Abstract
Hepatic encephalopathy (HE) may occur in patients with liver failure. The most critical pathophysiologic mechanism of HE is cerebral edema following systemic hyperammonemia. The dysfunctional liver cannot eliminate circulatory ammonia, so its plasma and brain levels rise sharply. Astrocytes, the only cells that are responsible for ammonia detoxification in the brain, are dynamic cells with unique phenotypic properties that enable them to respond to small changes in their environment. Any pathological changes in astrocytes may cause neurological disturbances such as HE. Astrocyte swelling is the leading cause of cerebral edema, which may cause brain herniation and death by increasing intracranial pressure. Various factors may have a role in astrocyte swelling. However, the exact molecular mechanism of astrocyte swelling is not fully understood. This article discusses the possible mechanisms of astrocyte swelling which related to hyperammonia, including the possible roles of molecules like glutamine, lactate, aquaporin-4 water channel, 18 KDa translocator protein, glial fibrillary acidic protein, alanine, glutathione, toll-like receptor 4, epidermal growth factor receptor, glutamate, and manganese, as well as inflammation, oxidative stress, mitochondrial permeability transition, ATP depletion, and astrocyte senescence. All these agents and factors may be targeted in therapeutic approaches to HE.
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Abbreviations
- ALF:
-
Acute liver failure
- AQP4:
-
Aquaporin-4 water channel
- ATP:
-
Adenosine triphosphate
- BBB:
-
Blood-brain barrier
- cGMP:
-
Cyclic guanosin monophosphate
- CLF:
-
Chronic liver failure
- CNS:
-
Central nervous system
- EAAT:
-
Excitatory amino acid transporters
- EGFR:
-
Epidermal growth factor receptor
- GFAP:
-
Glial fibrillary acidic protein
- Gln:
-
Glutamine
- Glu:
-
Glutamate
- GS:
-
Glutamine synthetase
- HE:
-
Hepatic encephalopathy
- HMGB-1:
-
High-mobility group box protein-1
- ICH:
-
Intracranial hypertension
- ICP:
-
Intracranial pressure
- (INFϒ):
-
interferon-gamma
- IL-1:
-
Interleukin-1
- IL-1β:
-
interleukin 1 beta
- IL-6:
-
Interleukin-6
- MAPKs:
-
Mitogen-activated protein kinases
- MPT:
-
Mitochondrial permeability transition
- MSO:
-
Methionine sulfoximine
- NF-kB:
-
Nuclear factor-kappaB
- NMDA:
-
N-methyl-D-aspartate
- NO:
-
Nitric oxide
- PAG:
-
Phosphate activated glutaminase
- PCA/S:
-
Portocaval anastomosis/shunt
- PTBRs:
-
Peripheral type benzodiazepine receptors
- RNS:
-
Reactive nitrogen species
- ROS:
-
Reactive oxygen species
- Sur1-TRPM4:
-
Sulfonyl urea receptor 1- transient receptor potential melastatin 4
- TLR4:
-
Toll-like receptor 4
- TNFα:
-
Tumor necrosis factor-alpha
- TSPO:
-
18 KDa Translocator protein
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Ali Sepehrinezhad, Roger Williams and Ali Shahbazi designed the study, carried out the literature review and drafted the manuscript. Gholamreza Namvar carried out the literature review and participated in drafting the manuscript. Also, Roger Williams and Asadollah Zarifkar critically edited the manuscript and corrected grammatical errors in the revised manuscript. All authors read and approved the final manuscript.
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Sepehrinezhad, A., Zarifkar, A., Namvar, G. et al. Astrocyte swelling in hepatic encephalopathy: molecular perspective of cytotoxic edema. Metab Brain Dis 35, 559–578 (2020). https://doi.org/10.1007/s11011-020-00549-8
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