Pathogenesis of Hepatic Encephalopathy in Chronic Liver Disease

Abstract

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that occurs during chronic liver disease (CLD). While ammonia and other precipitating factors in liver disease including inflammation, bile acids, oxidative stress, and lactate play a role in the pathogenesis of HE, the exact mechanism that leads to HE is not fully understood. Notably, accumulating evidence points toward a synergic effect rather than independent actions among precipitating factors that contributes to the development and severity of HE in CLD. Hence, this review is aimed to briefly discuss the single and synergic interplay of pathological factors in the progression and severity of HE.

Keywords: AQP4, Aquaporin 4; BAs, Bile Acids; BBB, Blood-Brain Barrier; BDL, Bile Duct Ligation; CLD, Chronic Liver Disease; CSF, Cerebrospinal Fluid; GABA, Gamma-Aminobutyric Acid; GAMSAs, GABAA Receptor Modulating Steroid Antagonists; GFAP, Glial Fibrillary Acid Protein; GLAST, Glial Glutamate-Aspartate Transporter; GPR81, G-Protein-Coupled Receptor 81; GS, Glutamine Synthetase; HE, Hepatic Encephalopathy; ICP, Intracranial Pressure; ILs, Interleukins; MRI, Magnetic Resonance Imaging; NF-?B, Nuclear Factor Kappa B; NMDA, N-Methyl-d-Aspartate Glutamate Receptor; NO, Nitric Oxide; PCA, Portacaval Anastomosis; ROS, Reactive Oxygen Species; TJ, Tight Junction; TNF-a, Tumor Necrosis Alpha; ammonia; astrocyte swelling; bile acids; brain edema; cGMP, Cyclic Guanosine Monophosphate; cirrhosis; hepatic encephalopathy; inflammation; lactate; mGluR, Metabotropic Glutamate Receptor; neurotransmission; oxidative stress.

Figure 1

Blood-brain barrier (BBB) impairment, astrocyte swelling, and brain edema in chronic liver disease promotes hepatic encephalopathy (HE). Precipitating factors affect the BBB permeability, which facilitates the entry of neurotoxic substances into brain extracellular space resulting in brain edema. Additionally, neurotoxic substances exert detrimental actions on astrocytes, which disturb glutamate and glutamine metabolism, leading to astrocyte swelling. Thus, astrocyte swelling contributes to brain edema and affects astrocyte-neuronal communication, resulting in a disturbance of glutamatergic and GABAergic neurotransmission systems, which finally accounts for HE. AQP4, Aquaporin 4; TJ, Tight Junction; ROS, Reactive Oxygen Species; mGluR, Metabotropic Glutamate Receptor; NMDA, N-Methyl-d-Aspartate Glutamate Receptor; NO, Nitric Oxide; cGMP, Cyclic Guanosine Monophosphate; GABA, Gamma-Aminobutyric Acid.