Ammonia is recognized as one of the most important factors involved in the pathogenesis of hepatic encephalopathy (Bosoi and Rose, 2009).
The Chemistry of Ammonia
Ammonia is composed of nitrogen and hydrogen (NH3). When dissolved in a solution, it separates into NH3 (gas) and NH4+ (ion). At physiologic pH, Hasselbach’s equation predict a majority of ionic form (~98%).
Where ammonia come from?
Proteins need to be hydrolysed in amino acids in order to be absorbed by the organism. Ammonia is produced in several processes, mostly in the gut, including during the digestion of proteins and deamination. This byproduct is detoxified by the liver through the urea cycle. The liver regulates the concentration of ammonia in the systemic circulation, maintaining low blood ammonia levels. Urea, a major component of urine, is eliminated by the kidneys.
In Hepatic Encephalopathy
Liver failure leads to an increase in blood ammonia, called hyperammonemia. HE patients that have a damaged liver cannot manage ammonia. Consequently, hyperammonemia develops (up to 1 mM in severe cases, normal values in adults : 30-50 umol/L).
Both NH3 (gas) and NH4+ (ion) are capable of crossing cell membranes, and therefore can easily affect organs, particularly brain. Ammonia is neurotoxic and leads to brain dysfunction. Effectively, at elevated concentrations, ammonia is toxic to the brain having a direct effect on the pH factor (acid/alkaline balance), metabolism and membrane potential (necessary for equilibrium of nerve cells). In turn, this leads to numerous alterations in the brain causing brain cells (neurons) not to function properly.
Ammonia in brain
It has been observed in patients suffering from HE that a cerebral edema occurs, due to a swelling of the astrocytes. This effect is induced by ammonia and reactive oxygen species. Ammonia is responsible for a change in the pH and an increase in calcium (Rose et al, 2005). Calcium is important for enzymatic signalling pathways and triggers several reactions such as glutamate release.
Glutamate and Glutamine
Glutamate is an excitatory neural transmitter and is used as a substrate in the enzymatic reaction. In the brain, glutamine synthetase is only found in the astrocytes. It enables the detoxication of cerebral ammonia. However, this protein is susceptible to modification through ROS, which decreases its function. This all results in a vicious circle that further amplifies the damage.
Cristina R. Bosoi, Christopher F. Rose (2009) Identifying the direct effects of ammonia on the brain. Metab Brain Dis, 24: 95-102. doi: 10.1007/s11011-008-9112-7
Srinivasan Dasarathy, Rajeshwar P. Mookerjee, Veronika Rackayova, Vinita Rangroo Thrane, Balasubramaniyan Vairappan, Peter Ott, Christopher F. Rose (2017) Ammonia toxicity: from head to toe? Metab Brain Dis, 32: 529-538. doi: 10.1007/s11011-016-9938-3
Christopher Rose, Wolfgang Kresse, Helmut Kettenmann (2005) Acute insult of ammonia leads to calcium-dependent glutamate release from cultured astrocytes, an effect of pH. J Biol Chem, 280: 20937-20944. doi: 10.1074/jbc.M412448200