Glymphatic Dysfunction in Hepatic Encephalopathy: A Novel Pathogenetic Pathway and Potential Target for New Therapeutic Opportunities

Abstract

Hepatic encephalopathy (HE) is a common complication of decompensated liver cirrhosis and acute-on-chronic liver failure. It encompasses a range of symptoms, from minimal cognitive impairments to severe personality changes and even coma. Liver dysfunction, coupled with the development of portosystemic shunting (PSS), leads to the accumulation of toxic substances in the brain, adversely affecting its function. Common precipitating factors for HE include variceal bleeding, infections, and electrolyte imbalances. However, other mechanisms likely contribute to the onset of HE, as some patients experience episodes without identifiable predisposing factors. These patients may remain in a chronic state of latent HE or have increasingly frequent episodes of HE. One potential contributing factor to HE is dysfunction of the glymphatic system (GS), which clears metabolic waste from the brain. This review aims to highlight the mechanisms underlying GS dysfunction in individuals with liver cirrhosis and explore how it may relate to the development of HE. Additionally, it will provide information on therapeutic interventions that target glymphatic dysfunction, potentially offering new treatment options for HE in the future.