Hepatic Encephalopathy
Grading, precipitants, lactulose, rifaximin and preventing recurrence
Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of liver disease, resulting from the accumulation of toxins — primarily ammonia — that the damaged liver fails to clear. It ranges from subtle cognitive impairment to deep coma. Identifying and treating the precipitant, alongside specific pharmacological management, is the cornerstone of treatment. Careful evaluation of the underlying cause and trigger is essential at every episode.
Pathophysiology and Grading
Hepatic encephalopathy occurs when the liver fails to clear gut-derived toxins, particularly ammonia produced by colonic bacteria from protein metabolism. Ammonia crosses the blood-brain barrier and causes astrocyte swelling, impaired neurotransmission, and cerebral oedema in severe cases. HE is graded using the West Haven Criteria: Grade I (mild confusion, altered mood, sleep disturbance), Grade II (lethargy, disorientation, asterixis), Grade III (confused, responding to stimuli but not verbal, marked asterixis), Grade IV (coma, no response to painful stimuli). Covert or minimal HE (detectable only by psychometric testing) affects up to 80% of patients with cirrhosis and significantly impairs driving ability and quality of life.
Common Precipitants
In most cases of HE, a precipitant can be identified and treated — this is as important as treating the encephalopathy itself. Common precipitants include: gastrointestinal bleeding (blood in the gut is metabolised to ammonia), constipation (prolongs gut transit, increases ammonia production), infections especially spontaneous bacterial peritonitis (SBP), urinary tract infections, and chest infections, dehydration and electrolyte imbalance especially hyponatraemia and hypokalaemia, over-diuresis (reduces renal ammonia excretion), high protein intake, sedative drugs including benzodiazepines and opioids, and hepatorenal syndrome. A systematic search for the precipitant should accompany every episode of HE.
Pharmacological Management
Lactulose is the cornerstone of HE management. It is a non-absorbable disaccharide that acidifies the colon (converting ammonia to ammonium ions which cannot be absorbed) and acts as a laxative to reduce gut transit time. The dose is titrated to produce 2–3 soft stools per day (typically 15–30 ml two to four times daily). Rifaximin 550 mg twice daily is a minimally absorbed antibiotic that reduces ammonia-producing gut bacteria. It is licensed in the UK for the prevention of recurrent HE in patients who have had two or more overt episodes — added to lactulose, it reduces recurrence by 58% (NEJM RFHE trial). Zinc supplementation (zinc acetate or zinc sulphate) may be useful in malnourished patients — zinc is a cofactor for urea cycle enzymes. L-ornithine L-aspartate (LOLA) is an alternative ammonia-lowering agent used in some centres.
Dietary Management and Nutrition
Protein restriction is no longer recommended — adequate protein intake (1.0–1.5 g/kg/day) is essential to prevent muscle wasting (sarcopenia), which itself worsens HE by reducing peripheral ammonia uptake by muscle. Small, frequent meals and a late-evening carbohydrate snack reduce overnight catabolism. Branched-chain amino acids (BCAAs) — leucine, isoleucine, valine — may be used in patients intolerant of standard dietary protein. Nutritional support via NG feeding should be considered early in hospitalised patients who are unable to eat adequately.
Preventing Recurrence
After a first overt episode of HE, the risk of recurrence within 6 months exceeds 40%. Maintenance lactulose (titrated to 2–3 soft stools per day) is the mainstay of prevention. Rifaximin is added after a second episode. Patients should be counselled on recognising early warning signs of HE and when to seek medical help. Driving should be stopped and DVLA informed. Screening for and treating infection promptly, avoiding sedatives, maintaining adequate nutrition, and monitoring electrolytes and renal function all reduce recurrence risk. Patients should be assessed for liver transplantation — transplantation resolves HE by restoring hepatic function.