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

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.

New Insight Into Mechanisms of Hepatic Encephalopathy: An Integrative Analysis Approach to Identify Molecular Markers and Therapeutic Targets.

Hepatic encephalopathy (HE) is a set of complex neurological complications that arise from advanced liver disease. The precise molecular and cellular mechanism of HE is not fully understood. Differentially expressed genes (DEGs) from microarray technologies are powerful approaches to obtain new insight into the pathophysiology of HE. We analyzed microarray data sets of cirrhotic patients with HE from Gene Expression Omnibus to identify DEGs in postmortem cerebral tissues. Consequently, we uploaded significant DEGs into the STRING to specify protein-protein interactions. Cytoscape was used to reconstruct the genetic network and identify hub genes. Target genes were uploaded to different databases to perform comprehensive enrichment analysis and repurpose new therapeutic options for HE. A total of 457 DEGs were identified in 2 data sets totally from 12 cirrhotic patients with HE compared with 12 healthy subjects. We found that 274 genes were upregulated and 183 genes were downregulated. Network analyses on significant DEGs indicated 12 hub genes associated with HE. Enrichment analysis identified fatty acid beta-oxidation, cerebral organic acidurias, and regulation of actin cytoskeleton as main involved pathways associated with upregulated genes; serotonin receptor 2 and ELK-SRF/GATA4 signaling, GPCRs, class A rhodopsin-like, and p38 MAPK signaling pathway were related to downregulated genes. Finally, we predicted 39 probable effective drugs/agents for HE. This study not only confirms main important involved mechanisms of HE but also reveals some yet unknown activated molecular and cellular pathways in human HE. In addition, new targets were identified that could be of value in the future study of HE.