Clinical meaning
Hepatic encephalopathy (HE) is a spectrum of neuropsychiatric abnormalities resulting from liver failure's inability to metabolize neurotoxins, most importantly ammonia (NH₃). In normal physiology, intestinal bacteria produce ammonia through protein catabolism and urease activity; ammonia is absorbed from the intestine via the portal circulation and efficiently converted to urea in the liver via the urea cycle (ornithine transcarbamylase pathway). In cirrhosis, two mechanisms cause hyperammonemia: (1) reduced hepatocyte mass decreases urea cycle capacity, and (2) portosystemic shunting diverts ammonia-laden portal blood directly into systemic circulation, bypassing hepatic detoxification. Ammonia crosses the blood-brain barrier and is metabolized by astrocytes via glutamine synthetase, converting glutamate to glutamine. Glutamine accumulation causes osmotic swelling of astrocytes (Alzheimer type II astrocytosis), disrupting astrocyte function, neurotransmitter metabolism, and cerebral autoregulation. Additional neurotoxic mechanisms include manganese accumulation in the basal ganglia (causing extrapyramidal symptoms), increased GABAergic tone (contributing to somnolence), and neuroinflammation from systemic inflammatory mediators. HE is classified as covert (minimal HE — psychometric testing abnormalities without clinical signs) or overt (clinically apparent: Grade I — mild confusion, sleep disturbance; Grade II — lethargy, asterixis, disorientation; Grade III — somnolence, marked confusion; Grade IV — coma). Precipitating factors include GI bleeding (protein load), infection/sepsis, constipation, dehydration, hypokalemia/alkalosis (increases renal ammonia production), excess dietary protein, benzodiazepine/opioid use, and non-adherence to lactulose. The clinician identifies and treats precipitants, initiates lactulose to achieve 2-3 soft bowel movements per day (traps ammonia as ammonium in the acidified colonic lumen), adds rifaximin for secondary prophylaxis, and considers TIPS occlusion for refractory post-TIPS HE.