Treatment of Hepatic Encephalopathy: Targeting the Gut-liver-brain Axis

The pathogenesis of hepatic encephalopathy (HE) involves the interaction between two pathophysiological mechanisms: ammonia detoxification and inflammation. The neuropathology of HE is characterised by astrocyte dysfunction and swelling due to ammonia detoxification. The enzyme glutamine synthetase, which is located mainly in astrocytes, protects neurons by absorbing excess ammonia and glutamate, converting it to glutamine. The concentration of ammonia is increased in patients with hepatic failure when compared with healthy individuals, clearly indicating the significance of ammonia in the pathogenesis of HE, and as an important target for treatment. Bacterial translocation is a significant factor in driving the progression of cirrhosis, hepatic fibrosis, compensated and decompensated cirrhosis and the recurrence of HE (Figure 1). Bacterial translocation appears to be a key event in the transition from well-compensated to decompensated cirrhosis (or acute on chronic liver failure). This transition manifests in severe levels of HE, and probably contributes directly to the ‘second hit’ which is inflammation.