Role of Peripheral Inflammation in Hepatic Encephalopathy

A growing body of evidence now highlights a key role for systemic inflammation in altering behavior and mood in patients with liver disease. How inflammation occurring in the periphery in the context of liver disease, communicates with the brain to mediate changes in neurotransmission and thereby behavior is incompletely understood. Traditional routes of communication between the periphery and the brain involve neural (i.e. vagal afferent nerves) and humoral (blood-borne) pathways, with increased circulating levels of endotoxin and cytokines (especially Tumor Necrosis Factor α, TNFα) that occur during systemic inflammatory responses, as being primarily implicated in mediating signaling via these pathways. However, in recent years communication via peripheral immune-cell-to-brain and the gut-microbiota-to-brain routes have received increasing attention in the context of liver disease for their ability to modulate brain function, and generate a spectrum of symptoms ranging from fatigue and altered mood to overt Hepatic Encephalopathy (HE). In this review, we discuss periphery-to-brain communication pathways and their potential role in mediating systemic inflammation-associated alterations in behavior, that are in turn ultimately part of a spectrum of brain changes linked to the development of clinically apparent HE.