Hyperammonemia as a manifestation of post-covid syndrome in patients with nonalcoholic fatty liver disease: post-hoc analysis of the LIRA - COVID observational clinical program

Post-Covid syndrome (PCS) is considered as a consequence of a previous coronavirus infection. The liver in COVID-19 is one of the most frequently affected organs, with the development of asthenia, cognitive impairment, as well as increased activity of alanine and aspartic transaminases (ALT and AST), which persist in some patients up to 4-6 months after discharge from the hospital. The cause of asthenia may be hyperammonemia (HA), which in COVID-19 is a manifestation of liver dysfunction against the background of the direct cytotoxic effect of SARS-CoV-2 on hepatocytes, which was previously shown as part of the clinical observational program protocol “LIRA - COVID”. Due to the great relevance of the problem of the combination of PCS, non-alcoholic fatty liver disease (NAFLD) and HA a post-hoc analysis of the observational clinical program LIRA - COVID was carried out. It was shown that NAFLD has a significant effect on the level of AST before the start of treatment with L-ornithine - L-aspartate (LOLA). The presence of NAFLD has a significant effect on ammonia levels after 14 days of treatment, since in the group of patients with NAFLD the ammonia level was significantly higher than in the group without NAFLD. It was concluded that it is advisable to include in the examination scheme of patients with PCS and NAFLD, determination of the level of ammonia in the blood, when elevated, the administration of the drug to such patients is justified LOLA course for 4 weeks at a standard dose of 9 g per day.

post covid syndrome, hyperammonemia, NAFLD

1. Lazebnik L.B., Turkina S. V., Myazin R. G. et al. Results of a multicenter prospective observational study “Clinical significance of hyperammonemia in patients with post-Covid syndrome (LIRA - COVID)”: efficacy of L-ornithine L-aspartate. Experimental and Clinical Gastroenterology. 2022;(11):5-16. (In Russ.) doi: 10.31146/1682-8658-ecg-207-11-5-16.@@ Лазебник Л. Б., Туркина С. В., Мязин Р. Г. и соавт. Эффективность L-орнитин L-аспартата (LOLA) для коррекции когнитивных и гепатотропных расстройств в постковидном периоде: результаты многоцентрового проспективного наблюдательного исследования «Клиническое значение гипераммониемии у пациентов с постковидным синдромом (ЛИРА-COVID)». Экспериментальная и клиническая гастроэнтерология. 2022;(11):5-16. doi: 10.31146/1682-8658-ecg-207-11-5-16.

2. Raveendran A.V., Jayadevan R., Sashidharan S. Long COVID: An overview. Diabetes Metab Syndr. 2021;15(3):869-875. doi: 10.1016/j.dsx.2021.04.007.

3. Maev I.V., Andreev D. N., Kucheryavyy Yu. A. Prevalence of non-alcoholic fat disease liver in Russian Federation: meta-analysis. Consilium Medicum. 2023;25(5):313-319. (In Russ.) doi: 10.26442/20751753.2023.5.202155.@@ Маев И. В., Андреев Д. Н., Кучерявый Ю. А. Распространенность неалкогольной жировой болезни печени в России: метаанализ. Consilium Medicum. 2023;25(5):313-319. doi: 10.26442/20751753.2023.5.202155.

4. Pan L., Mu M., Yang P., Et al. Clinical Characteristics of COVID-19 Patients With Digestive Symptoms in Hubei, China: A Descriptive, Cross- Sectional, Multicenter Study. Am J Gastroenterol. 2020;115(5):766-773. doi: 10.14309/ajg.0000000000000620.

5. Sachdeva S, Khandait H, Kopel J. et al. NAFLD and COVID-19: a Pooled Analysis. SN Compr Clin Med. 2020;2(12):2726-2729. doi: 10.1007/s42399-020-00631-3.

6. Alekseenko S.A., Ageeva E. A., Polkovnikova О. P. Modern approaches to diagnostics and treatment of hyperammonemia in patients with chronic liver disease at a precirrhotic stage. RMJ. Medical Review. 2018;7(1):19-23. (In Russ.)@@ Алексеенко С. А., Агеева Е. А., Полковникова О. П. Современные подходы к диагностике и лечению гипераммониемии у пациентов с хроническими заболеваниями печени на доцирротической стадии. РМЖ. Медицинское обозрение. 2018;7(1):19-23.

7. Ermolova T.V., Ermolov S. Yu., Belova A. A. Ammonia - new therapeutic target for chronic liver diseases. Experimental and Clinical Gastroenterology. 2020; 4(176):5-16. (In Russ.) doi: 10.31146/1682-8658-ecg-176-4-24-30.@@ Ермолова Т. В., Ермолов С. Ю., Белова А. А. Аммиак - новая терапевтическая мишень при хронических заболеваниях печени. Экспериментальная и клиническая гастроэнтерология. 2020; 4(176):24-30. doi: 10.31146/1682-8658-ecg-176-4-24-30.

8. Chen F., Chen W., Chen J. et al. Clinical features and risk factors of COVID-19-associated liver injury and function: A retrospective analysis of 830 cases. Ann Hepatol. 2021;21:100267. doi: 10.1016/j.aohep.2020.09.01126.

9. Ridruejo E., Soza A. The liver in times of COVID-19: What hepatologists should know. Ann Hepatol. 2020 JulAug;19(4):353-358. doi: 10.1016/j.aohep.2020.05.001.

10. Lazebnik L.B., Golovanova E. V., Alekseenko S. A. et al.Russian Consensus on “Hyperammonemia in Adults”: The 2021 Version (in English). Experimental and Clinical Gastroenterology. 2021;(12):154-172. doi: 10.31146/1682-8658-ecg-196-12-154-172.

11. Riazi K., Azhari H., Charette J. H., Underwood F. E. et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7(9):851-861. doi: 10.1016/S2468-1253(22)00165-0.

12. Portincasa P., Krawczyk M., Smyk W., Lammert F., Di Ciaula A. COVID-19 and non-alcoholic fatty liver disease: Two intersecting pandemics. Eur J Clin Invest. 2020;50(10): e13338. doi: 10.1111/eci.13338.

13. Thomsen K.L., Eriksen P. L., Kerbert A. J. et al. Role of ammonia in NAFLD: An unusual suspect. JHEP Rep. 2023;5(7):100780. doi: 10.1016/j.jhepr.2023.100780.

14. Aldridge D.R., Tranah E. J., Shawcross D. L. Pathogenesis of hepatic encephalopathy: role of ammonia and systemic inflammation. J Clin Exp Hepatol. 2015;5(Suppl 1): S7-S20. doi: 10.1016/j.jceh.2014.06.004.

15. 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(1):51-8. doi: 10.1007/s11011-011-9269-3.

16. Jalan R., De Chiara F., Balasubramaniyan V. et al. Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension. J Hepatol. 2016(4):823-33. doi: 10.1016/j.jhep.2015.11.019.

17. Mukhametova D.D., Belousova E. N., Fashieva Z. I. et al. Evaluation of Hyperammonemia and Cognitive Impairment in post-COVID patients. Experimental and Clinical Gastroenterology. 2023;(8):66-72. (In Russ.) doi: 10.31146/1682-8658-ecg-216-8-66-72.@@ Мухаметова Д. Д., Белоусова Е. Н., Фасхиева З. И. и соавт. Оценка гипераммониемии и когнитивных нарушений у пациентов в постковидном периоде. Экспериментальная и клиническая гастроэнтерология. 2023;(8):66-72. doi: 10.31146/1682-8658-ecg-216-8-66-72.

18. Milic J., Barbieri S., Gozzi L. et al. Metabolic-Associated Fatty Liver Disease Is Highly Prevalent in the Postacute COVID Syndrome. Open Forum Infect Dis. 2022 Jan 10;9(3): ofac003. doi: 10.1093/ofid/ofac003.

19. Hadizadeh F., Faghihimani E., Adibi P. Nonalcoholic fatty liver disease: Diagnostic biomarkers. World J Gastrointest Pathophysiol. 2017 May 15;8(2):11-26. doi: 10.4291/wjgp.v8.i2.11.

20. Plotnikova E.Y., Sinkova M. N., Isakov L. K. Asthenia and fatigue in hyperammonemia: etiopathogenesis and methods of correction. Medical Council. 2021;(21-1):95-104. (In Russ). doi: 10.21518/2079-701X-2021-21-1-95-104.@@ Плотникова Е. Ю., Синькова М. Н., Исаков Л. К. Астения и утомление при гипераммониемии: этиопатогенез и методы коррекции. Медицинский совет. 2021;(21-1):95-104. doi: 10.21518/2079-701X-2021-21-1-95-104.

21. Sas E. I. Use of L-ornithine-L-aspartate in patients with non-alcoholic fatty liver disease. Medical alphabet. 2018;1(7):17-21. (In Russ.)@@ Сас Е. И. Применение L-орнитина-L-аспартата у пациентов с неалкогольной жировой болезнью печени. Медицинский алфавит. 2018;1(7):17-21.

22. Butterworth R.F., Canbay A. Hepatoprotection by L-Ornithine L-Aspartate in Non-Alcoholic Fatty Liver Disease. Dig Dis. 2019;37(1):63-68. doi: 10.1159/000491429.

23. Canbay A., Sowa J. P. L-Ornithine L-Aspartate (LOLA) as a Novel Approach for Therapy of Non-alcoholic Fatty Liver Disease. Drugs. 2019;79(Suppl 1):39-44. doi: 10.1007/s40265-018-1020-5.

24. Butterworth R.F., Canbay A. Hepatoprotection by L-Ornithine L-Aspartate in Non-Alcoholic Fatty Liver Disease.Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2019;29(1):24-30. (In Russ.) doi: 10.22416/1382-4376-2019-29-1-24-30.@@ Баттерворт Р. Ф., Канбэй А. Гепатопротекция с использованием L-орнитина-L-аспартата при неалкогольной жировой болезни печени. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2019;29(1):24-30. doi: 10.22416/1382-4376-2019-29-1-24-30.

25. 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. Indian J Pharmacol. 2010;42(6):384-7. doi: 10.4103/0253-7613.71926.

26. Kizova E. A., Potekhina Yu. P. Effect of l-ornithine-l-aspartate therapy on the hyperammonemia level and results of the number connection test of patients suffering from nonalcoholic fatty liver disease. Experimental and Clinical Gastroenterology. 2019;169(9): 80-84. (In Russ.) doi: 10.31146/1682-8658-ecg-169-9-80-84.@@ Кизова Е. А., Потехина Ю. П. Влияние терапии препаратом l-орнитин-l-аспартат на уровень гипераммониемии и результаты теста связывания чисел у пациентов с неалкогольной жировой болезнью печени. Экспериментальная и клиническая гастроэнтерология. 2019;169(9): 80-84. doi: 10.31146/1682-8658-ecg-169-9-80-84.

27. Garanina E. V. Effect of L-Ornithine-L-Aspartate on Liver Fibrosis and Steatosis in Patients with Metabolic-Associated Fatty Liver Disease (Non-alcoholic Fatty Liver Disease) and Hyperammonaemia.Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2021;31(4):31-36. (In Russ.) doi: 10.22416/1382-4376-2021-31-4-31-36.@@ Гаранина Е. В. Влияние курсового приема L-орнитин-L-аспартата на фиброз и стеатоз печени у больных ассоциированной с нарушениями метаболизма жировой болезнью печени (неалкогольной жировой болезнью печени), имеющих гипераммониемию. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2021;31(4):31-36. doi: 10.22416/1382-4376-2021-31-4-31-36.