Hepatic encephalopathy as a result of ammonia-induced increase in GABAergic tone with secondary reduced brain energy metabolism

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome caused by liver insufficiency and/or portosystemic shunting. HE is mostly episodic and as such reversible. Hyperammonemia clearly plays a key role in the pathophysiology, but the precise detrimental events in the brain leading to HE remain equivocal. Several pathogenic models have been proposed, but few have been linked to clinical studies and observations. Decreased oxygen metabolism is observed in both type A and C HE and in this review, we advocate that this reflects an actual reduced oxygen demand and not a primary cause of HE. As driving force, we propose that the hyperammonemia via astrocytic glutamine synthetase causes an increased γ-aminobutyric acid (GABA) mediated neuro-inhibition which subsequently leads to an overall decreased energy demand of the brain, something that can be enhanced by concomitant neuroinflammation. This also explains the reversibility of the condition.

Keywords: CBF; Glutamine; Liver insufficiency; Organic delirium; Oxygen demand.

Fig. 1

Proposed model for hyperammonemia-induced hepatic encephalopathy (HE) in liver insufficiency. Increased levels of circulating blood ammonia (NH₄⁺) lead to increased flux into astrocytes where it is fixed in glutamine. Glutamine is used as precursor for γ-aminobutyric acid (GABA) in GABAergic neurons which subsequently leads to increased GABAergic tone with inhibition of neuronal activity and thus energy demand. Astrocytes also provide glutamine for glutamatergic (excitatory) neurons, but GABAergic neurons exert a powerful control over most of the excitatory signaling (see text for discussion). Abbreviation not explained above: AAT, aspartate aminotransferase; GDH, glutamate dehydrogenase GS, glutamine synthetase; PAG, phosphate-activated glutaminase; TCA cycle, tricarboxylic acid cycle