What is the role of L-ornithine L-aspartate in the treatment of hepatic encephalopathy in adults?

Role of L-ornithine L-aspartate in Adults with Hepatic Encephalopathy

L-ornithine L-aspartate (LOLA) is recommended as an adjunctive therapy for adults with overt hepatic encephalopathy, particularly in acute-on-chronic liver failure (ACLF) patients, with intravenous administration at 30 g/day showing the most benefit. 1

Mechanism of Action

• LOLA serves as a substrate for the urea cycle and stimulates enzymatic activity in residual hepatocytes, leading to increased urea excretion and lowered plasma ammonia concentrations 1
• Both ornithine and aspartate are important substrates used to metabolize ammonia to urea and glutamine, which helps improve hepatic encephalopathy symptoms 1
• LOLA plays a role in muscle metabolism, leading to glutamine production that is useful for detoxifying ammonia 1

Clinical Evidence and Recommendations

Intravenous LOLA

• The recommended dosage for intravenous LOLA is 30 g/day for patients with hepatic encephalopathy 1, 2
• For patients with West-Haven criteria grade 1-2 hepatic encephalopathy, intravenous LOLA lowers number connection test (NCT)-A time and plasma ammonia concentrations more effectively than placebo 1, 3
• A randomized controlled trial showed that patients treated with the combination of lactulose and intravenous LOLA (30 g/day) had:
  • Lower grade of hepatic encephalopathy within 1-4 days of treatment (OR 2.06-3.04)
  • Shorter duration until symptom recovery (1.92 vs. 2.50 days, P=0.002) compared with lactulose alone 1
• Intravenous LOLA has demonstrated greater improvement in mental state grade and postprandial blood ammonia levels compared to placebo 4

Oral LOLA

• Oral LOLA can lower the NCT-A time and plasma ammonia concentrations 1, 5
• In a placebo-controlled double-blind study, oral LOLA (18 g/day) improved:
  • Number Connection Test performance times (p<0.01)
  • Fasting (p<0.01) and postprandial (p<0.05) venous blood ammonia concentrations
  • Mental state grade (p<0.05)
  • Portosystemic Encephalopathy Index (p<0.01) 5
• Further studies are required to fully assess its efficacy in managing overt hepatic encephalopathy 1

Treatment Algorithm

1. First-line therapy: Nonabsorbable disaccharides (lactulose) to achieve 2-3 soft stools per day 1
2. Add LOLA as adjunctive therapy:
   • For critically ill ACLF patients with overt hepatic encephalopathy: Intravenous LOLA 30 g/day 1
   • For stable chronic hepatic encephalopathy: Consider oral LOLA 5
3. Consider adding rifaximin (400 mg three times/day or 550 mg twice/day) in patients not responding adequately to lactulose and LOLA 1

Safety Profile

• LOLA has been shown to be safe and well-tolerated with no significant adverse events reported in clinical trials 5, 4
• It has a better safety profile compared to antibiotics such as neomycin and metronidazole, which are not recommended for hepatic encephalopathy management due to their side effects (intestinal malabsorption, nephrotoxicity, ototoxicity for neomycin; peripheral neuropathy for metronidazole) 1

Limitations and Considerations

• The quality of evidence supporting LOLA use is considered very low by some guidelines, leading to uncertainty about findings 1
• LOLA is more frequently used for treatment of hepatic encephalopathy outside the United States 1
• There is insufficient evidence to issue a recommendation on using LOLA in critically ill acute liver failure (ALF) patients with hyperammonemia 1
• Recent meta-analyses suggest a possible beneficial effect of LOLA on mortality, hepatic encephalopathy, and serious adverse events compared to placebo or no intervention 1