Systemic Ammonia Toxicity: An Underestimated Driver of Cerebral Energy Crisis in Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a complex of pathological processes in the brain caused by liver failure or portosystemic shunting. Even though ammonia (In this review, the term "ammonia" refers to total ammonia (ammonia gas and ammonium ion)) is widely recognized as the primary neurotoxin responsible for triggering the cerebral energy crisis and subsequent neurological manifestations of HE, its broader systemic effects are often overlooked. Meanwhile, the brain, which features the highest level of oxidative metabolism and extremely low energy reserves requires a constant supply of highly oxygenated and glucose-rich blood. Therefore, ammonia-induced disruptions in interorgan metabolic communication, leading to a restriction of vital energy substrates reaching the brain, are highly likely involved in this pathology. Currently, ammonia-related impairment of the metabolic relationship between the brain and extracerebral tissues is underestimated. This review summarizes generally accepted concepts and focuses on recent advances detailing how ammonia pathologically disrupts the highly integrated metabolic pathways in the liver and erythrocytes, thereby impairing the delivery of vital energy substrates to the brain. Additionally, the role of glutamate NMDA receptors in these metabolic disorders is discussed. The gathered information provides a deeper understanding of the indirect mechanisms by which ammonia compromises brain energy homeostasis, thereby ultimately leading to encephalopathy. Simultaneous measurement of plasma and erythrocyte ammonia is required to avoid measurement artifacts.