Pathophysiology of hepatic encephalopathy: a new look at ammonia

Metab Brain Dis. 2002 Dec;17(4):221-7. doi: 10.1023/a:1021989230535.


Results of neuropathologic, spectroscopic, and neurochemical studies continue to confirm a major role for ammonia in the pathogenesis of the central nervous system complications of both acute and chronic liver failure. Damage to astrocytes characterized by cell swelling (acute liver failure) or Alzheimer Type II astrocytosis (chronic liver failure) can be readily reproduced by acute or chronic exposure of these cells in vitro to pathophysiologically relevant concentrations of ammonia. Furthermore, exposure of the brain or cultured astrocytes to ammonia results in similar alterations in expression of genes coding for key astrocytic proteins. Such proteins include the structural glial fibrillary acidic protein, glutamate transporters, and peripheral-type (mitochondrial) benzodiazepine receptors. Brain-blood ammonia concentration ratios (normally of the order of 2) are increased up to fourfold in liver failure and arterial blood ammonia concentrations are good predictors of cerebral herniation in patients with acute liver failure. Studies using 1H magnetic resonance spectroscopy in patients with chronic liver failure reveal a positive correlation between the severity of neuropsychiatric symptoms and brain concentrations of the brain ammonia-detoxification product glutamine. Increased intracellular glutamine may be a contributory cause of brain edema in hyperammonemia. Positron emission tomography studies using 13HN3 provide evidence of increased blood-brain ammonia transfer and brain ammonia utilization rates in patients with chronic liver failure. In addition to the use of nonabsorbable disaccharides and antibiotics to reduce gut ammonia production, new approaches to the treatment of hepatic encephalopathy by lowering of brain ammonia include the use of L-ornithine-L-aspartate and mild hypothermia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Ammonia / antagonists & inhibitors
  • Ammonia / metabolism*
  • Brain / pathology
  • Hepatic Encephalopathy / diet therapy
  • Hepatic Encephalopathy / drug therapy
  • Hepatic Encephalopathy / physiopathology*
  • Humans
  • Liver Failure / metabolism
  • Liver Failure / pathology


  • Ammonia