Changing face of hepatic encephalopathy: role of inflammation and oxidative stress

Abstract

The face of hepatic encephalopathy (HE) is changing. This review explores how this neurocognitive disorder, which is associated with both acute and chronic liver injury, has grown to become a dynamic syndrome that spans a spectrum of neuropsychological impairment, from normal performance to coma. The central role of ammonia in the pathogenesis of HE remains incontrovertible. However, over the past 10 years, the HE community has begun to characterise the key roles of inflammation, infection, and oxidative/nitrosative stress in modulating the pathophysiological effects of ammonia on the astrocyte. This review explores the current thoughts and evidence base in this area and discusses the potential role of existing and novel therapies that might abrogate the oxidative and nitrosative stresses inflicted on the brain in patients with, or at risk of developing, HE.

Figure 1

The “Two-hit” hypothesis. In a background of liver injury and hyperammonemia, a second “hit”, such as an ammonia load following an upper gastrointestinal bleed, systemic inflammation/infection, or the development of hyponatremia can drive further astrocyte swelling, oxidative stress and lead to a rapid deterioration in neurocognitive function. The close relationship between astrocyte swelling and oxidative stress leads to an “auto-amplifying signalling loop”. The sites of action of potential therapies are indicated on the Figure. L-OL-A: L-ornithine L aspartate; NMDA: N-methyl D-aspartate; NSAID: Non-steroidal anti-inflammatory; TLR: Toll-like receptor.