What is the role of ornithine (amino acid) aspartate in treating hepatic encephalopathy, particularly in patients with a history of liver disease such as cirrhosis?

L-Ornithine L-Aspartate (LOLA) for Hepatic Encephalopathy

Intravenous L-ornithine L-aspartate at 30 g/day is an effective adjunctive therapy for hepatic encephalopathy in cirrhotic patients, particularly for West-Haven grade 1-2 encephalopathy, where it accelerates recovery when combined with lactulose and reduces ammonia levels more effectively than placebo. 1

Mechanism and Rationale

LOLA works by providing ornithine and aspartate as substrates for ammonia metabolism, facilitating conversion to urea in periportal hepatocytes and glutamine production, thereby lowering plasma ammonia concentrations that drive hepatic encephalopathy. 1, 2

Clinical Evidence and Positioning

Intravenous Administration (Recommended)

• Dosing: 30 g/day intravenous LOLA is the guideline-recommended dose 1

• Efficacy in mild-moderate HE: For West-Haven grade 1-2 hepatic encephalopathy, intravenous LOLA reduces Number Connection Test-A times and plasma ammonia concentrations more effectively than placebo 1

• Combination therapy advantage: When combined with lactulose, intravenous LOLA (30 g/day) produces:

  • Lower hepatic encephalopathy grades within 1-4 days (OR 2.06-3.04)
  • Faster symptom recovery (1.92 vs 2.50 days, P=0.002) compared to lactulose alone 1

• Treatment positioning: LOLA occupies a third-line position after lactulose and rifaximin, recommended as an alternative or additional ammonia-lowering agent for patients nonresponsive to conventional therapy (GRADE I, B, 2) 2

Oral Administration (Limited Evidence)

• Conflicting guidance: The KASL guidelines (2020) suggest oral LOLA can lower NCT-A times and plasma ammonia concentrations, but acknowledge further studies are needed for overt hepatic encephalopathy 1

• Contradictory evidence: The EASL/AASLD guidelines explicitly state oral LOLA is ineffective and should not be used 2

• Research support: One older placebo-controlled trial (1998) showed oral LOLA at 18 g/day improved Number Connection Test performance, mental state grades, and ammonia levels in chronic hepatic encephalopathy 3

Clinical caveat: Given the conflicting guideline recommendations, intravenous administration should be strongly preferred over oral formulations in clinical practice. 2

Safety Profile

• Favorable tolerability: LOLA demonstrates a better safety profile compared to older antibiotics like neomycin (nephrotoxicity, ototoxicity) and metronidazole (peripheral neuropathy), which are not recommended for hepatic encephalopathy management 1

• No specific contraindications: Major guidelines document no specific contraindications for LOLA use in decompensated cirrhosis 2

• Adverse events: Clinical trials report no significant adverse events with LOLA treatment 3, 4, 5

Comparative Effectiveness

• Versus lactulose: LOLA shows no difference in mortality, hepatic encephalopathy resolution, or adverse events when compared head-to-head with lactulose 6

• Versus rifaximin: No significant differences in mortality, hepatic encephalopathy, or adverse events 6

• Versus probiotics: LOLA may have a beneficial effect on hepatic encephalopathy (RR 0.71,95% CI 0.56-0.90) but no mortality benefit 6

Evidence Quality Considerations

The Cochrane systematic review (2018) found very low quality evidence for LOLA's benefits on mortality and hepatic encephalopathy when all trials were included, but these benefits disappeared when analysis was restricted to low risk of bias trials only. 6 This highlights that while LOLA appears beneficial in clinical practice and is guideline-supported, the highest quality evidence base remains limited.

Practical Implementation Algorithm

1. First-line: Initiate lactulose (titrate to 2-3 soft stools daily) 1

2. Second-line: Add rifaximin 550 mg twice daily if inadequate response 1

3. Third-line: Consider intravenous LOLA 30 g/day for:

   • Persistent hepatic encephalopathy despite lactulose/rifaximin 2
   • West-Haven grade 1-2 encephalopathy requiring faster recovery 1
   • Patients requiring additional ammonia-lowering therapy 2

4. Avoid: Oral LOLA formulations given conflicting evidence and explicit recommendations against use 2