The role of astrocytes in hepatic encephalopathy

Abstract

The Alzheimer type II astrocyte change is the distinctive morphologic alteration in brain of humans and experimental animals succumbing to hepatic encephalopathy (HE). Whether this change is a primary event in the pathogenesis of HE or whether it is secondary to injury of some other component(s) of the CNS has not been clarified. Studies in a rat model of HE have revealed early reactive changes in astrocytes characterized by cytoplasmic hypertrophy. During the later phases, degenerative changes ensue corresponding to the Alzheimer type II change observed by light microscopy. In view of the role of astrocytes in ammonia detoxification and the importance of ammonia in the pathogenesis of HE, we have suggested that the initial astrocytic changes are the morphological correlates of ammonia detoxification. We have speculated that the later degenerative alterations could lead to failure by astrocytes to carry out key functions (e.g., neurotransmitter uptake, ion regulation, and the like) and contribute the development of the encephalopathy. Recently, the potential involvement of astrocytes in HE has been further investigated, using primary astrocyte cultures. Exposure of cultures to ammonia at clinically relevant concentrations has shown morphologic changes closely resembling those observed in experimental HE in vivo. These deleterious effects can partly be prevented by raising cyclic AMP levels in cells. Other potential toxins (octanoic acid, phenol) have shown pathologic changes as well. Although some alterations were common to all three, they each possessed distinctive pathological effects. A synergistic interaction has also been demonstrated with these toxins. Functional studies of ammonia-treated astrocytes have shown the following: With low doses or short-term exposure, the uptakes of K+, glutamate, and GABA remained unchanged or slightly increased, whereas with higher doses or longer treatment, those activities diminished. A fall in ATP values occurred with prolonged ammonia treatment. Preliminary findings have shown no significant derangements in the beta-adrenergic receptor, except for a slight decrease in receptor affinity. However, cyclic AMP production was diminished following stimulation with isoproterenol. A slight rise in the number of benzodiazepine receptors was found. These studies indicate that profound changes occur in astrocytes following exposure to ammonia and other putative toxins. It is proposed that toxins and factors involved in the precipitation of HE do so by affecting astroglial properties. Derangements in such properties may lead to glial dysfunction (primary gliopathy), resulting in an encephalopathic state.

Neuroinflammation in Hepatic Encephalopathy: Mechanistic Aspects

“…Such findings prompted the suggestion that HE fundamentally represents a primary "astrogliopathy". 13 While the precise involvement of astrocytes in HE is incompletely understood, it is known that the enzyme responsible for ammonia metabolism in brain, glutamine synthetase, is exclusively found in astrocytes.…”

“…For review, see Norenberg 13 ; Norenberg et al, 1992. 15 While the molecular basis for the neurological disorder in acute and chronic liver failure remains incompletely understood, elevated blood and brain ammonia levels have been strongly implicated in its pathogenesis.…”

Neuroinflammatory Signals during Acute and Chronic Liver Diseases

“…The increased levels of glutamine inside of astrocytes cause an osmotic gradient which results in the swelling of astrocytes and cytotoxic edema [19]. This results in a morphological change in astrocytes, which have been characterized as Alzheimer type II astrocytes, which are a neuropathological marker of this disease state [20].…”

L-carnitine in Hyperammonemia and Hepatic Encephalopathy

“…HE due to both chronic liver failure (CLF) and acute liver failure (ALF) is manifested by neuropathological changes that primarily affect astrocytes. The main pathological manifestation in CLF and chronic HA is the appearance of Alzheimer type II astrocytosis (Norenberg, 1977(Norenberg, , 1987. In HA and HE due to ALF, death most frequently results from brainstem herniation due to increased intracranial pressure as a result of a progressive increase of brain water content (brain edema) due to astrocyte swelling Butterworth, 1998;Chung et al, 2001;Cordoba & Blei, 1995;Larsen et al, 2001).…”