First-Line Treatment for Hepatic Encephalopathy

Lactulose is the first-line treatment for hepatic encephalopathy (HE). 1, 2, 3

Treatment Algorithm

Identify and treat precipitating factors including gastrointestinal bleeding, infection, constipation, excessive protein intake, dehydration, renal dysfunction, electrolyte imbalances, and medications such as benzodiazepines or opioids 1, 2
Begin lactulose at 30-45 mL (20-30 g) orally every 1-2 hours until the patient has at least 2 bowel movements per day 2
After initial response, titrate lactulose to maintain 2-3 soft stools daily 2

For patients unable to take oral medications, administer lactulose via nasogastric tube 2
For severe HE (West-Haven criteria grade ≥3) or when oral/nasogastric administration isn't possible, use lactulose enema (300 mL lactulose in 700 mL water) 3-4 times daily until clinical improvement 2

Lactulose reduces intestinal pH through bacterial degradation to acetic and lactic acids 1, 2
Increases lactobacillus count, which doesn't produce ammonia 1, 2
Converts ammonia to non-absorbable ammonium 1, 2
Creates an osmotic laxative effect that flushes ammonia out of the intestines 1

Lactulose therapy reduces blood ammonia levels by 25-50%, which generally parallels improvement in mental state and EEG patterns 3
Clinical response has been observed in approximately 75% of patients 3
Lactulose has been used for over 2 years in controlled studies for chronic portal-systemic encephalopathy 3

Rifaximin (550 mg twice daily) should be added to lactulose when patients experience recurrent episodes of HE despite lactulose therapy 1, 2, 4
Combination therapy with rifaximin and lactulose shows better recovery from HE (76% vs. 44%) and shorter hospital stays compared to lactulose alone 2
In clinical trials for rifaximin, 91% of patients were using lactulose concomitantly 4

Oral branched-chain amino acids (BCAA) at 0.25 g/kg/day can be used as an alternative or additional agent for patients not responsive to conventional therapy 1, 2
Intravenous L-ornithine L-aspartate (LOLA) at 30 g/day can be used as an alternative or additional agent for patients not responsive to conventional therapy (note: oral LOLA is ineffective) 1, 2
Neomycin and metronidazole are alternative choices for HE treatment but are not recommended as first-line agents due to significant side effects including ototoxicity, nephrotoxicity, and neurotoxicity with long-term use 1, 2

Titrate lactulose dosage to achieve 2-3 soft bowel movements daily 2
Monitor for excessive diarrhea, dehydration, and electrolyte imbalances which can worsen HE 1
Venous blood ammonia levels are not proportional to the degree of HE and are not associated with its prognosis; however, if patients with suspected HE show normal ammonia concentrations, differentiation from other diseases is required 1

Lactulose may cause abdominal cramping, flatulence, and diarrhea which can lead to dehydration and electrolyte imbalances if not properly monitored 5
Rifaximin has not been studied extensively in patients with MELD scores >25, and only 8.6% of patients in controlled trials had MELD scores over 19 4
There is increased systemic exposure to rifaximin in patients with more severe hepatic dysfunction 4
Patients with TIPS (transjugular intrahepatic portosystemic shunt) may develop HE that doesn't respond well to standard therapy; in these cases, shunt diameter reduction may be necessary 2