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Benzodiazepines in hepatic encephalopathy: sleeping with the enemy
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  1. S DASARATHY,
  2. K D MULLEN
  1. Division of Gastroenterology,
  2. Metrohealth Medical Center,
  3. Case Western Reserve University,
  4. Cleveland, OH 44109, USA

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See article on page861

This issue of the journal contains an article on the sometimes controversial area of the pathogenesis of hepatic encephalopathy (see page 861). There is little consensus in the field but most accept that failure of hepatic clearance of toxic compounds originating in the gut causes hepatic encephalopathy. Most evidence suggests that ammonia is the key gut derived toxin mediating hepatic encephalopathy.1 Initially there was doubt whether ammonia was truly present in blood in vivo. Once this issue was resolved, many studies were undertaken to establish whether the level of hyperammonaemia correlated with the clinical severity of hepatic encephalopathy. The result of these efforts has largely been negative. To quote Stahl’s classic study published in 1963, “A considerable overlap still persists amongst the ammonia values of the different degrees of coma.”2 Other gut derived compounds have been proposed as possible mediators of hepatic encephalopathy and include gamma amino butyric acid and benzodiazepines.3 These benzodiazepines refer to a group of largely lipophillic compounds of low molecular weight, which bind to specific benzodiazepine receptors. Since the discovery of central nervous system (CNS) benzodiazepine receptors in 1977, a vigorous search has been made to identify endogenous ligands that bind to these receptors.4 ,5Unlike the analogous situation with opiate receptors where endogenously synthesised ligands were identified (for example, endorphins and enkephalins) the benzodiazepine receptor ligands may be xenobiotic in origin. That is, these receptors exist in mammalian brain because of exposure to natural benzodiazepines present in food or generated in the gut.6-8 The endogenous benzodiazepine hypothesis should probably therefore be renamed the “natural benzodiazepine hypothesis” unless subsequently evidence of endogenous synthesis of these compounds becomes available.

The natural benzodiazepine hypothesis simply states that hepatic encephalopathy may arise in a proportion of patients as …

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