Current concepts in the pathophysiology and management of hepatic encephalopathy

Abstract

Hepatic encephalopathy (HE) represents a broad continuum of neuropsychological dysfunction in patients with acute or chronic liver disease and/or portosystemic shunting of blood flow. The pathophysiology of this disease is quite complex, as it involves overproduction and reduced metabolism of various neurotoxins, particularly ammonia. Recent hypotheses implicate low-grade cerebral edema as a final common pathway for the pathophysiology of HE. Management of this condition is multifaceted and requires several steps: elimination of precipitating factors; removal of toxins, both by reducing them at their source and by augmenting scavenging pathways; modulation of resident fecal flora; proper nutritional support; and downregulation of systemic and gut-derived inflammation.

Keywords: Hepatic encephalopathy; ammonia; cerebral edema; glutaminase; urea cycle.

Figure 1

Hypothesis of the multifactorial nature of hepatic encephalopathy. Various neurotoxins and NTs act independently or perhaps synergistically to cause astrocyte swelling and subsequent astrocyte dysfunction. In addition, increased “GABA-ergic tone” and depletion of Ach may contribute to neurologic dysfunction in patients with hepatic encephalopathy. A vicious cycle may perpetuate the disease, as ROS trigger astrocyte swelling, and further swelling causes production of more ROS and RNS and subsequent mitochondrial energy failure. Ach

acetylcholine

AChE

acetylcholinesterase

BBB

blood brain barrier

GABA

gamma aminobutyric acid

Gln Synth

glutamine synthetase

NMDA

N-metyhl-D-aspartic acid

NT

neurotransmitter

RNS

reactive nitrogen species

ROS

reactive oxygen species