Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure

Abstract

Neuropathologic investigations in acute liver failure (ALF) reveal significant alterations to neuroglia consisting of swelling of astrocytes leading to cytotoxic brain edema and intracranial hypertension as well as activation of microglia indicative of a central neuroinflammatory response. Increased arterial ammonia concentrations in patients with ALF are predictors of patients at risk for the development of brain herniation. Molecular and spectroscopic techniques in ALF reveal alterations in expression of an array of genes coding for neuroglial proteins involved in cell volume regulation and mitochondrial function as well as in the transport of neurotransmitter amino acids and in the synthesis of pro-inflammatory cytokines. Liver-brain pro-inflammatory signaling mechanisms involving transduction of systemically-derived cytokines, ammonia neurotoxicity and exposure to increased brain lactate have been proposed. Mild hypothermia and N-Acetyl cysteine have both hepatoprotective and neuro-protective properties in ALF. Potentially effective anti-inflammatory agents aimed at control of encephalopathy and brain edema in ALF include etanercept and the antibiotic minocycline, a potent inhibitor of microglial activation. Translation of these potentially-interesting findings to the clinic is anxiously awaited. ( J CLIN EXP HEPATOL 2015;5:S96-S103) A cute liver failure (ALF), also referred to as fulminant hepatic failure, invariably leads to central nervous system dysfunction that may include encephalopathy, seizures and brain edema, a major cause of intracranial hypertension and brain herniation, a leading cause of mortality in ALF. An increase in cerebral blood flow frequently accompanies the onset of brain edema. 1Neuropathological assessments of the brain in both human and experimental ALF reveals significant changes to neuroglia in general and to astrocytes and microglia, in particular. Astrocytes in brain sections from patients who died in ALF are swollen 2 as are their mitochondria (Figure 1). Based upon these observations, it is generally assumed that the brain edema that accompanies ALF is primarily, if not exclusively, cytotoxic in nature. Studies in experimental animals with ALF due to toxic liver injury show a similar pattern of changes as well as alterations in expression of genes coding for key astrocytic proteins. 3Although gross alterations of the blood-brain barrier (BBB) are not generally a feature of ALF, alterations of cerebrovascular endothelial cell function have occasionally been described. 2,4 On the other hand, material from ALF animals in which edema and encephalopathy were precipitated by infection manifest clear alterations of both BBB function and of expression of BBB tight junction proteins.5 These latter findings suggest that, in ALF accompanied by significant infection/inflammation, brain edema may comprise both cytotoxic and vasogenic components. BRAIN METABOLISM IN ACUTE LIVER FAILUREALF leads to severe compromise of cerebral metabolism and includes increases of cerebral blood flow, decrea...

Acute liver failure: An up-to-date approach

“…Liver-brain proinflammatory signaling mechanisms involve the transduction of systemically derived cytokines as well as the gliotoxic effects of ammonia and lactate [53].…”

Hepatobiliary Quiz (Answers)—14 (2015)

“…The blood-brain barrier permeability is not grossly altered. [15][16][17] Glutamine levels in the brain are significantly increased in patients with ALF. Previously, these levels were not found to correlate with the severity of encephalopathy or presence of cerebral edema.…”

Hepatobiliary Quiz (Answers)—15 (2015)

“…Previously, these levels were not found to correlate with the severity of encephalopathy or presence of cerebral edema. 15,18,19 However, a recent study has shown a progressive increase in glutamine and glutamate peak on magnetic resonance spectroscopy with the increase in severity of HE. 20 …”