Pathophysiology of cerebral edema in fulminant hepatic failure

Abstract

F ULMINANT hepatic failure (FHF) is a devastating disease and is still associated with a high mortality (1). FHF results in progressive multi-organ failure with a dramatic impact on the brain. Indeed, development of intracranial hypertension (IH) is a leading cause of death in FHE During this decade two theories have independently emerged to explain the pathogenesis of cerebral edema and intracranial pressure in FHE The glutamine hypothesis is based on the fact that ammonia is detoxified in the brain to glutamine, whose osmotic effects in astrocytes may account for the development of brain edema (2). Astrocyte swelling is a prominent neuropathological feature in FHF (3). In humans, hyperammonemia induces brain edema in several medical conditions (4). Experimentally, inhibition of glutamine synthesis with methionine-sulfoximine (MSO) prevents the development of ammoniainduced brain edema in normal rats (5), decreases astrocyte swelling (6) and ameliorates brain edema in rats after portacaval anastomosis (PCA) receiving an ammonia infusion (7). A second hypothesis suggests that cerebral edema arises as a consequence of cerebral vasodilatation (8). Physiological studies in patients with FHF (9,lO) and in experimental models (11) indicate that cerebral arterioles are dilated. Furthermore, patients with signs of cerebral edema and IH have a higher cerebral blood flow (CBF) compared to patients without brain swelling (12,13). Two recent experimental studies suggest that development of brain edema may depend both on glutamine accumulation in astrocytes and changes in CBE First, Cordoba et al. (14) found in PCA rats receiving an ammonia infusion that an increase in brain glutamine was associated with a marked rise in CBF at the time of an increase in brain water and intracranial pressure.