Hyperammonemia as a direction to correct the pathogenesis of chronic liver diseases

Recently, there has been an increase in the prevalence of chronic liver disease (CLD), which is one of the frequent causes of mortality, especially in developing countries. The main goal of treatment of CLD is the etiological therapy of the disease and the treatment of complications if they are present. It is also important to prevent the progression of the disease and the initial stages of CLD. A separate place in the treatment of CLD belongs to hepatoprotectors, most of which are treated for a long time, since their mechanism of action is not focused on reducing the toxic load on the liver. This is important at the beginning of therapy, because the binding and elimination of toxins (ammonium) to unload the liver at this stage promotes a faster recovery of hepatocyte function. The pharmaceutical market of Ukraine has the original L-ornithine-L-aspartate (Hepa-Mertz), which is an effective means of reducing the level of ammonium in the blood, muscles and brain due to the stimulation of ammonium removal through the synthesis of urea in residual hepatocytes, prevention of hepatocellular damage due to production of antioxidants (glutathione, glutamine) and muscle exhaustion (development of sarcopenia) through the synthesis of glutamine in muscles. The use of the original drug Hepa-Mertz will prevent the accumulation of toxins (ammonium) in the liver both at the initial stages of the development of CLD, and during their progression with the development of liver cirrhosis and hepatic encephalopathy. Thus, lowering blood ammonium levels may be a new therapeutic strategy to control symptoms and prevent progression of CLD.

References

1. Ashish Sharma, Shivaraj Nagalli. Chronic liver disease. In StatPearls. StatPearls Publishing.
2. Joel J Heidelbaugh, Michael Bruderly. Cirrhosis and chronic liver failure: part I. Diagnosis and evaluation. Am Fam Physician. 2006;74(5):756–762.
3. Marcel CG van de Poll et al. Effect of major liver resection on hepatic ureagenesis in humans. Am J Physiol Gastrointest Liver Physiol. 2007;293:G956–G962.
4. Karen Louise Thomsen et al. Experimental nonalcoholic steatohepatitis compromises ureagenesis, an essential hepatic metabolic function. Am J Physiol Gastrointest Liver Physiol. 2014;307:G295–G301.
5. Francesco De Chiara et al. Ammonia scavenging prevents progression of fibrosis in experimental nonalcoholic fatty liver disease. Hepatol. 2020;71(3):874–892.
6. Maria M Adeva et al. Ammonium metabolism in humans. Metabolism. 2012;61(11): 1495–1511. doi:10.1016/j.metabol.2012.07.007.
7. Janus P Ong et al. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med. 2003;114(3):188–193. doi: 10.1016/s0002-9343(02)01477-8. PMID: 12637132.
8. William Bernal et al. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatol. 2007;46(6):1844–1852. doi: 10.1002/hep.21838.
9. Jing-Hang Xu et al. Management of chronic liver diseases and cirrhosis: current status and future directions. Chinese Med J. 2020;133(22):2647–2649.
10. Lorenz Balcar et al. Impact of ammonia levels on outcome in clinically stable outpatients with advanced chronic liver disease. JHEP Reports. 2023;5(4):100682.
11. Rajiv Jalan et al. Ammonia produces pathological changes in human hepatic stellate cells and is a target of therapy of portal hypertension. J Hepatol. 2016;64:823–833.
12. Bin Jia et al. Hyperammonaemia induces hepatic injury with alteration of gene expression profiles. Liver Int. 2014;34:748–758.
13. Robert Flisiak Tomasiewicz et al. Recommendations for the management of non-alcoholic fatty liver disease (NAFLD). Clinical and Experiment. Hepatol. 2018;4(3):153–157.
14. Скрипник Н.В. Патогенетичне обґрунтування гепатопротекторної терапії у хворих на цукровий діабет. Міжнар ендокринол журн. 2014;6(62):85–90.
15. Hepa-Merz (n.d.). Welcome to Hepa-Merz. http://www.hepa-merz.com/welcome-tohepa-merz/hepa-merz/mode-of-action/.
16. Roger F. Butterworth L‐Ornithine L‐aspartate for the treatment of sarcopenia in chronic liver disease: the taming of a vicious cycle. Can J Gastroenterol Hepatol. 2019;8182195. doi: 10.1155/2019/8182195.
17. Gerald Kircheis, Stefan Lüth. Pharmacokinetic and Pharmacodynamic Properties of l-Ornithine lAspartate (LOLA) in Hepatic Encephalopathy. Drugs, 2019;79(s1):23–29. doi: 10.1007/s40265-018-1023-2.
18. Ali Canbay, Jan-Peter Sowa. L-Ornithine L-Aspartate (LOLA) as a novel approach for therapy of non-alcoholic fatty liver disease. Drugs. 2019;79(Suppl 1):39–44.
19. Roger F. Butterworth. L-Ornithine L-Aspartate for the Prevention and Treatment of Liver Cirrhosis and its Complications. 2022; In book: Pharmacotherapy for Liver Cirrhosis and Its Complications (pp.205–221). doi: 10.1007/978-981-19-2615-0_13.