Author information

¹UCM Digestive Diseases, Virgen del Rocío University Hospital. Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain.

²Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.

³The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK.

⁴Faculty of Life Sciences and Medicine, King's College London, London, UK.

⁵Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada.

⁶Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, London, UK.

⁷European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain.

⁸UCM Digestive Diseases, Virgen del Rocío University Hospital. Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain. mromerogomez@us.es.

⁹Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain. mromerogomez@us.es.

^#Contributed equally.

Abstract

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.