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

Nature Reviews Gastroenterology & Hepatology (2024)Cite this article

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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.

Key points

  • 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.

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Fig. 1: The inter-organ metabolism of ammonia, including sites of action of different drugs.
Fig. 2: The effect of ammonia on intracellular pH.
Fig. 3: The downstream effects of interactions between ammonia and inflammatory pathways known to induce neurological alterations in hepatic encephalopathy.
Fig. 4: The direct effects of ammonia on cells, beyond pH changes.
Fig. 5: Measuring ammonia levels.
Fig. 6: Proposed algorithm for the diagnosis of hepatic encephalopathy in hospitalized patients with cirrhosis and the assessment of stable outpatients with cirrhosis for primary and secondary prophylaxis.
Fig. 7: Potential molecules and compounds able to therapeutically target ammonia in MASLD.

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Author information

Author notes

  1. These authors contributed equally: Rocío Gallego-Durán, Anna Hadjihambi.

  2. These authors jointly supervised this work: Rajiv Jalan, Manuel Romero-Gómez.

Authors and Affiliations

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

    Rocío Gallego-Durán, Javier Ampuero & Manuel Romero-Gómez

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

    Rocío Gallego-Durán, Javier Ampuero & Manuel Romero-Gómez

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

    Anna Hadjihambi

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

    Anna Hadjihambi

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

    Christopher F. Rose

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

    Rajiv Jalan

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

    Rajiv Jalan

Authors
  1. Rocío Gallego-Durán
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  2. Anna Hadjihambi
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  3. Javier Ampuero
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  4. Christopher F. Rose
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  5. Rajiv Jalan
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  6. Manuel Romero-Gómez
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Manuel Romero-Gómez.

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Nature Reviews Gastroenterology & Hepatology thanks Lorenzo Ridola and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Gallego-Durán, R., Hadjihambi, A., Ampuero, J. et al. Ammonia-induced stress response in liver disease progression and hepatic encephalopathy. Nat Rev Gastroenterol Hepatol (2024). https://doi.org/10.1038/s41575-024-00970-9

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