Metabolically associated fatty liver disease: why ammonium levels should be considered even in the early stages

Metabolically associated fatty liver disease (MAFLD) is the most common chronic liver disease, affecting approximately a quarter of the world’s adult population. In the pathogenesis of its development, special attention should be paid to hyperammonemia, which occurs as a result of imbalance of the urea synthesis in the liver and the work of the glutamine/glutamate system. The accumulation of ammonium in the tissue of the organ and blood in MAFLD patients, leads to the development of inflammation, activation of stellate cells, stimulation of fibrogenesis and «silent» progression of the disease to nonalcoholic steatohepatitis with possible further transformation the disease into liver cirrhosis and hepatocellular carcinoma. In addition, hyperammonemia can affect muscle function through the toxic effect of ammonium on the nervous system, which can cause sarcopenia. Therefore, monitoring the level of ammonium in the blood at the initial stages of MAFLD allows to diagnose the liver dysfunction, which opens the possibility of starting early treatment measures aimed at reducing the load on the liver function and preventing the development of neurological complications. Today, no drug is licensed and approved for the treatment of MAFLD, but research is ongoing in this direction. There is evidence that lowering ammonium levels in MAFLD can reduce the progression of the disease. One of these drugs, which is presented on the pharmaceutical market of Ukraine, is L-ornithine L-aspartate (the original Hepa-Mertz). This drug has a dual mechanism of action, possessing hepatoprotective properties and the ability to reduce the level of ammonium in the blood, which can contribute to its early effect on the factors that trigger the process of fibrogenesis and the «silent» progression of MAFLD, which will improve the prognosis for this group of patients in the future.

References

1. Riazi K., Azhari H., Charette J.H. et al. (2022) The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol., 7(9): 851–861. doi: 10.1016/S2468-1253(22)00165-0.
2. Quek J., Chan K.E., Wong Z.Y. et al. (2023) Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroent. Hepatol., 8: 20–30.
3. Yin X., Guo X., Liu Z. et al. (2023) Advances in the Diagnosis and Treatment of Non-Alcoholic Fatty Liver Disease. Int. J. Mol. Sci., 24: 2844. doi: 10.3390/ijms24032844.
4. Thomsen K.L., Eriksen P.L., Kerbert A.J. et al. (2023). Role of ammonia in NAFLD: an unusual suspect. JHEP Rep., 5(7): 100780. doi: 10.1016/j.jhepr.2023.100780.
5. Bedogni G., Bellentani S., Miglioli L. et al. (2006) The Fatty Liver Index: A simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol., 6: 33. doi: 10.1186/1471-230X-6-33.
6. Kotronen A., Peltonen M., Hakkarainen A. et al. (2009) Prediction of Non-Alcoholic Fatty Liver Disease and Liver Fat Using Metabolic and Genetic Factors. Gastroenterol., 137: 865–872.
7. Lee J.H., Kim D., Kim H.J. et al. (2010) Hepatic steatosis in-dex: a simple screening tool reflecting nonalcoholicfatty liver disease. Dig. Liver Dis., 42: 503–550.
8. Poynard T., Ratziu V., Naveau S. et al. (2005) The diagnosticvalue of biomarkers (SteatoTest) for the prediction ofliver steatosis. Comp. Hepatol., 4: 1–10.
9. Rojas Á., García-Lozano M.R., Gil-Gómez A. et al. (2022) Glutaminolysis-ammonia-urea Cycle Axis, Non-alcoholic Fatty Liver Disease Progression and Development of Novel Therapies. J. Clin. Transl. Hepatol., 10(2): 356–362.
10. Azagra M., Pose E., De Chiara F. et al. (2022) Ammonium quantification in human plasma by proton nuclear magnetic resonance for staging of liver fibrosis in alcohol‐related liver disease and nonalcoholic fatty liver disease. NMR Biom., 35: e4745.
11. Balcar L., Krawanja J., Scheiner B. et al. (2023) Impact of ammonia levels on outcome in clinically stable outpatients with advanced chronic liver disease. JHEP Rep., 5(4): 100682. doi: 10.1016/j.jhepr.2023.100682.
12. Kjærgaard A.C.D., Mikkelsen C.W., Wernberg L.L. et al. (2021) Cognitive dysfunction in non-alcoholic fatty liver disease-current knowledge, mechanisms and perspectives. J. Clin. Med., 10: 673. doi: 10.3390/jcm10040673.
13. Canbay A., Sowa J.P. (2019) L-Ornithine L-Aspartate (LOLA) as a Novel Approach for Therapy of Non-alcoholic Fatty Liver Disease. Drugs, 79(Suppl. 1): 39–44.
14. Grüngreiff K., Lambert-Baumann J. (2001) Efficacy of L-ornithin-L-aspartate-granules in chronic liver diseases. Die Medizinische Welt, 52(7): 219–226.
15. Butterworth R.F., Canbay A. (2018) Hepatoprotection by L-ornithine L-aspartate in non-alcoholic fatty liver disease. Digest. Dis., 37(1): 63–68. doi: 10.1159/000491429.
16. Ermolova T., Ermolov S. (2018) Correction of intrahepatic microcirculation disorders by L-ornithine-L-aspartate at the chronic liver diseases patients. J. Hepatol., 68: S585–S586.