Role of Ammonia in the Pathogenesis of Hepatic Encephalopathy

Abstract

There is consensus that ammonia is a key factor in the pathogenesis of hepatic encephalopathy (HE). Clinical studies have documented a satisfactory correlation between the advancement of HE symptoms and the increase in blood ammonia. The risk of development of HE cirrhotic patients is associated with increased ammonia production from glutamine in the intestines or kidney. Both clinical and animal model studies favor the role of ammonia in inducing brain edema, which is the major cause of death in patients with acute liver failure. Brain edema associated with HE has a profound cytotoxic component which results from astrocytic swelling. Infusion of ammonia in rats and application of ammonia on cultured astrocytes result in an increase in astrocytic cell volume. Ammonia induces astrocytic swelling by triggering a vicious cycle of oxidative/nitrosative stress and intracellular osmotic imbalance. The edema-inducing effect is to a considerable degree mediated by glutamine, which acts via two complementary mechanisms: (a) by increasing the intracellular osmotic pressure; (b) by causing mitochondrial damage following its entry to the inside of the organelle, where it unloads ammonia in a glutaminase-mediated reaction (the “Trojan horse” mode of action). Recent evidence indicates that ammonia may also induce brain edema by a vasogenic mechanism, in a process which involves subtle blood–brain barrier impairment associated with degradation of tight junction proteins and activation of matrix metalloproteinases. It is thought to be responsible for the shift of balance from excitation to inhibition which evolves with the advancement of HE. Changes in the glutamatergic tone primarily result from altered NMDA receptor function; its initial overactivation is followed by decreased activity. One of the consequences of NMDA receptor inactivation is decreased production of cGMP which contributes to the impairment of cognitive and motor functions in HE. Ammonia activates inhibitory GABAergic transmission mainly by increasing the synthesis and activation of peripheral benzodiazepine receptor agonists, which are positive modulators of the GABAA receptor. Furthermore it contributes to the increase in inhibitory serotoninergic transmission by promoting the blood-to-brain transfer of the serotonin precursor, tryptophan. It has been noticed that the nature and magnitude of neurotoxic effects of ammonia demonstrates differential distribution in brain.