Ammonia and inflammation in the pathogenesis of hepatic encephalopathy: Pandora's box?

Hepatic encephalopathy (HE), the neuropsychiatric manifestation of liver disease, incorporates a spectrum of manifestations ranging from minimal derangements in neuropsychological function to confusion and coma. Over the past 10 years, studies have confirmed the strong association between hyperammonemia due to liver dysfunction and infection/inflammation in the pathogenesis of HE, in acute liver failure,1 cirrhosis,2 and more recently in acute-on-chronic liver failure.3 An improvement in HE following interventions which modulate inflammatory responses, such as hypothermia,4 and the use of indomethacin (cyclo-oxygenase pathway),5,6 albumin and albumin dialysis (free radicals, free metals, nonspecific protein-bound substances)7 and, probiotics (endotoxin)8 indicates that reducing inflammation is also a valid modality for treating HE. In this issue, Cauli et al.9 report in a rat model improved learning ability in animals with HE following the administration of the nonsteroidal anti-inflammatory drug (NSAID), ibuprofen. They showed that the chronic administration of ibuprofen (from day 10 up to 4 weeks after portacaval shunting [PCS]) at 5-6 times the therapeutic doses resulted in a “normalization” of cyclo-oxygenase (COX) and inducible nitric oxide synthase (iNOS) activity. Moreover, administration of ibuprofen was also associated with improvement in the glutamate–nitric oxide–cyclic guanosine monophosphate (Glu-NOcGMP) pathway. In PCS rats, brain interleukin-6 was elevated but tumor necrosis factor alpha (TNF ) remained unchanged, and controversially, TNF increased significantly in the ibuprofen-treated animals. It is important to note that this model is more akin to that observed in “minimal HE” as opposed to more severe forms of liver disease and therefore must be interpreted in this light. This study touches on the complex processes and multiple cell types involved in the pathogenesis of HE, highlighting the importance of inflammatory pathways and their modulation in the treatment of “minimal HE”. The questions that need to be addressed in the interpretation of the data presented and implications for pathogenic mechanisms and therapy are: