Current Theories on the Pathogenesis of Hepatic Encephalopathy

Abstract

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of both acute and chronic liver disease. Several hypotheses have emerged following the development of appropriate animal models of HE and following studies using postmortem brain tissue from HE patients. It was originally suggested that primary energy failure was responsible for HE; however, there is now mounting evidence that the pathogenetic defect involves neurotransmission failure. Specific neurotransmitter systems implicated in the pathogenesis of portal-systemic encephalopathy (PSE) include the excitatory amino acid glutamate as well as neuroactive and/or neurotoxic biogenic amine metabolites. Although it has been proposed that alterations in the gamma-aminobutyric acid (GABA) system may play a pathogenic role in HE associated with both chronic and acute liver failure, there is now overwhelming evidence to the contrary. On the other hand, there is evidence to suggest that a subgroup of patients with HE have increased blood and CSF concentrations of substances that bind to GABA-related benzodiazepine receptors in brain. Alterations of both the glutamatergic and serotoninergic neurotransmitter systems in PSE likely result from the metabolic consequences of chronic exposure of brain to toxic levels of ammonia. In addition to its effects on glutamatergic and serotoninergic systems during chronic liver disease, ammonia has been intimately associated with the brain edema invariably observed in acute liver failure. It is evident that, regardless of the type of liver failure, effective reductions of ammonia levels remains the strategy of choice in the prevention of encephalopathy. The further elucidation of neurotransmitter alterations in HE could result in novel "downstream" neuropharmacologic approaches to its prevention and treatment.

Role of Helicobacter pylori infection in the pathogenesis of minimal hepatic encephalopathy and effect of its eradication

“…Ammonia has been one of the most widely studied etiological factors in the pathogenesis of hepatic encephalopathy [10]. About half of the ammonia produced in the intestine is synthesized by luminal bacteria, with the remainder coming from dietary protein and glutamine.…”

Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage

“…In addition, we observed in our patch-clamp experiments that higher concentrations of ammonium caused large currents with unusual characteristics that suggested that the cell was being damaged. Thus, ammonium-sensitive ASICs may participate in the pathological conditions of the brain caused by elevated blood ammonium content arising from cirrhosis or hepatic failure (31)(32)(33)(34)(35).…”

Altered open-field behavior in experimental chronic hepatic encephalopathy after single venlafaxine and citalopram challenges

“…The PCS rat displays several neurochemical, neurophysiological and neurohistopathological changes resembling those seen in human chronic HE, including substantially increased blood and brain ammonia and tryptophan levels and enhanced brain serotonin (5-hydroxytryptamine; 5-HT) metabolism (for recent overviews see, e.g. Mousseau and Butterworth 1994;Bengtsson et al 1997). The most frequently reported behavioral change in PCS rats has been that of hypoactivity, especially evidenced as lowered spontaneous locomotor activity (Tricklebank et al 1978(Tricklebank et al , 1981Martin et al 1980Martin et al , 1986Bengtsson et al 1986Bengtsson et al , 1988Bengtsson 1987;Ribeiro et al 1992;Apelqvist et al 1997Apelqvist et al , 1998.…”

“…Furthermore, these patients may have altered diurnal rhythms, particularly with respect to sleep pattern (Adams and Foley 1953;Elsass et al 1978;Conn and Lieberthal 1979;Jones and Gammal 1988). Such diverse symptomatology may indicate multilevel neuronal dysfunction, possibly reßecting primary neurotransmission alteration in the brain (Mousseau and Butterworth 1994;Bengtsson et al 1997).…”