Alterations in expression of genes coding for key astrocytic proteins in acute liver failure.

Neuroscience Research Unit, Hôpital Saint-Luc du CHUM (University of Montreal), 1058 St-Denis Street, Montreal, Quebec H2X 3J4, Canada.
Journal of Neuroscience Research (Impact Factor: 2.73). 01/2002; 66(5):967-71. DOI: 10.1002/jnr.10045
Source: PubMed

ABSTRACT Cerebral edema and hepatic encephalopathy are major complications of acute liver failure. Brain herniation caused by increased intracranial pressure as a result of cell swelling is the major cause of death in this condition. Evidence available currently suggests that the rapid accumulation of ammonia by the brain is the major cause of the central nervous system complications of acute liver failure. Increased brain ammonia may cause cell swelling via the osmotic effects of an increase in astrocytic glutamine concentrations or by inhibition of glutamate removal from brain extracellular space. Acute liver failure results in altered expression of several genes in brain, some of which code for important proteins involved in CNS function such as the glucose (GLUT-1) and glutamate (GLT-1) transporters, the astrocytic structural protein glial fibrillary acidic protein (GFAP) the "peripheral-type" benzodiazepine receptor (PTBR) and the water channel protein, aquaporin IV. Loss of expression of GLT-1 results in increased extracellular brain glutamate in acute liver failure. Experimental acute liver failure also results in post-translational modifications of the serotonin and noradrenaline transporters resulting in increased extracellular concentrations of these monoamines. Therapeutic measures currently used to prevent and treat brain edema and encephalopathy in patients with acute liver failure include mild hypothermia and the ammonia-lowering agent L-ornithine-L-aspartate.

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    • "The transport across the endothelial cell includes passive diffusion for lipid soluble and non-polar molecules; solute carriers including glucose, amino acids, and nucleosides; and receptor and adsorptive mediated transcytosis (Abbott et al., 2010). Glutamate and glucose transporters are significantly altered in brains of ALF animals (Belanger et al., 2006; Desjardins et al., 2001; Knecht et al., 1997). Increased vesicles have been observed in brain endothelial cells of animals and patients with ALF (Gove et al., 1997; Kato et al., 1992; Traber et al., 1987). "
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    • "To date, there are limited data on changes in the composition of brain endothelial cells in FHF. Certain astrocyte genes have been shown to be significantly altered in FHF [10]. Both endothelial and astrocytic glucose transporter proteins are selectively altered in brains of FHF animals [11]. "
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    ABSTRACT: Brain edema secondary to increased blood-brain barrier (BBB) permeability is a lethal complication in fulminant hepatic failure (FHF). Intact tight junctions (TJ) between brain capillary endothelial cells are critical for normal BBB function. However, the role of TJ in FHF has not been explored. We hypothesized that alterations in the composition of TJ proteins would result in increased BBB permeability in FHF. In this study, FHF was induced in C57BL/6J mice by using azoxymethane. BBB permeability was assessed with sodium fluorescein. Expression of TJ proteins was determined by Western blot, and their cellular distribution was examined using immunofluorescent microscopy. Comatose FHF mice had significant cerebral sodium fluorescein extravasation compared with control and precoma FHF mice, indicating increased BBB permeability. Western blot analysis showed a significant decrease in zonula occludens (ZO)-2 expression starting in the precoma stage. Immunofluorescent microscopy showed a significantly altered distribution pattern of ZO-2 in isolated microvessels from precoma FHF mice. These changes were more prominent in comatose FHF animals. Significant alterations in ZO-2 expression and distribution in the tight junctions preceded the increased BBB permeability in FHF mice. These results suggest that ZO-2 may play an important role in the pathogenesis of brain edema in FHF.
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    ABSTRACT: Ryan George was two months old when he suffered from cardiac arrest 9 days after receiving his second injection of Hepatitis B vaccine (HBV). He was successfully resuscitated at Coney Island Hospital in New York. His chest X-ray and CT scan showed evidence of pulmonary edema, bleed- ing, and pneumonia. A CT exam of his head showed brain edema. He had a blood pH of 6.83 and a potassium level of 6.0 mEq/L. He was stabilized and transferred to Maimonides Medical Center (MMC). Blood tests performed at MMC revealed that Ryan had an elevated band neutrophil count, hyperglycemia, hyperkalemia, hyperammonimia, hemolytic anemia, liver damage, hyperphosphatemia, and hypermagnesiumia. In addition, his PT, PTT, and INR were elevated. Ryan was treated with four types of antibiotics and other medications. Ryan had an MRI head exam and an eye exam performed at 8 days and 9 days after admission, respectively. His MRI showed intracranial bleed- ing and his eye exam revealed retinal bleeding. Ryan's father was accused of causing his son's injuries by shaking him vigorously (Shaken Baby Syndrome). My investigation indicates that infection with Streptococcus pneumoniae caused Ryan's illness and led to the development of hemorrhagic pneu- monia, hemolytic uremic syndrome, kidney and liver problems, hepatic encephalopathy, seizure, coma, and cardiac arrest. The likely causes of Ryan's intracranial and retinal bleeding are liver damage, infections, vitamin K deficiency, and severe anemia. Hepatitis B vaccine increased Ryan susceptibility to infection. The allegation of child abuse in this case is false. © Copyright 2008, Medical Veritas International Inc. All rights reservered
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