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

Epidemiological data suggests that approximately 10-65% of patients with mild to moderate COVID-19 have persistent symptoms already after an acute infection, which may last for six months or more. Previous clinical studies have shown that similar symptoms may also occur in the liver. Russian scientists have studied the phenomenon of hyperammonemia in the acute phase of COVID-19, but the problem of elevated blood ammonia levels in post - COVID syndrome has not been studied before. One possible option for the correction of hyperammonemia is the L-ornithine - L-aspartate (LOLA) preparation. The aim of the study was to investigate the manifestation of hyperammonemia in post - COVID syndrome and the possibility of its correction by using LOLA. Eighty-three patients (mean age 51.71 ± 12.82) with post-COVID syndrome, attention and memory impairment, chronic fatigue, hyperammonemia, 2-fold increase of alanine transaminase (ALT) and aspartate transaminase (AST) levels were included into multicenter, prospective observational study. L-ornithine-L-aspartate (LOLA) was given (3 g 3 times per day orally) for 4 weeks to correct hyperammonemia. Patients were accessed by the number connection test (NCT), fatigue evaluation test, measurement of ammonia and ALT, AST levels at baseline, and after 4 weeks. At week 4 the ammonia level was significantly decreased in 81 patients (97.6%). Time (sec) to complete the NCT was 49,43 ± 15,85 vs 64.67 ± 24.95 at baseline (p<0.001). Before treatment, the majority of patients had stage 1 hepatic encephalopathy (HE) - 50.6% and stage 1-2 (intermediate) HE - 30.1%, stage 2 HE - 10.9%, stage 3 HE - 2.4%. After LOLA treatment, the distribution changed: 41% of patients had no HE, 36.1% had stage 1 of HE, 22.9% had stage 1-2 (intermediate) of HE, and stage 2 and 3 of HE was no longer defined. The mean score in fatigue evaluation test was 46,27 ± 10.0 vs 64,71 ± 19,18 at baseline (p<0.001). ALT and AST levels were 47,83 ± 38,21 units/l vs 95,75 ± 68.99 units/l at baseline and 40,10 ± 35,97 units/l vs 78,51 ± 90,90 units/l at baseline respectively (p<0.001). This study showed that the inclusion of LOLA in a dose of 3 g 3 times a day for 4 weeks was associated with significant improvement in the objective and subjective outcomes in patients with post-COVID syndrome.

COVID-19, hyperammonemia, LOLA, liver encephalopathy, L-ornithine-L-aspartate

1. Khasanova D. R., Zhitkova S. V., Vaskayeva G. R. Postvoid syndrome: a review of knowledge on pathogenesis, neuropsychiatric manifestations and treatment perspectives. Neurology, neuropsychiatry, psychosomatics.2021;13(3):93-98. (In Russ) doi: 10.14412/2074-2711-2021-3-93-98.@@ Хасанова Д. Р., Житкова Ю. В., Васкаева Г. Р. Постковидный синдром: обзор знаний о патогенезе, нейропсихиатрических проявлениях и перспективах лечения. Неврология, нейропсихиатрия, психосоматика.2021;13(3):93-98. (In Russ) doi: 10.14412/2074-2711-2021-3-93-98.

2. Carod-Artal F. J. Post-COVID-19 syndrome: epidemiology, diagnostic criteria and pathogenic mechanisms involved. Rev Neurol. 2021;72(11):384-396. English, Spanish. doi: 10.33588/rn.7211.2021230.

3. Pavli A., Theodoridou M., Maltezou H. C. Post-COVID Syndrome: Incidence, Clinical Spectrum, and Challenges for Primary Healthcare Professionals. Arch Med Res. 2021;52(6):575-581. doi: 10.1016/j.arcmed.2021.03.010.

4. Pazukhina E., Andreeva M., Spiridonova E., et al. Prevalence and risk factors of post-COVID-19 condition in adults and children at 6 and 12 months after hospital discharge: a prospective, cohort study in Moscow (StopCOVID). BMC Medicine. 2022; 20 (1): 1-12. doi:10.1186/s12916-022-02448-4

5. Liu T., Wu D., Yan W., et al. Twelve-Month Systemic Consequences of Coronavirus Disease 2019 (COVID-19) in Patients Discharged From Hospital: A Prospective Cohort Study in Wuhan, China. Clin Infect Dis. 2022;74(11):1953-1965. doi: 10.1093/cid/ciab703.

6. Liao X., Li D., Ma Z., et al. 12-Month Post-Discharge Liver Function Test Abnormalities Among Patients With COVID-19: A Single-Center Prospective Cohort Study. Front Cell Infect Microbiol. 2022: 431. doi: 10.3389/fcimb.2022.864933.

7. Caterino M., Costanzo M., Fedele R., et al. The Serum Metabolome of Moderate and Severe COVID-19 Patients Reflects Possible Liver Alterations Involving Carbon and Nitrogen Metabolism.Int J Mol Sci. 2021;22(17):9548. doi: 10.3390/ijms22179548.

8. Bueverov A. O. Ammonium as neuro - and hepatotoxin: clinical aspects. Medical advise. 2015; 13: 80-85. (In Russ.)@@ Буеверов А. О. Аммиак как нейро-и гепатотоксин: клинические аспекты. Медицинский совет. 2015;13: 80-85. (In Russ.)

9. Bobermin L.D., Quincozes-Santos A. COVID-19 and hyperammonemia: Potential interplay between liver and brain dysfunctions. Brain Behav Immun Health. 2021;14:100257. doi: 10.1016/j.bbih.2021.100257.

10. Lazebnik L. B., Tarasova L. V., Komarova E. A., et al. Change in concentration of ammonia and other biochemical indicators in patients with new coronaviral infection. Experimental and Clinical Gastroenterology. 2021;(4):76-83. (In Russ.) doi: 10.31146/1682-8658-ecg-188-4-76-83.@@ Лазебник Л. Б., Тарасова Л. В., Комарова Е. А. и соавт. Изменение концентрации аммиака и других биохимических показателей у пациентов с новой коронавирусной инфекцией. Экспериментальная и клиническая гастроэнтерология. 2021;188(4): 76-83. doi: 10.31146/1682-8658-ecg-188-4-76-83.

11. Lazebnik L. B., Golovanova E. V., Alekseenko S. A., et al.Russian Consensus on “Hyperammonemia in Adults”: The 2021 Version. Experimental and Clinical Gastroenterology. 2021;(12):154-172. (In Russ.) doi: 10.31146/1682-8658-ecg-196-12-154-172.@@ Лазебник Л. Б., Голованова Е. В., Алексеенко С. А. и соавт. Российский консенсус «Гипераммониемии у взрослых» (Версия 2021). Экспериментальная и клиническая гастроэнтерология. 2021;(12):154-172. (In Russ.) doi: 10.31146/1682-8658-ecg-196-12-154-172.

12. Castanares-Zapatero D., Chalon P., Kohn L., et al. Pathophysiology and mechanism of long COVID: a comprehensive review. Ann Med. 2022;54(1):1473-1487. doi: 10.1080/07853890.2022.2076901

13. Doberman L. D., Quincozes-Santos A. COVID-19 and hyperammonemia: Potential interplay between liver and brain dysfunctions. Brain, Behavior, & Immunity-Health. 2021;(14):100257.

14. Kolesova O., Vanaga I., Laivacuma S., et al.Intriguing findings of liver fibrosis following COVID-19. BMC Gastroenterology. 2021; 21 (1): 1-9 doi: 10.1186/s12876-021-01939-7.

15. 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;64(4):823-33. doi: 10.1016/j.jhep.2015.11.019.

16. Mittal V. V., Sharma B. C., Sharma P., et al. A randomized controlled trial comparing lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol. 2011;23(8):725-32. doi: 10.1097/MEG.0b013e32834696f5.

17. Alvares da Silva M. R., de Araujo A., Vicenzi J. R., et al. Oral l-ornithine-l-aspartate in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled trial. Hepatol Res. 2014;44:956-963. doi: 10.1111/hepr.12235.

18. Butterworth R. F., Kircheis G., Hilger N., et al. Efficacy 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;8(3):301-313. doi: 10.1016/j.jceh.2018.05.004.

19. Poo J. L., Góngora J., Sánchez-Avila F., et al. Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study. Ann Hepatol. 2006;5(4):281-8. doi: 10.1016/S1665-2681(19)31989-1.

20. Butterworth R., Kircheis G., Hilger N., et al. Efficacy 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 Hepat. 2018;8(3):301-313. doi:10.1016/j.jceh.2018.05.004.

21. Plotnikova E. Yu. Role of L - ornitine - L - aspartate in complex treatment patients with hyperammonemia. Clinical perspective of gastroenterology and hepatology. 2013; 2: 41-49. (In Russ.)@@ Плотникова Е. Ю. Роль L-орнитина-L-аспартата в комплексном лечении больных с гипераммониемией. Клинические перспективы гастроэнтерологии, гепатологии. 2013; 2: 41-49.

22. 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(1):39-44. doi: 10.1007/s40265-018-1020-5.

23. Ermolova T.V., Ermolov S. U., Sologub T. V., et al. Some mechanisms of intrahepatic hemodynamic disorders and its correction in chronic liver diseases with an initial stage of fibrosis. Experimental and Clinical Gastroenterology. 2018;150(2): 183-191. (In Russ)@@ Ермолова Т. В., Ермолов С. Ю., Сологуб Т. В. и соавт. Некоторые механизмы нарушений внутрипеченочной микроциркуляции при хронических заболеваниях печени на начальных стадиях фиброза и их коррекция. Экспериментальная и клиническая гастроэнтерология 2018;150(2): 183-191. (In Russ)

24. Grungreiff K., Lambert-Baumann J. Efficacy of L-ornithin-L-aspartate-granules in chronic liver diseases. MEDIZINISCHE WELT-STUTTGART. 2001; 52 (7/8): 219-226.

25. 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.

26. 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.2020.09.011.

27. Honore P.M., Barreto Gutierrez L., Kugener L., et al. Liver injury without liver failure in COVID-19 patients: how to explain, in some cases, elevated ammonia without hepatic decompensation. Crit Care. 2020 16;24(1):352. doi: 10.1186/s13054-020-03088-x.