Neuroinflammation in Hepatic Encephalopathy: Mechanistic Aspects

Abstract

Hepatic encephalopathy (HE) is a major neurological complication of severe liver disease that presents in acute and chronic forms. While elevated brain ammonia level is known to be a major etiological factor in this disorder, recent studies have shown a significant role of neuroinflammation in the pathogenesis of both acute and chronic HE. This review summarizes the involvement of ammonia in the activation of microglia, as well as the means by which ammonia triggers inflammatory responses in these cells. Additionally, the role of ammonia in stimulating inflammatory events in brain endothelial cells (ECs), likely through the activation of the toll-like receptor-4 and the associated production of cytokines, as well as the stimulation of various inflammatory factors in ECs and in astrocytes, are discussed. This review also summarizes the inflammatory mechanisms by which activation of ECs and microglia impact on astrocytes leading to their dysfunction, ultimately contributing to astrocyte swelling/ brain edema in acute HE. The role of microglial activation and its contribution to the progression of neurobehavioral abnormalities in chronic HE are also briefly presented. We posit that a better understanding of the inflammatory events associated with acute and chronic HE will uncover novel therapeutic targets useful in the treatment of patients afflicted with HE. ( J CLIN EXP HEPATOL 2015;5:S21-S28) H epatic encephalopathy (HE) is the major neurological complication of severe liver disease. It presents in two forms, chronic HE and acute HE. Chronic HE (portal-systemic encephalopathy) usually occurs in patients with alcoholic liver cirrhosis and is characterized by impaired neurological function, including changes in personality, altered mood, diminished intellectual capacity, and abnormal muscle tone and tremor. 1 Acute HE (AHE, acute liver failure, ALF; fulminant hepatic failure) generally occurs following massive liver necrosis due to viral hepatitis (hepatitis B and C), hepatic neoplasms, vascular causes, or exposure to acetaminophen and other hepatotoxins. AHE is associated with the abrupt onset of delirium, seizures, and coma.The principal pathological change in chronic HE is characterized by Alzheimer type II astrocytosis, 2,3 which is characterized by astrocytes possessing enlarged, pale nuclei, often occurring in pairs, with the nuclei frequently displaying prominent nucleoli. Cerebral edema and associated increase in intracranial pressure leading to brain herniation are the characteristic features of AHE which occurs in upto 80% of patients with AHE 4-6 and represents the most frequent cause of death in these patients (70% mortality). 4,7 While the basis for the edema in AHE is poorly understood, astroglial swelling (cytotoxic edema) dominates the pathology in experimental animals, [8][9][10][11] as well as in humans. 12 Of interest, no significant or consistent morphologic changes have been identified in neurons or other neural cells. Such findings prompted the suggestion that HE fundamentally represents a pr...

Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1

“…In contrast to our results, RXR agonists have been shown to have anti-inflammatory effects (Gonzalez et al, 2009; Kang et al, 2000; Lefterov et al, 2015; Uchimura et al, 2001). One plausible explanation for the conflicting results may be due to hepatic neuropathy caused by liver dysfunction, in which astrocytosis and microglial activation are characteristic pathological changes (Butterworth, 2013; Jayakumar et al, 2015). Although we did not assess the effects of lower doses of bexarotene treatment to potentially reduce these deleterious effects in the current study, the clinical application of this drug in aged patients to treat aging-associated cognitive decline requires great caution.…”

Multifactorial Effects on Different Types of Brain Cells Contribute to Ammonia Toxicity

“…Increased [Ca 2+ ] i also occurs in brain slices exposed to as little as 1-2 mM ammonia, and inhibition of GS results in a significantly larger [Ca 2+ ] increases [153], perhaps due to impaired ammonia detoxification. The reason for the delayed response at relative low ammonia concentrations is a gradually developing, marked nitrosative and oxidative damage after ammonia exposure [154][155][156][157] Fig. 5 Similarity between effects of ammonia (5 mM) on protein expression of both NKCC1 and phosphorylated NKCC1 (p-NKCC1) in cultured rat astrocytes (a1, a2) and the effect of thioacetamideinduced acute liver failure in rats in vivo, leading to hyperammonemia (b1, b2).…”

“…It is therefore important that cultured cerebral endothelial cells treated with ammonia also react with oxidative/nitrosative stress [161] and that the transcription factor NF-κB is activated in cortical endothelial cells from thioacetamide-treated animals [162]. A multitude of inflammatory mediators are increased in hepatic encephalopathy and microglia is activated by ammonia [157]. In liver cirrhosis patients with and without hepatic encephalopathy expression levels are altered for more than 1000 genes related to oxidative stress, microglia activation, receptor signaling, inflammatory and anti-inflammatory pathways, cell proliferation, and apoptosis [163].…”

L‐ornithine L‐aspartate in bouts of overt hepatic encephalopathy

“…However, other authors have shown increased levels of serum TNF‐α, IL‐1β, and IL‐6 and their arteriovenous differences consistent with a brain cytokine efflux in patients with a bout of HE. This supports the presence of a central nervous system inflammatory component (neuroinflammation) in HE …”