The role of ammonia in chronic liver disease

Hepatic encephalopathy (HE) is a major neuropsychiatric complication of chronic liver disease that contributes substantially to morbidity, mortality, and healthcare burden. Ammonia, a neurotoxic metabolite, plays a central role in its pathogenesis. Although traditionally considered a byproduct of liver failure, growing evidence supports a more direct and causal role for ammonia, linking it not only to the clinical features of HE but also to key processes involved in disease progression, including liver injury, inflammation, immune dysfunction, muscle wasting, and impaired cellular energetics. Beyond its mechanistic implications, renewed interest has focused on ammonia as a clinically useful biomarker. Advances in risk stratification, dynamic testing, and longitudinal monitoring are improving the ability to use ammonia levels to identify patients at high risk of HE, predict clinical outcomes, and assess response to therapy. At the same time, emerging ammonia-lowering therapies are reshaping the treatment landscape. Whether these therapies may modify disease trajectory, beyond reversing HE, is an interesting hypothesis requiring validation in future studies. This review summarises current knowledge on ammonia metabolism, its role in the pathophysiology of HE and chronic liver disease, and its evolving clinical utility. By integrating molecular mechanisms with advances in measurement and treatment, we propose a reframing of ammonia as a central driver of liver-brain axis dysfunction and a meaningful target for precision-based therapeutic strategies.