medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2020-21-136-143medsovet-5977Research ArticleГАСТРОЭНТЕРОЛОГИЯGASTROENTEROLOGYОсобенности терапии неалкогольной жировой болезни печени у коморбидных пациентовFeatures of the therapy of non-alcoholic fatty liver disease in comorbid patientshttps://orcid.org/0000-0001-8913-140XМаевскаяМ. В.MaevskayaM. M.

д.м.н., профессор кафедры пропедевтики внутренних болезней, гастроэнтерологии и гепатологии Института клинической медицины им. Н.В.  Склифосовского,

119991, Москва, ул. Погодинская, д. 1, корп. 1

Dr. of Sci. (Med.), Professor of the Department of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology of the Institute of Clinical Medicine named after N.V. Sklifosovsky, 

8, Bldg. 2, Trubetskaya St., Moscow, 119991

liver.orc@mail.ruПервый Московский государственный медицинский университет им. И.М. Сеченова (Сеченовский Университет)РоссияSechenov First Moscow State Medical University (Sechenov University)Russian Federation202015012021021136143Copyright © Маевская М.В., 20212021Маевская М.В.Maevskaya M.M.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/5977

Проблему современной медицины и современного общества представляет собой коморбидный пациент с метаболическими нарушениями. Гипотетический портрет такого пациента: старше 40 лет, с избыточной массой тела, артериальной гипертензией, коронарным атеросклерозом, нарушением углеводного и липидного обмена, стеатозом печени или стеатогепатитом, нередко – с изменениями функции опорно-двигательного аппарата. Рациональная фармакотерапия такого пациента имеет принципиальное значение. В статье анализируются с точки зрения полипотентности, эффективности и безопасности основные препараты, которые применяются в РФ для лечения неалкогольной жировой болезни печени у коморбидных пациентов. Внимание уделено витамину Е, глицирризину, урсодезоксихолевой кислоте. Проанализированы отечественные и зарубежные исследования данных препаратов, показана сфера их рационального применения: уменьшение риска развития сердечно-сосудистых осложнений, позитивное влияние на липидный спектр, уменьшение активности сывороточных трансаминаз и другие гепатотропные эффекты. Также рассмотрены их побочные действия, которые необходимо учитывать при выборе терапии коморбидного пациента. Сделан анализ эффективности и безопасности новых молекул, которые находятся в клинических исследованиях и/или еще не зарегистрированы в нашей стране, например обетихолевая кислота, ценикривирок, тропифексор и т.д. Также освещается способность некоторых молекул выступать в качестве биологических энхансеров, что важно учитывать при назначении комбинированной терапии. Врачам рекомендуется тщательно взвешивать и учитывать все особенности коморбидного пациента и выбирать для такой категории больных безопасные препараты гепатотропного действия с одновременным позитивным эффектом на сердечно-сосудистую систему. Кроме всего прочего, это позволит избежать полипрагмазии.

The problem of modern medicine and modern society is a comorbid patient with metabolic disorders. Hypothetical portrait of such a patient: over 40 years old, overweight, arterial hypertension, coronary atherosclerosis, impaired carbohydrate and lipid metabolism, liver steatosis or steato-hepatitis, often with changes in the function of the musculoskeletal system. Rational pharmacotherapy of this patient is of fundamental importance. The article analyzes, from the point of view of polypotency, efficacy and safety, the main drugs used in Russia for treatment of non-alcoholic fatty liver disease in comorbid patients. Attention is paid to vitamin E, glycyrrhizin, ursodeoxycholic acid. Domestic and foreign studies of these drugs are analyzed, and the scope of their rational use is shown: reducing the risk of cardiovascular complications, a positive effect on the lipid spectrum, reducing the activity of serum transaminases and other hepatotropic effects. Their side effects are also considered, which should be taken into account when choosing the treatment of a comorbid patient. We have analyzed the efficacy and safety of new molecules that are in clinical trials and/or have not yet been registered in our country, e.g. obeticholic acid, cenicriviroc, tropifexor, etc. The ability of some molecules to act as biological enhancers is also highlighted, which is important to consider when prescribing combination therapy. Doctors are recommended to carefully consider and take into account all the features of a comorbid patient and choose for this category of patients safe drugs of hepatotropic action with simultaneous positive effect on the cardiovascular system. Among other things, it will avoid polypragmasy.

коморбидностьнеалкогольная жировая болезнь печенисердечно-сосудистая системагепатотропные препаратыполифункциональные молекулыбезопасностьэффективностьcomorbiditynon-alcoholic fatty liver diseasecardiovascular systemhepatotropic drugspolyfunctional moleculessafetyefficiencyReferencesYounossi Z.M., Ratziu V., Loomba R., Rinella M., Anstee Q.M., Goodman Z. et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394(10215):2184–2196. doi: 10.1016/S0140-6736(19)33041-7.Younossi Z.M., Ratziu V., Loomba R., Rinella M., Anstee Q.M., Goodman Z. et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2019;394(10215):2184–2196. doi: 10.1016/S0140-6736(19)33041-7.Ratziu V., Harrison S.A., Franque S., Bedossa P., Lehert P., Serfaty L. et al. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016;150(5):1147–1159.e5. doi: 10.1053/j.gastro.2016.01.038.Ratziu V., Harrison S.A., Franque S., Bedossa P., Lehert P., Serfaty L. et al. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 2016;150(5):1147–1159.e5. doi: 10.1053/j.gastro.2016.01.038.Pedrosa M., Seyedkazemi S., Francque S., Sanyal A., Rinella M., Charlton M. et al. A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial. Contemp Clin Trials. 2020;88:105889. doi: 10.1016/j.cct.2019.105889.Pedrosa M., Seyedkazemi S., Francque S., Sanyal A., Rinella M., Charlton M. et al. A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial. Contemp Clin Trials. 2020;88:105889. doi: 10.1016/j.cct.2019.105889.Rizzato G., Scalabrin E., Radaelli M., Capodaglio G., Piccolo O. A new exploration of licorice metabolome. Food Chem. 2017;221:959–968. doi: 10.1016/j.foodchem.2016.11.068.Rizzato G., Scalabrin E., Radaelli M., Capodaglio G., Piccolo O. A new exploration of licorice metabolome. Food Chem. 2017;221:959–968. doi: 10.1016/j.foodchem.2016.11.068.Albermann M.E., Musshoff F., Hagemeier L., Madea B. Determination of glycyrrhetic acid after consumption of liquorice and application to a fatality. Forensic Sci Int. 2010;197(1-3):35–39. doi: 10.1016/j.forsciint.2009.12.018.Albermann M.E., Musshoff F., Hagemeier L., Madea B. Determination of glycyrrhetic acid after consumption of liquorice and application to a fatality. Forensic Sci Int. 2010;197(1-3):35–39. doi: 10.1016/j.forsciint.2009.12.018.Hajiaghamohammadi A.A., Ziaee A., Samimi R. The Efficacy of Licorice Root Extract in Decreasing Transaminase Activities in Non‐alcoholic Fatty Liver Disease: A Randomized Controlled Clinical Trial. Phytother Res. 2012;26(9):1381–1384. doi: 10.1002/ptr.3728.Hajiaghamohammadi A.A., Ziaee A., Samimi R. The Efficacy of Licorice Root Extract in Decreasing Transaminase Activities in Non‐alcoholic Fatty Liver Disease: A Randomized Controlled Clinical Trial. Phytother Res. 2012;26(9):1381–1384. doi: 10.1002/ptr.3728.Ивашкин В.Т., Бакулин И.Г., Богомолов П.О., Мациевич М.В., Гейвандова Н.И., Корой П.В. и др. Результаты многоцентрового двойного слепого рандомизированного плацебоконтролируемого пострегистрационного (IV фаза) клинического исследования «Гепард» (PHG-M2/P02-12), проведенного с целью оценки эффективности и безопасности комбинированного препарата глицирризиновой кислоты и эссенциальных фосфолипидов (Фосфоглив) при неалкогольной жировой болезни печени. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2017;27(2):34–43. doi: 10.22416/1382-4376-2017-27-2-34-43.Ivashkin V.T., Bakulin I.G., Bogomolov P.O., Matsiyevich M.V., Geyvandova N.I., Koroy P.V. et al. Efficacy and safety of glycyrrhizic acid combined to essential phospholipids (Phosphogliv) at non-alcoholic fatty liver disease: results of multicenter double blind randomized placebo-controlled postregistration clinical study (IV phase) «Gepard» (PHG-M2/P02-12). Rossiyskiy zhurnal gastroehnterologii, gepatologii, koloproktologii = Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2017;27(2):34–43. (In Russ.) doi: 10.22416/1382-4376-2017-27-2-34-43.van Rossum T.G., Vulto A.G., de Man R.A., Brouwer J.T., Schalm S.W. Review article: Glycyrrhizin as a potential treatment for chronic hepatitis C. Aliment Pharmacol Ther. 1998;12(3):199–205. doi: 10.1046/j.1365-2036.1998.00309.x.van Rossum T.G., Vulto A.G., de Man R.A., Brouwer J.T., Schalm S.W. Review article: Glycyrrhizin as a potential treatment for chronic hepatitis C. Aliment Pharmacol Ther. 1998;12(3):199–205. doi: 10.1046/j.1365-2036.1998.00309.x.Kwon Y.J., Son D.H., Chung T.H., Lee Y.J. A Review of the Pharmacological Efficacy and Safety of Licorice Root from Corroborative Clinical Trial Findings. J Med Food. 2020;23(1):12–20. doi: 10.1089/jmf.2019.4459.Kwon Y.J., Son D.H., Chung T.H., Lee Y.J. A Review of the Pharmacological Efficacy and Safety of Licorice Root from Corroborative Clinical Trial Findings. J Med Food. 2020;23(1):12–20. doi: 10.1089/jmf.2019.4459.Leskinen M.H., Hautaniemi E.J., Tahvanainen A.M., Koskela J.K., Päällysaho M., Tikkakoski A.J. et al. Daily liquorice consumption for two weeks increases augmentation index and central systolic and diastolic blood pressure. PLoS One. 2014;9(8):e105607. doi: 10.1371/journal.pone.0105607.Leskinen M.H., Hautaniemi E.J., Tahvanainen A.M., Koskela J.K., Päällysaho M., Tikkakoski A.J. et al. Daily liquorice consumption for two weeks increases augmentation index and central systolic and diastolic blood pressure. PLoS One. 2014;9(8):e105607. doi: 10.1371/journal.pone.0105607.Hautaniemi E.J., Tahvanainen A.M., Koskela J.K., Tikkakoski A.J., Kähönen M., Uitto M. et al. Voluntary liquorice ingestion increases blood pressure via increased volume load, elevated peripheral arterial resistance, and decreased aortic compliance. Sci Rep. 2017;7(1):10947. doi: 10.1038/s41598-017-11468-7.Hautaniemi E.J., Tahvanainen A.M., Koskela J.K., Tikkakoski A.J., Kähönen M., Uitto M. et al. Voluntary liquorice ingestion increases blood pressure via increased volume load, elevated peripheral arterial resistance, and decreased aortic compliance. Sci Rep. 2017;7(1):10947. doi: 10.1038/s41598-017-11468-7.Mantani N., Oka H., Sahashi Y., Suzuki A. Relationship between incidence of pseudoaldosterinism and daily dose of Glycyrrhiza: Review of the literature. Kampo Med. 2015;66(3):197–202. doi: 10.3937/kampomed.66.197.Mantani N., Oka H., Sahashi Y., Suzuki A. Relationship between incidence of pseudoaldosterinism and daily dose of Glycyrrhiza: Review of the literature. Kampo Med. 2015;66(3):197–202. doi: 10.3937/kampomed.66.197.Xiaoying W., Han Z., Yu W. 14 – Glycyrrhiza glabra (Licorice): Ethnobotany and Health Benefits. In: Bagchi D. (ed.) Sustained Energy for Enhanced Human Functions and Activity. Academic Press; 2017. Available at: https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/glycyrrhizin.Xiaoying W., Han Z., Yu W. 14 – Glycyrrhiza glabra (Licorice): Ethnobotany and Health Benefits. In: Bagchi D. (ed.) Sustained Energy for Enhanced Human Functions and Activity. Academic Press; 2017. Available at: https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/glycyrrhizin.Khanuja S.P.S., Kumar S., Arya J.S., Shasany A.K., Singh M., Awasthi S. et al. Composition comprising pharmaceutical/nutraceutical agent and a bioenhancer obtained from Glycyrrhiza glabra. United States Patent. Available at: https://patents.google.com/patent/US6979471B1.Khanuja S.P.S., Kumar S., Arya J.S., Shasany A.K., Singh M., Awasthi S. et al. Composition comprising pharmaceutical/nutraceutical agent and a bioenhancer obtained from Glycyrrhiza glabra. United States Patent. Available at: https://patents.google.com/patent/US6979471B1.Golden J.M., Escobar O.H., Nguyen M.V.L., Mallicote M.U., Kavarian P., Frey M.R., Gayer C.P. Ursodeoxycholic acid protects against intestinal barrier breakdown by promoting enterocyte migration via EGFR- and COX-2-dependent mechanisms. Am J Physiol Gastrointest Liver Physiol. 2018;315(2):G259–G271. doi: 10.1152/ajpgi.00354.2017.Golden J.M., Escobar O.H., Nguyen M.V.L., Mallicote M.U., Kavarian P., Frey M.R., Gayer C.P. Ursodeoxycholic acid protects against intestinal barrier breakdown by promoting enterocyte migration via EGFR- and COX-2-dependent mechanisms. Am J Physiol Gastrointest Liver Physiol. 2018;315(2):G259–G271. doi: 10.1152/ajpgi.00354.2017.Ratziu V., Bellentani S., Cortez-Pinto H., Day C., Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol. 2010;53(2):372–384. doi: 10.1016/j.jhep.2010.04.008.Ratziu V., Bellentani S., Cortez-Pinto H., Day C., Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol. 2010;53(2):372–384. doi: 10.1016/j.jhep.2010.04.008.Mueller M., Thorrel A., Claudel T., Jha P., Koefeler H., Lackner C. et al. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J Hepatol. 2015;62(6):1398–1404. doi: 10.1016/j.jhep.2014.12.034.Mueller M., Thorrel A., Claudel T., Jha P., Koefeler H., Lackner C. et al. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J Hepatol. 2015;62(6):1398–1404. doi: 10.1016/j.jhep.2014.12.034.Xiang Z., Chen Y.P., Ma K.F., Ye Y.F., Zheng L., Yang Y.D. et al. The role of ursodeoxycholic acid in non-alcoholic steatohepatitis: a systematic review. BMC Gastroenterol. 2013;13:140. doi: 10.1186/1471-230X-13-140.Xiang Z., Chen Y.P., Ma K.F., Ye Y.F., Zheng L., Yang Y.D. et al. The role of ursodeoxycholic acid in non-alcoholic steatohepatitis: a systematic review. BMC Gastroenterol. 2013;13:140. doi: 10.1186/1471-230X-13-140.Ozel Coskin B.D., Yucesov M., Gursoy S., Baskol M., Yurci A., Yaqbasan A. et al. Effects of ursodeoxycholic acid therapy on carotid intima media thickness, apolipoprotein A1, apolipoprotein B, and apolipoprotein B/A1 ratio in nonalcoholic steatohepatitis. Eur J Gastroenterol Hepatol. 2015;27(2):142– 149. doi: 10.1097/MEG.0000000000000264.Ozel Coskin B.D., Yucesov M., Gursoy S., Baskol M., Yurci A., Yaqbasan A. et al. Effects of ursodeoxycholic acid therapy on carotid intima media thickness, apolipoprotein A1, apolipoprotein B, and apolipoprotein B/A1 ratio in nonalcoholic steatohepatitis. Eur J Gastroenterol Hepatol. 2015;27(2):142– 149. doi: 10.1097/MEG.0000000000000264.Маевская М.В., Надинская М.Ю., Луньков В.Д., Пирогова И.Ю., Чесноков Е.В., Кодзоева Х.Б., Ивашкин В.Т. Влияние урсодезоксихолевой кислоты на воспаление, стеатоз и фиброз печени и факторы атерогенеза у больных неалкогольной жировой болезнью печени: результаты исследования УСПЕХ. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2019;29(6):22–29. doi: 10.22416/1382-4376-2019-29-6-22-29.Mayevskaya M.V., Nadinskaia M.Yu., Lunkov V.D., Pirogova I.Yu., Chesnokov E.V., Kodzoeva K.B., Ivashkin V.T. An Effect of Ursodeoxycholic Acid on Inflammation, Steatosis and Liver Fibrosis and Atherogenesis Factors in Patients with Non-Alcoholic Fatty Liver Disease: Results of the USPEH Study. Rossiyskiy zhurnal gastroehnterologii, gepatologii, koloproktologii = Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2019;29(6):22–29. (In Russ.) doi: 10.22416/1382-4376-2019-29-6-22-29.Маевская М.В., Ивашкин В.Т., Ивашкин К.В., Луньков В.Д., Люсина Е.О., Зозуля В.Н., Лещенко В.И. Неалкогольная жировая болезнь печени как причина и следствие кардиометаболических осложнений. Особенности фармакотерапии. Место урсодезоксихолевой кислоты. Терапевтический архив. 2019;91(2):109–117. doi: 10.26442/00403660.2019.02.000122.Maevskaya M.V., Ivashkin V.T., Ivashkin K.V., Lunkov V.D., Liusina E.O., Zozula V.N., Leshchenko V.I. Non-alcoholic fatty liver disease as a cause and consequence of cardio-metabolic complications. Rrole of the ursodeoxicholic acid in the pharmacotherapy. Terapevticheskiy arkhiv = Therapeutic Archive. 2019;91(2):109–117. doi: 10.26442/00403660.2019.02.000122.Hempfling W., Dikger K., Beures U. Systematic review ursodeoxycholic acid – adverse effects and drug interactions. Aliment Pharmacol Ther. 2003;18(0):963–972. doi: 10.1046/j.1365-2036.2003.01792.x.Hempfling W., Dikger K., Beures U. Systematic review ursodeoxycholic acid – adverse effects and drug interactions. Aliment Pharmacol Ther. 2003;18(0):963–972. doi: 10.1046/j.1365-2036.2003.01792.x.Targher G., Marchesini G., Byrne C.D. Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon? Diabetes Metab. 2016;42(3):142–156. doi: 10.1016/j.diabet.2016.04.002.Targher G., Marchesini G., Byrne C.D. Risk of type 2 diabetes in patients with non-alcoholic fatty liver disease: Causal association or epiphenomenon? Diabetes Metab. 2016;42(3):142–156. doi: 10.1016/j.diabet.2016.04.002.Targher G., Byrne C.D., Lonardo A., Zoppini G., Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A metaanalysis. J Hepatol. 2016;65(3):589–600. doi: 10.1016/j.jhep.2016.05.013.Targher G., Byrne C.D., Lonardo A., Zoppini G., Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A metaanalysis. J Hepatol. 2016;65(3):589–600. doi: 10.1016/j.jhep.2016.05.013.

The authors declare that there are no conflicts of interest present.