gastro-jРоссийский журнал гастроэнтерологии, гепатологии, колопроктологииRussian Journal of Gastroenterology, Hepatology, Coloproctology1382-43762658-6673«Gastro» LLC10.22416/1382-4376-2019-29-1-24-30gastro-j-322Research ArticleОБЗОРЫREVIEWSГепатопротекция с использованием L-орнитина-L-аспартата при неалкогольной жировой болезни печениHepatoprotection by L-Ornithine L-Aspartate in Non-Alcoholic Fatty Liver DiseaseБаттервортР. Ф.ButterworthRoger F.rb@enceph.comКанбэйА.CanbayAliМонреальский университет (Больница св. Луки), Монреаль, КвебекКанадаUniversity of Montreal (St-Luc Hospital), Montreal, QCCanadaМагдебургский университет (университетская клиника), МагдебургГерманияUniversity of Magdeburg (University Hospital), MagdeburgGermany2019290320192912430Copyright © Баттерворт Р.Ф., Канбэй А., 20192019Баттерворт Р.Ф., Канбэй А.Butterworth R.F., Canbay A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.gastro-j.ru/jour/article/view/322Общая информация

Общая информация. Во всем мире неалкогольная жировая болезнь печени (НАЖБП) является лидером среди хронических заболеваний печени, при этом число новых методов контроля и лечения является ограниченным.

Резюме

Резюме. L-орнитин-L-аспартат (LOLA) обладает гепатопротекторными свойствами у пациентов с жировой инфильтрацией печени различной этиологии, а результаты многоцентрового рандомизированного клинического исследования продемонстрировали, что 12-недельное лечение принимаемым внутрь L-орнитином-L-аспартатом (6–9 г/день) приводит к дозозависимому уменьшению активности ферментов печени и уровня триглицеридов, а также к значимым улучшениям соотношений плотности печени/селезенки на КТ. В предварительном отчете описано улучшение печеночной микроциркуляции у пациентов с неалкогольным стеатогепатитом (НАСГ) после лечения L-орнитином-L-аспартатом. Механизмы, обеспечивающие благоприятное действие L-орнитина-L-аспартата при неалкогольной жировой дистрофии печени / неалкогольном стеатогепатите, помимо доказанного эффекта — снижения уровня аммиака, включают метаболические трансформации компонентов LOLA (аминокислот L-орнитина и L-аспартата) в L-глутамин, L-аргинин и глутатион. Действие этих метаболитов установлено и заключается в предотвращении перекисного окисления липидов, улучшении печеночной микроциркуляции, кроме того, они обладают противовоспалительными и антиоксидантными свойствами.

Ключевые положения

Ключевые положения. (1) L-орнитин-L-аспартат эффективно улучшает ключевые проявления неалкогольной жировой дистрофии печени/неалкогольного стеатогепатита; (2) были предложены и описаны новые механизмы действия LOLA, отличные от снижения уровня аммиака; (3) в настоящее время необходимо проведение дальнейших исследований в клинических условиях.

Background

Background. Non-alcoholic fatty liver disease (NAFLD) is the leading chronic hepatic condition worldwide and new approaches to management and treatment are limited.

Summary

Summary. L-ornithine L-aspartate (LOLA) has hepatoprotective properties in patients with fatty liver of diverse etiology and results of a multicenter randomized clinical trial reveal that 12 weeks treatment with oral LOLA (6–9 g/d) results in a dose-related reduction in activities of liver enzymes and triglycerides together with significant improvements of liver/spleen CT ratios. A preliminary report described improvements of hepatic microcirculation in patients with nonalcoholic steatohepatitis (NASH) following treatment with LOLA. Mechanisms responsible for the beneficial effects of LOLA in NAFLD/NASH involve, in addition to its established ammonia-lowering effect, metabolic transformations of the LOLA-constituent amino acids L-ornithine and L-aspartate into L-glutamine, L-arginine, and glutathione. These metabolites have well-established actions implicated in the prevention of lipid peroxidation, improvement of hepatic microcirculation in addition to anti-inflammatory, and anti-oxidant properties.

Key messages

Key messages. (1) LOLA is effective for the treatment of key indices in NAFLD/NASH. (2) Mechanisms other than LOLA’s ammonia-lowering action have been postulated. (3) Further assessments in the clinical setting are now required.

L-орнитин-L-аспартатнеалкогольная жировая болезнь печенинеалкогольный стеатогепатитгепатопротекцияантиоксидантпеченочная микроциркуляцияглутаминL-ornithine L-aspartatenon-alcoholic fatty liver diseasenon-alcoholic steatohepatitishepatoprotectionantioxidanthepatic microcirculationglutamineИсследование частично финансировано Канадскими институтами исследований в области здравоохранения (CIHR).Study funded in part by The Canadian Institutes of Health Research (CIHR).ReferencesBlachier M., Leleu H., Peck-Radosavljevic M., Valla D.C., Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58:593–608.Blachier M., Leleu H., Peck-Radosavljevic M., Valla D.C., Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58:593–608.Felipo V., Urios A., Montesinos E. et al. Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. Metab Brain Dis. 2012;27:51–8.Felipo V., Urios A., Montesinos E. et al. Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. Metab Brain Dis. 2012;27:51–8.Gutierez-de-Juan V., Lopez de Davalilo S., FernandezRamos D. et al. A morphological method for ammonia detection in liver. PLoS One. 2017;12:e0173914.Gutierez-de-Juan V., Lopez de Davalilo S., FernandezRamos D. et al. A morphological method for ammonia detection in liver. PLoS One. 2017;12:e0173914.Butterworth R.F., Kircheis G., Hilger N., McPhail M.J.W. Effect of L-ornithine L-aspartate for the treatment of hepatic encephalopathy and hyperammonemia in cirrhosis: systematic review and meta-analysis of randomized controlled trials. J Clin Exp Hepatol. 2018. DOI: 10.1016/j.jceh.2018.05.004Butterworth R.F., Kircheis G., Hilger N., McPhail M.J.W. Effect of L-ornithine L-aspartate for the treatment of hepatic encephalopathy and hyperammonemia in cirrhosis: systematic review and meta-analysis of randomized controlled trials. J Clin Exp Hepatol. 2018. DOI: 10.1016/j.jceh.2018.05.004Grungreiff K., Lambert-Baumann J. Efficacy of L-ornithine L-aspartate granules in chronic liver diseases. Med Welt. 2001;52:219–26.Grungreiff K., Lambert-Baumann J. Efficacy of L-ornithine L-aspartate granules in chronic liver diseases. Med Welt. 2001;52:219–26.Tian L.Y., Lu L.G., Tang C.W., Xie Y., Luo H.S., Tan S.Y. et al. Aspartate-ornithine granules in the treatment of non-alcoholic steatohepatitis: a multiple-dose parallel controlled clinical trial. Zhonghua Gan Zang Bing Za Zhi. 2013;21:528–32.Tian L.Y., Lu L.G., Tang C.W., Xie Y., Luo H.S., Tan S.Y. et al. Aspartate-ornithine granules in the treatment of non-alcoholic steatohepatitis: a multiple-dose parallel controlled clinical trial. Zhonghua Gan Zang Bing Za Zhi. 2013;21:528–32.Ermolova T., Ermolov S. Correction of intrahepatic microcirculation disorders by L-ornithine L-aspartate in chronic liver disease patients. J Hepatol. 2018;68(Suppl 1):S585–6.Ermolova T., Ermolov S. Correction of intrahepatic microcirculation disorders by L-ornithine L-aspartate in chronic liver disease patients. J Hepatol. 2018;68(Suppl 1):S585–6.Kaiser S., Gerok W., Haussinger D. Ammonia and glutamine metabolism in human liver slices: new aspects on the pathogenesis of hyperammonaemia in chronic liver disease. Eur J Clin Invest. 1988;18:535–42.Kaiser S., Gerok W., Haussinger D. Ammonia and glutamine metabolism in human liver slices: new aspects on the pathogenesis of hyperammonaemia in chronic liver disease. Eur J Clin Invest. 1988;18:535–42.Bhanji R.A., Narayanan P., Allen A.M., Watt K.D. Sarcopenia in hiding: the risk and consequence of underestimating muscle dysfunction in non-alcoholic steatohepatitis. Hepatology. 2017;66:2055–65.Bhanji R.A., Narayanan P., Allen A.M., Watt K.D. Sarcopenia in hiding: the risk and consequence of underestimating muscle dysfunction in non-alcoholic steatohepatitis. Hepatology. 2017;66:2055–65.Reynolds N., Downie K., Smith K., Kircheis G., Rennie M.J. Treatment with L-Ornithine L-Aspartate (LOLA) infusion restores muscle protein synthesis responsiveness to feeding in patients with cirrhosis. J Hepatol. 1999;30(Suppl 1):3.Reynolds N., Downie K., Smith K., Kircheis G., Rennie M.J. Treatment with L-Ornithine L-Aspartate (LOLA) infusion restores muscle protein synthesis responsiveness to feeding in patients with cirrhosis. J Hepatol. 1999;30(Suppl 1):3.Pasha Y., Leech R., Violante I.R., Cook N., Crossey M.M.E., Taylor-Robinson S.D. The brain-muscle axis in minimal hepatic encephalopathy (MHE): a placebo-controlled, longitudinal double-blind trial with L-ornithine Laspartate (LOLA) — preliminary results. J Clin Exp Hepatol. 2017;7:S1–S21.Pasha Y., Leech R., Violante I.R., Cook N., Crossey M.M.E., Taylor-Robinson S.D. The brain-muscle axis in minimal hepatic encephalopathy (MHE): a placebo-controlled, longitudinal double-blind trial with L-ornithine Laspartate (LOLA) — preliminary results. J Clin Exp Hepatol. 2017;7:S1–S21.Kumar A., Davuluri G., Silva R.N.E., Engelen M.P.K.J., Ten Have G.A.M., Prayson R. et al. Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis. Hepatology. 2017;65:2045–58.Kumar A., Davuluri G., Silva R.N.E., Engelen M.P.K.J., Ten Have G.A.M., Prayson R. et al. Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis. Hepatology. 2017;65:2045–58.Rose C., Michalak A., Pannunzio P., Therrien G., Quack G., Kircheis G. et al. L-ornithine Laspartate in experimental portal-systemic encephalopathy: therapeutic efficacy and mechanism of action. Metab Brain Dis. 1998;13:147–57.Rose C., Michalak A., Pannunzio P., Therrien G., Quack G., Kircheis G. et al. L-ornithine Laspartate in experimental portal-systemic encephalopathy: therapeutic efficacy and mechanism of action. Metab Brain Dis. 1998;13:147–57.Staedt U., Leweling H., Gladisch R., Kortsik C., Hagmuller E., Holm E. Effects of ornithine aspartate on plasma ammonia and plasma aminoacids in patients with cirrhosis. A doubleblind, randomized study using a four-fold crossover design. J Hepatol. 1993;19:424–30.Staedt U., Leweling H., Gladisch R., Kortsik C., Hagmuller E., Holm E. Effects of ornithine aspartate on plasma ammonia and plasma aminoacids in patients with cirrhosis. A doubleblind, randomized study using a four-fold crossover design. J Hepatol. 1993;19:424–30.Stangl R., Szijarto A., Onody P., Tamas J., Tatrai M., Hegedus V. et al. Reduction of liver ischemia-reperfusion injury via glutamine pretreatment. J Surg Res. 2011;166:95–103.Stangl R., Szijarto A., Onody P., Tamas J., Tatrai M., Hegedus V. et al. Reduction of liver ischemia-reperfusion injury via glutamine pretreatment. J Surg Res. 2011;166:95–103.Peng H.C., Chen Y.L., Chen J.R., Yang S.S., Huang K.H., Wu Y.C. et al. Effects of glutamine administration on inflammatory responses in chronic ethanol-fed rats. J Nutr Biochem. 2011;22:282–8.Peng H.C., Chen Y.L., Chen J.R., Yang S.S., Huang K.H., Wu Y.C. et al. Effects of glutamine administration on inflammatory responses in chronic ethanol-fed rats. J Nutr Biochem. 2011;22:282–8.Lin Z., Cai F., Lin N., Ye J., Zheng Q., Ding G. Effects of glutamine on oxidative stress and nuclear factor-κB expression in the livers of rats with non-alcoholic fatty liver disease. Exp Ther Med. 2014;7:365–70.Lin Z., Cai F., Lin N., Ye J., Zheng Q., Ding G. Effects of glutamine on oxidative stress and nuclear factor-κB expression in the livers of rats with non-alcoholic fatty liver disease. Exp Ther Med. 2014;7:365–70.Sellmann C., Jin C.J., Degen C., De Bandt J.P., Bergheim I. Oral glutamine supplementation protects female mice from non-alcoholic steatohepatitis. J Nutr. 2015;145:2280–6.Sellmann C., Jin C.J., Degen C., De Bandt J.P., Bergheim I. Oral glutamine supplementation protects female mice from non-alcoholic steatohepatitis. J Nutr. 2015;145:2280–6.Najmi A.K., Pillai K.K., Pal S.N., Akhtar M., Aqil M., Sharma M. Effect of L-ornithine L-aspartate against thioacetamide-induced hepatic damage in rats. Ind J Pharmacol. 2010;42:384–7.Najmi A.K., Pillai K.K., Pal S.N., Akhtar M., Aqil M., Sharma M. Effect of L-ornithine L-aspartate against thioacetamide-induced hepatic damage in rats. Ind J Pharmacol. 2010;42:384–7.Adams L.A., Angelo P. Treatment of non-alcoholic fatty liver disease. Postgrad Med J. 2006;82:315–22.Adams L.A., Angelo P. Treatment of non-alcoholic fatty liver disease. Postgrad Med J. 2006;82:315–22.Ramalho F.S., Fernandez-Monteiro I., Rosello-Catafau J., Peralta C. Hepatic microcirculatory failure. Acta Cir Bras. 2006;21:48–53.Ramalho F.S., Fernandez-Monteiro I., Rosello-Catafau J., Peralta C. Hepatic microcirculatory failure. Acta Cir Bras. 2006;21:48–53.Kus K., Walczak M., Maslak E., Zakrzewska A., Gonciarz-Dytman A., Zabielski P. et al. Hepatoselective Nitric Oxide (NO) Donors, VPYRRO/NO and V-PROLI/ NO, in non-alcoholic fatty liver disease: a comparison of antisteatotic effects with the biotransformation and pharmacokinetics. Drug Metab Dispos. 2015;43:1028–36.Kus K., Walczak M., Maslak E., Zakrzewska A., Gonciarz-Dytman A., Zabielski P. et al. Hepatoselective Nitric Oxide (NO) Donors, VPYRRO/NO and V-PROLI/ NO, in non-alcoholic fatty liver disease: a comparison of antisteatotic effects with the biotransformation and pharmacokinetics. Drug Metab Dispos. 2015;43:1028–36.Ijaz S., Yang W., Winslet M.C., Seifalian A.M. The role of nitric oxide in the modulation of hepatic microcirculation and tissue oxygenation in an experimental animal model of hepatic steatosis. Microvasc Res. 2005;70:129–36.Ijaz S., Yang W., Winslet M.C., Seifalian A.M. The role of nitric oxide in the modulation of hepatic microcirculation and tissue oxygenation in an experimental animal model of hepatic steatosis. Microvasc Res. 2005;70:129–36.

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