Cellular Pathogenesis of Hepatic Encephalopathy: An Update

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been fully elucidated, although it is generally accepted that HE occurs under the influence of miscellaneous factors, especially the synergistic effect of toxin accumulation and severe metabolism disturbance. This review summarizes the recently discovered cellular mechanisms involved in the pathogenesis of HE. Among the existing hypotheses, ammonia poisoning and the subsequent oxidative/nitrosative stress remain the mainstream theories, and reducing blood ammonia is thus the main strategy for the treatment of HE. Other pathological mechanisms mainly include manganese toxicity, autophagy inhibition, mitochondrial damage, inflammation, and senescence, proposing new avenues for future therapeutic interventions.

Keywords: astrocyte; autophagy; hepatic encephalopathy; hyperammonemia; inflammation; manganese toxicity; mitochondria; oxidative/nitrosative stress; senescence.

Figure 1

Major pathogenesis mechanisms of hepatic encephalopathy. Under liver dysfunction conditions, ammonia, manganese, and other heterogeneous precipitation factors cause astrocyte swelling and enhanced oxidative/nitrosative stress, which mutually reinforce each other. This self-amplifying loop then leads to a variety of harmful alterations in intracellular processes, including protein modification, RNA oxidation, multiple signaling pathway alterations, inflammation, autophagy inhibition, mitochondrial damage, and senescence. These unfavorable changes accumulatively impair astrocyte and neuron function/communication and stimulate the development of more severe HE symptoms. (Modified from [7,19]. The figure was partially generated using images from Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License).

Figure 2

Major mitochondria-related pathogenesis mechanisms induced by ammonia toxicity in astrocytes. In the pathogenesis of HE, hyperammonemia directly affects mitochondrial function in astrocytes. One possible explanation is the “Trojan horse” hypothesis: transport of glutamine into mitochondria leads to the subsequent generation of ROS and ammonia inside mitochondria. Ammonia also leads to a dramatic increase in the synthesis of glutamine and glutamate and thus a partial depletion of αKG, which further decreases the capacity of oxidative phosphorylation. An increase in mitochondrial dysfunction naturally activates a variety of mQC processes. For mitochondrial dynamics, ammonia increases mitochondrial fission. For mQC degradation pathways, on the one hand, ammonia enhances mitophagy initiation, for example, via a ubiquitination-mediated pathway; on the other hand, ammonia blocks the late stages of autophagic degradation via pH alteration, which in turn promotes relevant defense mechanisms such as TGM2 upregulation. αKG:α-ketoglutarate; GDH:glutamate dehydrogenase; GLN:glutamine; GLS:glutaminase; GLU:glutamate; GS:glutamine synthetase; OXPHOS:oxidative phosphorylation; ROS:reactive oxygen species.