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 hepato-protective 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.

Keywords: ALF, acute liver failure; ATP, adenosine triphosphate; BBB, blood-brain barrier; CCL2, chemokine ligand-2; CMRO2, cerebral metabolic rate for oxygen; CNS, central nervous system; EEG, electroencephalography; GABA, gamma-aminobutyric acid; GFAP, glial fibrillary acidic protein; IgG, immunoglobulin; MRS, magnetic resonance spectroscopy; NAC, N-Acetyl cysteine; NMDA, N-methyl-d-aspartate; SIRS, systemic inflammatory response syndrome; SNATs, several neutral amino acid transport systems; TLP, translocator protein; TNFα, tumor necrosis factor alpha; acute liver failure; hepatic encephalopathy; intracranial hypertension; microglial activation; neuroinflammation.

Figure 1

Electron micrograph of frontal cortex from a patient who died in acute liver failure. Note swelling and vacuolation of perivascular astrocyte (A) and mitochondria (M). Endoplasmic reticulum is dilated (arrows). Original magnification ×6000. From reference #2 with permission.

Figure 2

Increased de novo synthesis of lactate in brain in an animal with acute liver failure resulting from hepatic devascularisation (ALF-37) compared to a sham-operated control animal (Sham). Left hand panel shows lactate resonances [1H-12C] that appear as doublets centered at 1.25 ppm. Left hand panel shows fractional 13C-enrichment data indicative of de novo synthesis rates as mean ± SE from a group of n = 4 animals per group. Note protective effects of mild hypothermia (ALF-35) leading to attenuation of lactate resonances. Significant differences indicated by *P < 0.01 by ANOVA. Data are from reference #15 with permission.

Figure 3

Panel A: Microglial activation indicated by increased OX-42 immunostaining in frontal cortex of a rat with acute liver failure resulting from hepatic devascularisation at coma/edema stage of encephalopathy (ALF-coma) compared to a sham-operated control (Sham). Original magnification: ×200. Panel B: Increased expression of genes coding for the pro-inflammatory cytokines interleukin-1beta (IL-1b) and tumor necrosis factor alpha (TNFa) in samples of frontal cortex from rats with acute liver failure at coma/edema stage of encephalopathy (ALF-coma) compared to sham-operated controls (Sham). Histograms represent mean ± SE values from n  = 6 animals per group. Values that are significantly different from Sham indicated by *P < 0.02 **P < 0.01 by Student t test.

Figure 4

Minocycline (mino) inhibits microglial activation as assessed by OX-6 expression (shown in panels b and c) and, in so doing leads to a reduction in per cent brain water content (%), panel (a) in frontal cortex of rats with acute liver failure (ALF) resulting from hepatic devascularisation compared to sham-operated control animals (Sham). ALF-6 h: animals at 6 h after devascularisation, no coma, no edema. ALF-coma: animals at coma/edema stages of encephalopathy, ALF-mino : animals treated with minocycline (22.5 mg/kg). Significant differences indicated by *P < 0.01 compared to Sham, +P < 0.02 compared to AKLF-coma by ANOVA. From reference #39 with permission.