The Glymphatic System May Play a Vital Role in the Pathogenesis of Hepatic Encephalopathy: A Narrative Review

Abstract

Hepatic encephalopathy (HE) is a neurological complication of liver disease resulting in cognitive, psychiatric, and motor symptoms. Although hyperammonemia is a key factor in the pathogenesis of HE, several other factors have recently been discovered. Among these, the impairment of a highly organized perivascular network known as the glymphatic pathway seems to be involved in the progression of some neurological complications due to the accumulation of misfolded proteins and waste substances in the brain interstitial fluids (ISF). The glymphatic system plays an important role in the clearance of brain metabolic derivatives and prevents aggregation of neurotoxic agents in the brain ISF. Impairment of it will result in aggravated accumulation of neurotoxic agents in the brain ISF. This could also be the case in patients with liver failure complicated by HE. Indeed, accumulation of some metabolic by-products and agents such as ammonia, glutamine, glutamate, and aromatic amino acids has been reported in the human brain ISF using microdialysis technique is attributed to worsening of HE and correlates with brain edema. Furthermore, it has been reported that the glymphatic system is impaired in the olfactory bulb, prefrontal cortex, and hippocampus in an experimental model of HE. In this review, we discuss different factors that may affect the function of the glymphatic pathways and how these changes may be involved in HE.

Keywords: astrocytes; brain fluids; glymphatic system; hepatic encephalopathy; waste substances.

Figure 1

The components of the glymphatic pathway. In the region of Virchow-Robin spaces, CSF along with penetrating arterioles flow into the brain parenchyma. Arterial pulsation provides influx of CSF into the periarterial interstitial space. The system eliminates most neurotoxic agents and waste substances from ISF. AQP4 water channels that are localized in perivascular astrocyte end-feet mediate fluid movements throughout the system. AQP4: aquaporin 4; CSF: cerebrospinal fluid; ISF: interstitial fluid. Created with BioRender.com.

Figure 2

Injured astrocytes differentially express AQP4, impairing the glymphatic system. In several neurological disorders, AQP4 is primarily expressed on the cell body of swollen and reactive astrocytes (A1 phenotype). The AQP4 mislocalization disrupts the flow through the ISF and is responsible for impairment of the glymphatic system, resulting in accumulation of waste metabolites, microglial activation, neuroinflammation, and neuronal toxicity in the brain parenchyma. Similar astrogliosis and mislocalization of AQP4 have been observed in HE. These pathological changes in astrocytes, the main cellular component of the glymphatic pathway, may compromise clearance of ISF in HE. Created with BioRender.com.

Figure 3

Schematic representations of some pathological processes which may affect normal function of the glymphatic system following HE. All these factors can impair the function of the glymphatic system throughout the cerebral tissue. This induces accumulation of waste substances in the brain interstitial space and triggers neuroinflammation, resulting in neuronal injury and progression of hepatic encephalopathy. CBF: cerebral blood flow; HE: hepatic encephalopathy. Created with BioRender.com.