Alterations in expression of genes coding for key astrocytic proteins in acute liver failure.
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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ABSTRACT: Acute liver failure (ALF) is characterized by severe and sud-den liver cell dysfunction leading to coagulopathy and he-patic encephalopathy in previously healthy persons. A criti-cal degree of liver cell death not adequately decompensated by hepatocellular regenerative activity is fundamental to the development of ALF. Interaction between two dominant pathological pathways is illustrated as the triggering event: apoptosis and necrosis. A correlation has been demonstrated between the etiology of ALF and the dominating pathologi-cal pathway. Liver cell death signaling pathways modulated by an increasingly recognized number of tyrosine kinases, adapter molecules, transcription factors, proinflammato-ry and vasoactive cytokines and chemokines through both stimulating and depressant interactions have been demon-strated. What's more Systemic Inflammatory Response Syn-drome whether or not precipitated by infection, appears to be implicated in the progression of encephalopathy, reduc-ing the chances of transplantation and conferring a poorer prognosis. Hepatic encephalopathy and brain edema arising from exposure of the brain to circulating neurotoxins also signifies a serious prognosis in ALF.
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ABSTRACT: Children with urea cycle disorders (UCDs) or organic acidemias (OAs) and acute hyperammonemia and encephalopathy are at great risk for neurological injury, developmental delay, intellectual disability, and death. Nutritional support, intravenous alternative pathway therapy, and dialysis are used to treat severe hyperammonemia associated with UCDs and nutritional support and dialysis are used to treat severe hyperammonemia in OAs. Brain protective treatment while therapy is initiated may improve neurological and cognitive function for the lifetime of the child. Animal experiments and small clinical trials in hepatic encephalopathy caused by acute liver failure suggest that therapeutic hypothermia provides neuroprotection in hyperammonemia associated encephalopathy. We report results of an ongoing pilot study that assesses if whole body cooling during rescue treatment of neonates with acute hyperammonemia and encephalopathy is feasible and can be conducted safely. Adjunct whole body therapeutic hypothermia was conducted in addition to standard treatment in acutely encephalopathic, hyperammonemic neonates with UCDs and OAs requiring dialysis. Therapeutic hypothermia was initiated using cooling blankets as preparations for dialysis were underway. Similar to standard therapeutic hypothermia treatment for neonatal hypoxic ischemic encephalopathy, patients were maintained at 33.5°C±1°C for 72h, they were then slowly rewarmed by 0.5°C every 3h over 18h. In addition data of age-matched historic controls were collected for comparison. Seven patients were cooled using the pilot study protocol and data of seven historic controls were reviewed. All seven patients survived the initial rescue and cooling treatment, 6 patients were discharged home 2-4weeks after hospitalization, five of them feeding orally. The main complication observed in a majority of patients was hypotension. Adjunct therapeutic hypothermia for neonates with UCDs and OAs receiving standard treatment was feasible and could be conducted safely in pediatric and neonatal intensive care units experienced in the application of therapeutic hypothermia in critically ill neonates. However, including adjunct therapeutic hypothermia in the already involved treatment regimen of critically ill patients with hyperammonemia and encephalopathy adds to the complexity of care and should not be done unless it is proven efficacious in a randomized clinical trial.Molecular Genetics and Metabolism 05/2013; · 2.83 Impact Factor
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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