Recent advances in hepatic encephalopathy

Abstract

Hepatic encephalopathy describes the array of neurological alterations that occur during acute liver failure or chronic liver injury. While key players in the pathogenesis of hepatic encephalopathy, such as increases in brain ammonia, alterations in neurosteroid levels, and neuroinflammation, have been identified, there is still a paucity in our knowledge of the precise pathogenic mechanism. This review gives a brief overview of our understanding of the pathogenesis of hepatic encephalopathy and then summarizes the significant recent advances made in clinical and basic research contributing to our understanding, diagnosis, and possible treatment of hepatic encephalopathy. A literature search using the PubMed database was conducted in May 2017 using “hepatic encephalopathy” as a keyword, and selected manuscripts were limited to those research articles published since May 2014. While the authors acknowledge that many significant advances have been made in the understanding of hepatic encephalopathy prior to May 2014, we have limited the scope of this review to the previous three years only.

Bile Acids in Hepatic Encephalopathy

“…42 Taken together, it is conceivable that the role that aberrant FXR activation plays in the pathogenesis of hepatic encephalopathy may be via the disruption of a number of neurotransmitter systems known to be altered in hepatic encephalopathy. 43 Another indication for the possible identity of the downstream consequences of FXR signaling in the pathogenesis of hepatic encephalopathy may lie in the mechanisms by which the brain maintains cholesterol homeostasis. Approximately 25% of the body's cholesterol is found in the brain and the levels are tightly regulated so that fluctuations in dietary cholesterol have minimal effect on brain function.…”

Cerebrovascular reactivity and cerebral perfusion of rats with acute liver failure: role of L‐glutamine and asymmetric dimethylarginine in L‐arginine‐induced response

“…The pathomechanism of HE remains complex, however, the general consensus is that neurotoxic effects of blood‐derived ammonia in the brain compounded by central and systemic inflammatory processes play a dominant role (Butterworth ; Liere et al . ). It is generally assumed that intra‐astrocytic accumulation of glutamine, a product of ammonia detoxification via enzymatic conversion of glutamate by glutamine synthetase (Norenberg and Martinez‐Hernandez ), directly contributes to brain edema and other clinical manifestations of HE (Lavoie et al .…”

“…The accumulation of neurotoxic substances in the brain, owing to acute or chronic liver failure (ALF vs. CLF), results in neurological alterations known as hepatic encephalopathy (HE) (Butterworth 2003;Felipo 2013). The pathomechanism of HE remains complex, however, the general consensus is that neurotoxic effects of blood-derived ammonia in the brain compounded by central and systemic inflammatory processes play a dominant role (Butterworth 2013;Liere et al 2017). It is generally assumed that intra-astrocytic accumulation of glutamine, a product of ammonia detoxification via enzymatic conversion of glutamate by glutamine synthetase (Norenberg and Martinez-Hernandez 1979), directly contributes to brain edema and other clinical manifestations of HE (Lavoie et al 1987;Laubenberger et al 1997;Tofteng et al 2006).…”

The Pivotal Role of the Glutamate - glutamine Cycle in Minimal Hepatic Encephalopathy. An experimental magnetic resonance spectroscopy study

“…The ammonia accumulation in the plasma together with increased permeability of the blood-brain barrier induce an increase of ammonia in the astrocytes, which will quickly be incorporated into glutamine that will increase in concentration. The accumulated glutamine leads to astrocyte swelling that can trigger a downward spiral leading to increase in production of reactive oxygen and nitrogen species, which can downstream target gene transcription and translation [16]. Glutamine accumulation may be also related to a decreased capacity of astrocytes to take up glutamate, thus leading to glutamate excitotoxicity [15].…”