47. Ekstedt M, Franzen LE, Mathiesen UL et al. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol 2007; 47 (1): 135–41.
48. Kiderman A, Ben-Dov IZ, Glikberg F, Ackerman Z. Declining frequency of liver enzyme abnormalities with statins: experience from general practice in Jerusalem. Eur J Gastroenterol Hepatol 2008; 20 (10): 1002–5.
49. Ивашкин В.Т., Маевская М.В., Павлов Ч.С. и др. Клинические рекомендации по диагностике и лечению неалкогольной жировой болезни печени Российского общества по изучению печени и Российской гастроэнтерологической ассоциации. Рос. журн. гастроэнтерологии, гепатологии и колопроктологии. 2016; 2: 24–42.
[Ivashkin V.T., Maevskaia M.V., Pavlov Ch.S. et al. Klinicheskie rekomendatsii po diagnostike i lecheniiu nealkogol'noi zhirovoi bolezni pecheni Rossiiskogo obshchestva po izucheniiu pecheni i Rossiiskoi gastroenterologicheskoi assotsiatsii. Ros. zhurn. gastroenterologii, gepatologii i koloproktologii. 2016; 2: 24–42 (in Russian).]
50. Журавлева М.В. Применение Эслидина у больных сахарным диабетом типа 2. CardioСоматика. 2011; 2 (2): 75–81.
[Zhuravleva M.V. Primenenie Eslidina u bol'nykh sakharnym diabetom tipa 2. Cardiosomatics. 2011; 2 (2): 75–81. (in Russian).]
51. Gonciarz Z, Besser P, Lelek E et al. Randomised placebo-controlled doubleblind trial on essential phospholipids in the treatment of fatty liver associated with diabetes. Med Chir Dig 1988; 17 (1): 61–5.
52. Sas E, Grinevich V, Efimov O et al Beneficial influence of polyunsaturated Phosphatidylcholine enhances functional liver condition and liver structure in patients with Nonalcoholic steatohepatitis. Results of prolonged randomized blinded prospective clinical study. J Hepatol 2013; 58: S549.
53. Un C, Zheng X, Tan Z et al. Clinical Observation on Polyene Phosphatidyl Choline and Metformin in the Treatment of Type 2 Diabetes and Non-alcoholic Fatty Liver Disease. Clin Focus 2008; 23 (17): 1272–3.
54. Yin Kong. Observation for curative effect of Essentiale in treatment of fatty liver caused by diabetes mellitus. Med J Qilu 2000; 15: 277–8.
55. Ивашкин В.Т., Маевская М.В., Широкова Е.Н., Морозова М.А. Опыт применения препарата Эслидин у пациентов с неалкогольной жировой болезнью печени в практике врача амбулаторного звена (Global Observation of Liver Disease treatment with Eslidin®, «GOLD»). РМЖ. 2015; 21: 1272–7.
[Ivashkin V.T., Maevskaia M.V., Shirokova E.N., Morozova M.A. Opyt primeneniia preparata Eslidin u patsientov s nealkogol'noi zhirovoi bolezn'iu pecheni v praktike vracha ambulatornogo zvena (Global Observation of Liver Disease treatment with Eslidin®, "GOLD"). RMZh. 2015; 21: 1272–7 (in Russian).]
56. Finkelstein JD, Martin JJ. Methionine metabolism in mammals. Distribution of homocysteine between competing pathways. J Biol Chem 1984; 259: 9508–13.
57. Fernandez A, Matías N, Martínez L et al. Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-l-methionine and glutathione. J Biol Chem 2010; 285: 18528–36.
58. Moundras C, Rémésy C, Levrat MA, Demigné C. Methionine deficiency in rats fed soy protein induces hypercholesterolemia and potentiates lipoprotein susceptibility to peroxidation. Metabolism 1995; 44: 1146–52.
59. Dhar I, Lysne V, Seifert R et al. Plasma methionine and risk of acute myocardial infarction: Effect modification by established risk factors. Atherosclerosis 2018; 272: 175–81. https://doi.org/10.1016/j.atherosclerosis. 2018.03.038
60. Бубнова М.Г., Аронов Д.М., Евдаков В.А. Гиполипидемическая и гепатопротекторная эффективность фиксированной комбинации эссенциальных фосфолипидов с метионином на фоне терапии аторвастатином у больных с сердечно-сосудистыми заболеваниями и сахарным диабетом 2 типа, страдающих гиперлипидемией (исследование ОЛИМП, часть I). CardioСоматика. 2012; 3 (3): 82–93.
[Bubnova M.G., Aronov D.M., Evdakov V.A. Gipolipidemicheskaia i gepatoprotektornaia effektivnost' fiksirovannoi kombinatsii essentsial'nykh fosfolipidov s metioninom na fone terapii atorvastatinom u bol'nykh s serdechno-sosudistymi zabolevaniiami i sakharnym diabetom 2 tipa, stradaiushchikh giperlipidemiei (issledovanie OLIMP, chast' I). Cardiosomatics. 2012; 3 (3): 82–93 (in Russian).]
61. Бубнова М.Г., Аронов Д.М., Евдаков В.А., Выгодин В.А. Влияние аторвастатина при монотерапии и в комбинации с эссенциальными фосфолипидами на показатели углеводного обмена, функцию эндотелия и маркеры воспаления у больных с сердечно-сосудистыми заболеваниями и сахарным диабетом типа 2 в сочетании с гиперлипидемией (исследование ОЛИМП, часть II). CardioСоматика. 2012; 3 (4): 28–37.
[Bubnova M.G., Aronov D.M., Evdakov V.A., Vygodin V.A. Vliianie atorvastatina pri monoterapii i v kombinatsii s essentsial'nymi fosfolipidami na pokazateli uglevodnogo obmena, funktsiiu endoteliia i markery vospaleniia u bol'nykh s serdechno-sosudistymi zabolevaniiami i sakharnym diabetom tipa 2 v sochetanii s giperlipidemiei (issledovanie OLIMP, chast' II). Cardiosomatics. 2012; 3 (4): 28–37 (in Russian).]
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64. Biddinger SB, Hernandez-Onj A, Rask-Madsen C et al. Hepatic insulin resistance to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab 2008; 7: 125–34.
65. Ioannou GN, Weiss NS, Boyko EJ et al. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology 2006; 43: 1145–51.
66. Lee D-H, Silventoinen K, Hu G et al. Serum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28 838 middle-aged men and women. Eur Heart J 2006; 27: 2170–6.
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60. Bubnova M.G., Aronov D.M., Evdakov V.A. Gipolipidemicheskaia i gepatoprotektornaia effektivnost' fiksirovannoi kombinatsii essentsial'nykh fosfolipidov s metioninom na fone terapii atorvastatinom u bol'nykh s serdechno-sosudistymi zabolevaniiami i sakharnym diabetom 2 tipa, stradaiushchikh giperlipidemiei (issledovanie OLIMP, chast' I). Cardiosomatics. 2012; 3 (3): 82–93 (in Russian).
61. Bubnova M.G., Aronov D.M., Evdakov V.A., Vygodin V.A. Vliianie atorvastatina pri monoterapii i v kombinatsii s essentsial'nymi fosfolipidami na pokazateli uglevodnogo obmena, funktsiiu endoteliia i markery vospaleniia u bol'nykh s serdechno-sosudistymi zabolevaniiami i sakharnym diabetom tipa 2 v sochetanii s giperlipidemiei (issledovanie OLIMP, chast' II). Cardiosomatics. 2012; 3 (4): 28–37 (in Russian).
62. Younossi Z, Anstee QM, Marietti M et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018; 15 (1): 11–20.
63. Trombetta M, Spiazzi G, Zoppini G, Muggeo M. Review article: type 2 diabetes and chronic liver disease in the Verona diabetes study. Aliment Pharmacol Ther 2005; 22 (Suppl. 2): 24–7.
64. Biddinger SB, Hernandez-Onj A, Rask-Madsen C et al. Hepatic insulin resistance to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab 2008; 7: 125–34.
65. Ioannou GN, Weiss NS, Boyko EJ et al. Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States. Hepatology 2006; 43: 1145–51.
66. Lee D-H, Silventoinen K, Hu G et al. Serum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28 838 middle-aged men and women. Eur Heart J 2006; 27: 2170–6.
Авторы
М.Г. Бубнова*1, Л.Е. Парнес2
1 ФГБОУ «Национальный медицинский исследовательский центр профилактической медицины» Минздрава России, Москва, Россия;
2 ГБУЗ «Городская клиническая больница им. М.Е. Жадкевича» Департамента здравоохранения г. Москвы, Москва, Россия
*mbubnova@gnicpm.ru
1 National Medical Research Center for Preventive Medicine, Moscow, Russia;
2 Zhadkevich City Clinical Hospital, Moscow, Russia
*mbubnova@gnicpm.ru
1 ФГБОУ «Национальный медицинский исследовательский центр профилактической медицины» Минздрава России, Москва, Россия;
2 ГБУЗ «Городская клиническая больница им. М.Е. Жадкевича» Департамента здравоохранения г. Москвы, Москва, Россия
*mbubnova@gnicpm.ru
________________________________________________
1 National Medical Research Center for Preventive Medicine, Moscow, Russia;
2 Zhadkevich City Clinical Hospital, Moscow, Russia
*mbubnova@gnicpm.ru
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