Ammonia-induced stress response in liver disease progression and hepatic encephalopathy

Ammonia levels are orchestrated by a series of complex interrelated pathways in which the urea cycle has a central role. Liver dysfunction leads to an accumulation of ammonia, which is toxic and is strongly associated with disruption of potassium homeostasis, mitochondrial dysfunction, oxidative stress, inflammation, hypoxaemia and dysregulation of neurotransmission. Hyperammonaemia is a hallmark of hepatic encephalopathy and has been strongly associated with liver-related outcomes in patients with cirrhosis and liver failure. In addition to the established role of ammonia as a neurotoxin in the pathogenesis of hepatic encephalopathy, an increasing number of studies suggest that it can lead to hepatic fibrosis progression, sarcopenia, immune dysfunction and cancer. However, elevated systemic ammonia levels are uncommon in patients with metabolic dysfunction-associated steatotic liver disease. A clear causal relationship between ammonia-induced immune dysfunction and risk of infection has not yet been definitively proven. In this Review, we discuss the mechanisms by which ammonia produces its diverse deleterious effects and their clinical relevance in liver diseases, the importance of measuring ammonia levels for the diagnosis of hepatic encephalopathy, the prognosis of patients with cirrhosis and liver failure, and how our knowledge of inter-organ ammonia metabolism is leading to the development of novel therapeutic approaches. This Review describes inter-organ ammonia metabolism in liver disease and mechanisms underlying the pathogenic effect of hyperammonaemia in hepatic encephalopathy, liver disease progression in metabolic dysfunction-associated steatotic liver disease, immune dysfunction and hepatocellular carcinoma. It also addresses the principles of treating hyperammonaemia. Ammonia accumulates in patients with liver dysfunction owing to its increased production and impaired detoxification by urea cycle enzymes and glutamine synthetase.In addition to the central role of hyperammonaemia in the pathogenesis of hepatic encephalopathy, elevated blood ammonia levels have been shown to contribute to progression of hepatic fibrosis in steatotic liver disease, sarcopenia, immune dysfunction and cancer.Ammonia produces its deleterious effects through direct and indirect effects on cells, including but not limited to pH changes, altered metabolism, potassium homeostasis disruption, mitochondrial dysfunction, oxidative stress, inflammation, compromised oxygen homeostasis and dysregulation of neurotransmission.The presence of hyperammonaemia is critical for the diagnosis of hepatic encephalopathy and the prognosis of patients with compensated and decompensated cirrhosis and liver failure.Current and emerging therapies for hyperammonaemia are based on new insights into inter-organ ammonia trafficking and metabolism.