STUDIES OF THE PATHOGENESIS OF ACUTE HEPATIC COMA

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The abnormal pattern of visual evoked potentials (VEPs) in rabbits with hepatic encephalopathy (HE) due to fulminant hepatic failure (FHF) resembles that associated with coma induced by a barbiturate, a benzodiazepine or a gamma-amino-butyric acid (GABA) agonist. As these drugs induce neural inhibition by interacting with binding sites on the GABA receptor complex on postsynaptic neural membranes, these findings suggest that the pattern of neuronal activity in HE may resemble that associated with the activation of the GABA inhibitory neurotransmitter system. Outside the CNS the main source of GABA is gut bacteria and the main site of its catabolism is the liver. When FHF was induced in rabbits the onset of HE was preceded by a marked increase in the plasma levels of GABA and by a nonspecific increase in the permeability of the blood brain barrier (BBB) to a nonmetabolized isomer of GABA. To take account of the rapid metabolism of GABA a modified Oldendorf technique, which employed the use of a vascular marker, has been used to demonstrate that the brain uptake index for GABA is increased in HE. FHF was associated with significant increases in the densities of brain receptors for the inhibitory amino acid neurotransmitters, GABA and glycine, and for benzodiazepines (BZ). FHF was also associated with significant decreases in the densities of brain receptors for the excitatory amino acid neurotransmitters, glutamate and aspartate. FHF was not associated with any change in the densities of brain receptors for four non-amino acid neurotransmitters. These findings suggest that as the liver fails: (i) impaired hepatic metabolism of GABA contributes to an increase of gut-derived GABA in plasma, (ii) plasma GABA gains access to the brain through a permeable BBB and contributes to the neural inhibition of HE and (iii) the brain may be less sensitive to excitatory amino acid neurotransmitters and more sensitive to inhibitory amino acid neurotransmitters. In rabbits with FHF the administration of a BZ or GABA antagonist has been shown to ameliorate HE (both clinically and electrophysiologically).