Hepatic Encephalopathy Pharmacotherapy

Hepatic encephalopathy is a reversible neuropsychiatric syndrome from liver failure or portosystemic shunting, ranging from minimal encephalopathy detected only by testing, through West Haven grade 1 (altered sleep, attention and mood), grade 2 (lethargy, disorientation, asterixis), grade 3 (somnolence, confusion) to grade 4 (coma). Ammonia generated by gut bacteria and renal glutamine metabolism is the main driver, with inflammation, hyponatraemia and sarcopenia contributing.

Precipitants. Infection, gastrointestinal bleeding, constipation, dehydration from diuretics or lactulose, hypokalaemia, hyponatraemia, acute kidney injury, sedatives and opioids, alcohol, and transjugular intrahepatic portosystemic shunt placement.

Diagnosis. Clinical; exclude other causes of confusion with glucose, sodium, kidney function, infection screen, toxicology, and neuroimaging for focal signs or trauma. A normal ammonia level makes the diagnosis less likely but a raised level alone does not confirm it.

Treat the precipitant first. Give antibiotics for infection, stop diuretics and sedatives, correct electrolytes, stop bleeding and clear the bowel.

Acute episode (grades 1 to 4).

• Lactulose 30 to 45 mL (20 to 30 g) orally every 1 to 2 hours until the first bowel movement, then 15 to 30 mL two to three times daily titrated to 2 to 3 soft stools daily.
• If the patient cannot swallow or has ileus, give a lactulose enema of 300 mL in 700 mL of water, held for 30 to 60 minutes, repeated every 6 to 8 hours.
• Polyethylene glycol (a 4 litre electrolyte solution given over 4 hours) is an alternative for acute episodes, with faster resolution in some patients.
• Add rifaximin 550 mg orally twice daily when response is slow, in recurrent episodes, or while precipitants persist.

Secondary prevention after a first episode. Lactulose 15 to 30 mL orally two to three times daily titrated to 2 to 3 soft stools daily.

Secondary prevention after a recurrence. Add rifaximin 550 mg orally twice daily to lactulose, and continue long term.

Primary prevention. Lactulose may be used after variceal bleeding, and rifaximin in selected patients before transjugular intrahepatic portosystemic shunt.

Minimal encephalopathy. Treat if it affects driving or work, with lactulose.

Adjuncts with weaker evidence. - L-ornithine L-aspartate 20 to 40 g intravenously over 24 hours, or 3 g orally three times daily. - Oral branched-chain amino acids at 0.25 g/kg daily in patients who cannot tolerate dietary protein. - Zinc supplementation if deficient.

Not advised. Neomycin (nephrotoxic and ototoxic), long-term metronidazole (neurotoxicity), benzodiazepines, flumazenil as routine therapy, and protein restriction.

Nutrition. Give protein 1.2 to 1.5 g/kg/day and energy 35 to 40 kcal/kg/day, with a late evening snack, to counter sarcopenia.

Grade 3 or 4. Protect the airway, place in a high dependency or intensive care setting, intubate if Glasgow Coma Scale is 8 or less, and exclude intracranial pathology.

Lactulose adverse effects. Bloating, cramps, dehydration, hypernatraemia and hypokalaemia from over-purging, which worsen encephalopathy and kidney function.

Rifaximin. Well tolerated. Exposure rises in Child-Pugh C, so use with caution. Clostridioides difficile infection and resistance are possible with long courses.

Pregnancy. Lactulose is safe. Rifaximin has limited data and is used only if essential.

Breastfeeding. Lactulose is compatible. Rifaximin is minimally absorbed with limited data.

Children. Paediatric dosing of lactulose and rifaximin should be set with paediatric hepatology.

Older adults. Reduce lactulose increments and check sodium and kidney function closely.

Kidney impairment. Hepatorenal syndrome and dehydration often coexist; avoid over-purging.

East Africa. Rifaximin availability and cost vary across the region; secure lactulose supply first. Constipation, infection and gastrointestinal bleeding are common precipitants, and herbal enemas or remedies should be asked about.

Interactions. Avoid sedatives, opioids and anticholinergics. Neomycin with other nephrotoxins adds kidney injury risk.

Monitoring. Mental state and West Haven grade, asterixis, stool count, hydration, sodium, potassium and creatinine at least daily in hospital. Reduce lactulose if more than 3 stools daily or if dehydration develops.

Response targets. Improvement in grade within 24 to 48 hours; if there is none, look again for a missed precipitant, structural brain lesion, non-convulsive seizures, or large spontaneous portosystemic shunt.

Stopping. Continue lactulose indefinitely after a first episode while liver disease persists, unless side effects prevent it. Continue rifaximin until transplant or until liver function recovers.

Referral and escalation. Refer to hepatology for any recurrent episode, grade 3 or 4 encephalopathy, or persistent symptoms. Consider embolisation of large spontaneous shunts and transplant assessment in recurrent disease.