Pathophysiology of cerebral oedema in acute liver failure

Abstract

Cerebral oedema is a devastating consequence of acute liver failure (ALF) and may be associated with the development of intracranial hypertension and death. In ALF, some patients may develop cerebral oedema and increased intracranial pressure but progression to life-threatening intracranial hypertension is less frequent than previously described, complicating less than one third of cases who have proceeded to coma since the advent of improved clinical care. The rapid onset of encephalopathy may be dramatic with the development of asterixis, delirium, seizures and coma. Cytotoxic and vasogenic oedema mechanisms have been implicated with a preponderance of experimental data favouring a cytotoxic mechanism. Astrocyte swelling is the most consistent neuropathological finding in humans with ALF and ammonia plays a definitive role in the development of cytotoxic brain oedema. The mechanism(s) by which ammonia induces astrocyte swelling remains unclear but glutamine accumulation within astrocytes has led to the osmolyte hypothesis. Current evidence also supports an alternate 'Trojan horse' hypothesis, with glutamine as a carrier of ammonia into mitochondria, where its accumulation results in oxidative stress, energy failure and ultimately astrocyte swelling. Although a complete breakdown of the blood-brain barrier is not evident in human ALF, increased permeation to water and other small molecules such as ammonia has been demonstrated resulting from subtle alterations in the protein composition of paracellular tight junctions. At present, there is no fully efficacious therapy for cerebral oedema other than liver transplantation and this reflects our incomplete knowledge of the precise mechanisms underlying this process which remain largely unknown.

Keywords: Acute liver failure; Ammonia; Cerebral blood flow; Cerebral oedema; Hepatic encephalopathy; Intracranial hypertension; Intracranial pressure.

Figure 1

The ‘Trojan Horse’ hypothesis. This illustrates the synthesis of glutamine via the enzyme glutamine synthetase; its transport into mitochondria via the glutamine transporter (GLN-Tx); its hydrolysis by phosphate-activated glutaminase (PAG) resulting in glutamate (GLU) and ammonia (NH₄⁺) production and the subsequent generation of reactive oxygen species (ROS). MSO: L-methionine S-sulfoximinel; GS: Glutamine synthetase.

Figure 2

The role of oxidative stress, mitochondrial permeability transition and energy failure in ammonia-induced neurotoxicity. A schematic representation of the central role that ammonia plays in the production of oxidative/nitrosative stress and astrocyte swelling. Ammonia-induced astrocyte swelling is mediated by oxidative and nitrosative stress resulting in the induction of the MPT, activation of intracellular signaling kinases and alterations in gene expression. Mitochondrial dysfunction and energy failure culminates in astrocytes failing to regulate their cell volume, thereby resulting in astrocyte swelling. NMDA-R: N-methyl-D-aspartate-receptor; RNOS: Reactive nitrogen and oxygen species; MPT: Mitochondrial permeability transition; MAPKs: Mitogen-activated protein kinases; CsA: Cyclosporine A.

Figure 3

Blood-brain barrier dysfunction in acute liver failure. Anatomy of the blood-brain barrier (BBB) created by the brain capillary endothelial cell and its paracellular tight junction and adherens junction. In acute liver failure, activation of epidermal growth factor receptor (EGFR) and other signaling pathways results in a loss of BBB tight junction integrity. Tight junctional proteins are altered, resulting in increased permeability to small molecules, leading to astrocyte swelling. MMP-9: Matrix metalloproteinase-9; MAPK p38: Mitogen activated protein kinase p38; NFκB: Nuclear factor-κB.