HYPERAMMONIUM IN PATIENTS WITH PRECIRRHOSIS STAGE: CLINICAL REALITY?

Ammonia belongs to the common neuro- and cytotoxic metabolites in the human. It is established that ammonia has hepatotoxic properties. Ammonia induces the formation of oxygen active forms, reduces the activity of endothelial NO synthase, dose-dependently decreases the cellular metabolism and proliferation of stellate cells, and promotes fibrogenesis, disturbance of intrahepatic hemodynamics and, accordingly, the formation of portal hypertension. The article demonstrates causes of hyperammonemia in pathological conditions and disturbance of physiological functions. The increased level of ammonia is associated not only with various neuropsychiatric disorders in liver cirrhosis, but also is shown in patients with chronic liver disease (CLD) at the precirrhosis stage. The presence of minimal hepatic encephalopathy in patients with chronic hepatitis is a cognitive impairment, which manifests as a de-crease in concentration, in particular when driving. The effect on hyperammonemia becomes a target for therapy in steatohepatitis of various etiologies. The use of the oral form of L-ornithine-L-aspartate effectively reduces the level of ammonia in the blood, improves cognitive function and positively affects the functional state of the liver in patients with CLD at the precirrhotsis stage.

1. Vilstrup H., Amodio P., Bajaj J. et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J. Hepatol. 2014; 60: 715-735.

2. Hadjihambi A., Arias N., Mohammed Sh., Jalan R. Hepatic encephalopathy: a critical current review. Hepatol. Int. 2018; 2018; 2: 135–147.

3. Tranah T.H., Paolino A., Shawcross D.L. Pathophysiological Mechanisms of Hepatic Encephalopathy. Clinical Liver Disease. 2015; 5: doi: 10.1002/cld.445.

4. Kornerup L.S., Gluud L.L., Vilstrup H., Dam G. Update on the Therapeutic Management of Hepatic Encephalopathy. Curr. Gastroenterol. Rep. 2018; 20(5): 21. doi: 10.1007/s11894-018-0627-8.

5. Lockwood A.H. Blood ammonia levels and hepatic encephalopathy. Metab. Brain Dis. 2004; 19: 345-349.

6. Severin E.S. Biochemistry, GEOTAR-Media: 2004; 784 p. [in Russian].

7. 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. European Journal of Clinical Investigation. 1988; 18: 535-542.

8. Hassinger D., Steeb R., Gerok W. Ammonium and bicarbonate homeo-stasis in chronic liver disease. Klin. Wochenschr. 1990; 68: 175-182.

9. Walker V. Severe hyperammonaemia in adults not explained by liver disease. Annals of Clin. Biochemistry. 2012; 49: 214-228.

10. 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): 823-833. doi: 10.1016/j.jhep.2015.11.019. Epub 2015 Dec 2.

11. Ghallab А., Cellière G., Henkel S.G. et al. Model-guided identification of a therapeutic strategy to reduce hyperammonemia in liver diseases. Hepatology. 2016; 64: 860-871.

12. Suraweera C., Anandakumar D., Dahanayake D. et al. Validation of the Sinhala version of the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Ceylon Med. J. 2016; 61(4): 167-170.

13. Shura R.D., Brearly T.W., Rowland J.A. et al. Send to RBANS validity indices: a systematic review and Meta-Analysis. Neuropsychol. Rev. 2018 May 16. doi: 10.1007/s11065-018-9377-5.

14. Jepsen P., Ott P., Andersen P.K., Sorensen H.T., Vilstrup H. The clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study. Hepatology 2010; 51: 1675-1682.

15. Romero-Gomez M., Cordoba J., Jover R. et al. Value of the critical flicker frequency in patients with minimal hepatic encephalopathy. Hepatology 2007; 45: 879-885.

16. Bajaj J.S. Management options for minimal hepatic encephalopathy. Expert. Rev. Gastroenterol. Hepatol. 2008; 2: 785-790.

17. Ilchenko L.Yu., Shaposhnikova NA, Vinnitskaya E.V. et al. Early diagnosis and treatment of hepatic encephalopathy in patients with chronic liver diseases. Hepatology. 2005; 5: 4-9 [in Russian].

18. Ilchenko L.Yu., Topcheeva O.N., Vinnitskaya E.V et al. Clinical aspects of hepatic encephalopathy in patients with chronic liver diseases. Consilium medicum. 2007; 1: 23-28 [in Russian].

19. Ageyeva Ye.A., Alekseyenko S.A. Application of the oral «L-ornithine-L-aspartate» at hyperammoniemia at chronic liver diseases at precirrhotic stage. Clinical prospects of gastroenterol., hepatol. 2015; 6: 24-26 [in Russian].

20. Ageyeva Ye.A., Alekseyenko S.А. Use of oral L-ornithine-L-aspartate (LOLA) in the treatment of hyperammonemia in patients with chronic liver disease in the pre-cirrhotic stage. Effect. Pharmacother. 2017;

21. : 6-9 [in Russian].

22. Buyeverov A.O., Bogomolov P.O., Matsievich M.V., Uranova O.V. Implications of mental disorders and correction of minimal hepatic encephalopathy in patients with chronic hepatitis C, genotype 1. RJGHC; 2017: Appliation N 49: 111 [in Russian].

23. De Chiara F., Habiesion A., Davies N. et al. Early increase in ammonia is a feature of Non-Alcogolic Fatty Liver Disease and the ammonia lovering drug, Ornithine Phenylacetate (OP-OCR002) prevents progression of fibrosis in a rodent model. Presented at: International Liver Congress 52nd Annual Meeting of the European-Association-for-the-Study-of-the-Liver, Amsterdam, Netherlands, 2017.

24. Preisig R. Supplements to the editorial «Liver protection therapy». Schweiz. Rundsch. Med. Prax. 2007; 59: 1559-1560.

25. Necam K. Effect of in vivo treatment with ornitin-aspartate hepamerz on the activity and expression of superoxidedismutase SOD in patients with cirrhosis of the liver. Hepatol. 1991; 11: 75-81.

26. Grüngreiff K., Lambert-Baumann J. Efficacy of L-ornithine-L-aspartate granules in the treatment of chronic liver disease. Med. Welt. 2001; 52: 219–226.

27. Jiang Q., Jiang X.H., Zheng M.H., Chen Y.P. L-Ornithine-l-aspartate in the management of hepatic encephalopathy: a meta-analysis. J Gastroenterol Hepatol. 2009; 24: 9-14.

28. Osipenko M.F., Redkina A.V., Bikbulatova E.K. et al. Evaluation of L-ornithine-L-aspartate in the treatment of NASH. Consilium Mediсum. 2010; 1: 35-38 [in Russian].

29. Solovyova H.A., Kvacheniuk E.L. Hepa-Merz in treatment of alcoholic and non-alcoholic steatohepatitis. Drugs of Ukraine. 2011; 7: 64-70

30. [in Russian].

31. Dvorkina N.V., Holina I.M., Ermolova T.V. et al. The effectiveness of L-ornithine-L-aspartate in patients with steatohepatitis. Modern Gastroenterology and Hepatology. 2012; 1: 1-5 [in Russian].

32. Tkach S.M. Ornithine-aspartate as a universal hepatoprotectordetoxicant with pleiotropic effects. Health of Ukraine. 2013; 3: 60-61 [in Russian].

33. Ilchenko L.Y., Melnikova L.I., Zhuravleva M.V. Experience of ornithine aspartate (Hepa-Merz) and probiotics bioflorum forte in the treatment of non-severe forms of alcoholic and non-alcoholic fatty liver disease. The Russian Archives of Internal Medicine. 2016; 5: 45-52 [in Russian].

34. URL: www.merz.ru (Дата обращения: 05.05. 2018). URL: www.merz. ru (Date of circulation: 05.05. 2018).

35. Ermolova T.V., Ermolov S.Yu., Sologub T.V. et al. Portohepatic hemodynamic disturbances in patients with chronic liver disease at the initial stages of fibrosis and their correction. Pharmateca. 2016;

36. : 58-66 [in Russian].

37. URL: http://lab-medica.ru/biohimicheskie-analizatory/pocketchem_ ba (Дата обращения: 05.05. 2018). URL: http://lab-medica.ru/ biohimicheskie-analizatory/pocketchem_ba (Date of circulation: 05.05. 2018).