What is the first line treatment for hepatic encephalopathy?

First-Line Treatment for Hepatic Encephalopathy

Lactulose is the first-line treatment for hepatic encephalopathy, with a recommended dosage of 30-45 mL (20-30 g) orally every 1-2 hours until the patient has at least 2 bowel movements per day, then titrated to achieve 2-3 soft stools daily. 1, 2

Treatment Algorithm

Step 1: Identify and Treat Precipitating Factors

• First, identify and manage precipitating factors including gastrointestinal bleeding, infection, constipation, excessive protein intake, dehydration, renal dysfunction, electrolyte imbalance, psychoactive medications, and acute hepatic injury 1

Step 2: Initiate First-Line Therapy with Lactulose

• Begin lactulose at 30-45 mL (20-30 g) orally every 1-2 hours until the patient has at least 2 bowel movements daily 1
• After initial response, titrate to maintain 2-3 soft stools per day 1
• For patients unable to take oral medications, administer via nasogastric tube 1
• 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 1, 3

Step 3: Add-On Therapy for Inadequate Response

• Rifaximin (550 mg twice daily or 400 mg three times daily) can be added to lactulose for better outcomes 1, 4
• Combination therapy with rifaximin and lactulose shows better recovery from HE (76% vs. 44%) and shorter hospital stays (5.8 vs. 8.2 days) compared to lactulose alone 1, 5

Step 4: Alternative or Additional Agents for Non-Responders

• Oral branched-chain amino acids (BCAA) at 0.25 g/kg/day 1
• Intravenous L-ornithine L-aspartate (LOLA) at 30 g/day 1
• Intravenous albumin at 1.5 g/kg/day until clinical improvement or for maximum 10 days 1
• Polyethylene glycol (4 liters orally) as an alternative to non-absorbable disaccharides 1

Evidence Quality and Considerations

• Lactulose has been shown to reduce blood ammonia levels by 25-50%, which correlates with improvement in mental status and EEG patterns 2
• Clinical response to lactulose occurs in approximately 75% of patients 2, 6
• The mechanism of action involves:
  • Reduction of intestinal pH through bacterial degradation to acetic and lactic acids 1
  • Increasing lactobacillus count, which doesn't produce ammonia 1
  • Converting ammonia to non-absorbable ammonium 1, 3
  • Creating an osmotic laxative effect that flushes ammonia from the intestines 1, 7

Common Pitfalls and Caveats

• Neomycin and metronidazole, while effective in reducing ammonia production, are not recommended as first-line agents due to significant side effects:
  • Neomycin: intestinal malabsorption, nephrotoxicity, and ototoxicity 1
  • Metronidazole: peripheral neuropathy with long-term use 1
• Rifaximin alone is not recommended as first-line therapy; in clinical trials for hepatic encephalopathy, 91% of patients were using lactulose concomitantly 4
• Oral LOLA supplementation is ineffective, only the intravenous form shows benefit 1
• For prevention of recurrent HE, continued lactulose therapy is recommended, with rifaximin added for those who experience breakthrough episodes while on lactulose 1, 5
• 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 1