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.

Inhibition of autotaxin alleviates pathological features of hepatic encephalopathy at the level of gut–liver–brain axis: an experimental and bioinformatic study

“…There is some evidence to suggest a potential link between the expression of aquaporin-4 (AQP4) and hepatic encephalopathy (HE) through the glymphatic system [ 27 – 29 ], although the exact nature of this relationship is still being studied. Several studies have investigated the expression of AQP4 in the context of HE [ 30 , 31 ].…”

Modeling of age-related neurological disease: utility of zebrafish

“…Notably, the resting heart rate of adult zebrafish is around 120 bpm (Table 1), suggesting that zebrafish may possess brain clearance mechanisms closer to humans than to mice (Mousavi and Patil, 2020). Moreover, it is implied that dysregulation of cerebral blood flow affects glymphatic system (Sepehrinezhad et al, 2023). The cerebral blood flow is decreased with aging in humans and zebrafish, whereas this does not change in mice (Pantano et al, 1984;Wei et al, 2020;Mizoguchi et al, 2023) (Table 1).…”

Intrathecal Autologous Thrombin-Activated Condensed Platelet Cytokines in Chronic Neurodegenerative Disease: Anti-inflammatory and Regenerative Responses, Phase I

“…The glymphatic system is a perivascular network for CSF transport connecting distally to the dural/meningeal lymphatic system. As the chief efflux channel for brain tissue [38], the glymphatic network clears metabolic products to prevent pathologic accretion in brain parenchyma and interstitial fluid [39]. Produced at a rate of 500-700 mL/d, total average CSF volume is ~140mL in healthy adults [40,41].…”