Is it worth removing albumin-bound substances in Hepatic Encephalopathy?

Hepatic encephalopathy is the result of the exposure of the brain to circulating toxins rather than the consequence of a deficient trophic factor. For decades, controversy has characterized the nature of these toxins. Studies in imperfect animal models and the difficulty in performing pathogenic studies in humans have been hurdles in the elucidation of the pathogenesis of HE. Furthermore, it has become clear that exposure of brain to these toxins triggers additional intracranial events that become independent of the original toxin. For example, the increase in cerebral blood flow seen in fulminant hepatic failure [1], the increased synthesis of neurosteroids in the brain [2] and recently reported alterations in glutamatergic neurotransmission [3] all arise from mechanisms triggered after the initial exposure of the brain to such toxins. This paradigm has an anatomical counterpart in the alterations of astrocyte shape, volume and function that characterize hepatic encephalopathy [4].

What is the current status of knowledge of the role of albumin-bound toxins in HE?

Manganese. In cirrhosis, Mn accumulates in blood and brain as a result of both portal-systemic shunting and liver dysfunction, leading to pallidal signal hyperintensity on T1-weighted MR imaging. Mn is transported in the blood bound to albumin primarily in the divalent oxidation state (Mn2+) and crosses the BBB via specific carriers at a rate far slower than in other tissues. Within the CNS, Mn accumulates primarily within astrocytes, presumably because the astrocyte-specific enzyme, glutamine synthetase (GS), represents an important regulatory target of Mn 5. In addition, chronic exposure of rat primary astrocyte cultures to manganese results in increased binding sites for the ‘peripheral-type’ benzodiazepine receptor ligand 3H-PK 11 195, a factor that may promote increased synthesis of brain neurosteroids, a ligand of GABAA receptors. Endogenous benzodiazepines. Benzodiazepines such as diazepam and nordiazepam bind to GABAA receptors and their presence has been postulated in non-exposed human blood and brains as well as in medicinal plants and foods. In plasma and brain tissue other non-halogenated benzodiazepine-like compounds termed endozepines have been found. These compounds could be of exogenous source 6. Cirrhotic patients may accumulate these albumin-bound compounds because of decreased liver metabolic capacity. Increased binding sites for the ‘peripheral-type’ benzodiazepine receptor ligand 3H-PK 11 195 in cirrhosis have been demonstrated in human autopsy material. Single dose studies of flumazenil, a benzodiazepine receptor antagonist, have shown a positive, albeit small, arousal effect. Cytokines. Elevated levels of interleukin 6 have been noted in cirrhotic patients with HE 7. Entry of cytokines into brain tissue is not necessary in the case of IL-1, as receptors in the cerebral endothelial cell trigger transduction mechanisms that result in the generation of nitric oxide and prostanoids in microglia. High levels of cytokines are noted in specific liver conditions associated with encephalopathy, such as alcoholic hepatitis. Tryptophan. A serotoninergic precursor, tryptophan circulates bound to albumin and its availability to brain is increased in hypoalbuminemia. Alterations in serotoninergivc neurotransmission are well described in animal models of HE.

Among non-albumin bound toxins, ammonia continues to play a central role in our views of the pathogenesis of encephalopathy. Circulating glutamine and urea can be viewed as ammonia-equivalents. Any support system for HE that is based on the removal of albumin-bound toxins needs to consider the effects of such an approach on the removal of ammonia and equivalents.

References

• 1 Blei A T, Larsen F S. J Hepatol. 1999; 
• 2 Norenberg M D. et al . Adv Exp Med Biol. 1997;  420 95-111
• 3 Butterworth R F. J Hepatol. 2000;  32 171-80 (1 Suppl.)
• 4 Haussinger D. et al . J Hepatol. 2000 Jun;  32 1035-1038
• 5 Aschner M. et al . Neurotoxicology. 1999;  20 173-180
• 6 Baraldi M. et al . Therapie. 2000 Jan-Feb;  55 143-146
• 7 Genesca J. et al . Am J Gastroenterol. 1999 Jan;  94 169-175 (1)

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