Astrocyte Pathophysiology in Liver Disease

Abstract

Liver disease is one of the major chronic disabilities around the world. It is known that global casualties are increasing because of virus C infection, alcohol consumption, or nonalcoholic circumstances. One of the main derived comorbidities of liver disease is the hepatic encephalopathy (HE), a severe neuropsychological syndrome derived from the acute or chronic liver disease. A key feature accounting for HE symptoms in cirrhotic patients is brain edema, which is triggered by hyperammonemia. In basal conditions, ammonia can be metabolized in the central nervous system (CNS) by astrocytes, which synthetize glutamine using ammonia and glutamate as substrates. In hyperammonemic conditions, astrocytes synthetize large amounts of glutamine generating a hyperosmotic condition, inducing these cells to become swollen in shape, invoking the characteristic symptom clinically manifested in patients with HE, as brain edema; this condition is regulated by water channels called aquaporins (AQPs) and by other molecules such as myoinositol. Experimental evidence suggests that some small non-coding RNAs may regulate AQPs expression both in vivo an in vitro and that some pharmacological interventions improve cognitive impairment in cirrhotic patients. It is undeniable that astrocytes and the different signaling pathways beneath its plasma membrane play a crucial role in liver disease-derived HE and represent some of the novel pharmacological targets to treat comorbidities of the liver disease.

The Pathophysiology of Hepatic Encephalopathy at the Level of Gut-Liver-Brain Axis: The Role of Resident Innate Immune Cells

“…These agents changed the astrocyte state from resting to a reactive form that produced pro-inflammatory mediators and induced oxidative stress. Afterward, reactive astrocytes activate microglia through secretion of G-CSF and CCL11 [257][258][259][260]. Moreover, activated microglia, via production of GM-CSF, TNFα, and IL-1β trigger astrocytes to produce pro-inflammatory cytokines that exacerbate neuroinflammation [231].…”

“…Moreover, activated microglia, via production of GM-CSF, TNFα, and IL-1β trigger astrocytes to produce pro-inflammatory cytokines that exacerbate neuroinflammation [231]. Hyperammonemic cerebral conditions induce astrocyte swelling and brain edema through mislocalization of aquaporin four water channels, inflammation, TLR4 activation, mitochondrial dysfunction, glutamine accumulation, and induction of oxidative stress [7,257,261]. Although cerebral edema often progresses in acute forms of HE, patients with cirrhosis were found to have minimal levels of brain edema using 1 H-magnetic resonance (MR) spectroscopy [262].…”

Alterations of the Brain Glial Fibrillary Acidic Protein During Human Liver Cirrhosis

“…Elevated ammonia in the brain as well as systemic inflammation are considered key factors of acute HE [2]. Astrocytes are the most vulnerable brain cells to ammonia exposure being the only cells containing glutamine synthetase [3]. HE is characterized by generalized swelling of the astrocytes and acquiring of Alzheimer Type II phenotype [4].…”

Key astroglial markers in human liver cirrhosis of different degree: immunohistochemical study

“…According the WHO data, liver cirrhosis is among leading causes of non-infectious morbidity and one of the twenty most common causes of death worldwide (http://www.who.int/) [1]. Hepatic encephalopathy (HE) is a severe consequence of liver cirrhosis with incidence about 30-45 % [2], manifesting as a complex neuropsychiatric disorder and leading to lethal outcome in about 90 % of patients with acuteon-chronic liver failure [3]. The American Association for the Study of Liver Disease (AASLD)/European Association for the Study of the Liver (EASL) practice guidelines for HE defines HE as "Brain dysfunction caused by liver failure and/ or portal-systemic shunting, ..." [4].…”

“…Current hypotheses of HE is linked to abnormal metabolism of ammonia, glutamine, amino acids (Tyrosine, Phenylalanine, Valine, Isoleucine, Leucine), action of inflammatory cytokines IL-1, IL-6, TNFα, manganese, neuroinflammation, all resulted in dysregulated neurotransmission, neurocognitive and functional disability of patients with HE [3,4,7]. In the brain hyperammoniemic conditions, the most vulnerable appear astrocytes being the only source of glutamine synthetase to metabolize ammonia [8].…”