Ammonia
Ammonia, a byproduct of the metabolism of nitrogen-containing compounds, is neurotoxic at elevated concentrations.3 The liver clears almost all of the portal vein ammonia, converting it into glutamine and urea preventing entry into the systemic circulation. However, glutamine is metabolized in mitochondria yielding glutamate and ammonia, and glutamine-derived ammonia may interfere with mitochondrial function leading to astrocytes dysfunction. The increase in blood ammonia in advanced liver disease is a consequence of impaired liver function and of shunting of blood around the liver. Muscle wasting, a common occurrence in these patients, also may contribute since muscle is an important site for extrahepatic ammonia removal.4
In addition to direct neurotoxicity, low-grade astrocyte swelling may contribute to brain dysfunction. The enzyme glutamine synthetase (present in the endoplasmic reticulum of astrocytes) is responsible for the conversion of and ammonia to glutamine.5 As glutamine acts as osmolyte, water moves inside the astrocyte causing low-grade cerebral edema and a predominantly neuroinhibitory state (that is, slowing of mental processes) is pathognomonic of HE, which is associated with chronic liver disease.6,7