The mechanism of hepatic coma†

Zieve, Leslie

doi:10.1002/hep.1840010414

Cited by 157 publications

(62 citation statements)

References 18 publications

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“…In contrast to other hypotheses such as the ammonia [2,7,8,11], the synergistic neurotoxins [7,8], and the false neurotransmitter [12][13][14] hypotheses, in which the neural mechanisms responsible for inducing encephalopathy have not been precisely defined, an attractive feature of the GABA hypothesis is that the neural mechanisms responsible for mediating neural inhibition when the GABA neurotransmitter system is stimulated are well characterized [18][19][20][21][22][23][24]29]. Furthermore, some recent experimental data provide no support for the ammonia, the synergistic neurotoxins, and the false.neurotransmitter hypotheses.…”

Section: Concluding Perspectives and Speculationsmentioning

confidence: 70%

“…Some of these metabolites are neuroactive [2,[4][5][6][7][8]. However, it is not apparent which, if any, of the neuroactive metabolites that accumulate in liver failure plays a central role in the pathogenesis of hepatic encephalopathy.…”

Section: Introductionmentioning

confidence: 99%

“…Clearly if a metabolite in plasma contributes to the mediation of hepatic encephalopathy it must gain access to the brain by crossing the blood-brain barrier. Many studies, in which attempts have been made to draw inferences concerning the pathogenesis of hepatic encephalopathy, have involved deriving correlations between levels of putatively neuroactive metabolites in plasma, cerebrospinal fluid, or brain, and the degree of severity of hepatic encephalopathy [2,[4][5][6][7][8]. When such a correlation is found there are three possible explanations: (i) the increased level of the metabolite is causally related to hepatic encephalopathy; (ii) the increased level of the metabolite occurs as a consequence of hepatic encephalopathy; and (iii) some other pathophysiologic disturbance, perhaps liver failure per se, causes both hepatic encephalopathy and the increased level of the metabolite.…”

Section: Introductionmentioning

confidence: 99%

“…However, changes in the concentration of a metabolite at a critical site within the brain, such as synaptic clefts, could well be of critical importance [10]. A major deficiency of most hypotheses of the pathogenesis of hepatic encephalopathy is that the presence of putative neurotoxins cannot be correlated with specific neural mechanisms [7,8]. It seems unlikely that major advances in elucidating the pathogenesis of hepatic encephalopathy will come from studies that rely solely on measuring the levels of metabolites.…”

Section: Introductionmentioning

confidence: 99%

“…These are that the syndrome is mediated by (i) ammonia-induced neurotoxicity [2,7,8,11]; (ii) synergistic neurotoxic interactions between ammonia, mercaptans, and fatty acids [7,8]; (iii) false neurotransmitter-induced neural inhibition [12][13][14]; and (iv) activation of the gamma-aminobutyric acid (GABA) inhibitory neurotransmitter system [10,15]. Some of the observations on which the first three of these hypotheses are based and some of the main deficiencies of these three hypotheses have recently been discussed elsewhere [16,17].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

The GABA Hypothesis of the Pathogenesis of Hepatic Encephalopathy: Current Status

Jones

Schafer

Ferenci

et al. 1987

Assessment and Management of Hepatobiliary Disease

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Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter of the mammalian brain, can induce coma. Outside the central nervous system it is synthesized by gut bacteria and catabolized largely in the liver. GABA and its agonists, as well as benzodiazepines and barbiturates, induce neural inhibition as a consequence of their interaction with specific binding sites for each of these classes of neuroactive substances on the GABA receptor complex of postsynaptic neurons. In a rabbit model of acute liver failure: (i) the pattern of postsynaptic neuronal activity in hepatic coma, as assessed by visual evoked potentials, is identical to that associated with coma induced by drugs which activate the GABA neurotransmitter system (benzodiazepines, barbiturates, and GABA agonists); (ii) the levels of GABA-like activity in peripheral blood plasma increase appreciably before the onset of hepatic encephalopathy, due at least in part to impaired hepatic extraction of gut-derived GABA from portal venous blood;(iii) the blood-brain barrier becomes abnormally permeable to an isomer of GABA, a-aminoisobutyric acid, before the onset of hepatic encephalopathy; and (iv) hepatic coma is associated with an increase in the density of receptors for GABA and benzodiazepines in the brain. These findings are the bases of the following hypotheses: (i) when the liver fails, gut-derived GABA in plasma crosses an abnormally permeable blood-brain barrier and by mediating neural inhibition contributes to hepatic encephalopathy; (ii) an increased number of GABA receptors in the brain found in liver failure increases the sensitivity of the brain to GABA-ergic neural inhibition; and (iii) an increased number of drug binding sites mediates the increased sensitivity to benzodiazepines and barbiturates observed in liver failure by permitting increased drug effect. INTRODUCTIONHepatocellular failure, whether acute or chronic, is characterized by jaundice, fluid retention, a hemorrhagic diathesis, and hepatic encephalopathy [1]. Of these four complications of liver disease the pathogenesis of hepatic encephalopathy is least well understood. It has not even been established whether hepatic encephalopathy occurs as a result of failure of the liver to synthesize a substance that is necessary for the maintenance of normal brain function or failure of the liver to metabolize adequately neuroactive substances that are capable of inducing encephalopathy.

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