L-Ornithine L-Aspartate in Hepatic Encephalopathy
Intravenous L-ornithine L-aspartate (LOLA) at 30 g/day should be used as add-on therapy to lactulose for patients with persistent or overt hepatic encephalopathy (West-Haven grade 1-2), while oral LOLA is ineffective and should not be used. 1
Mechanism of Action
LOLA works by providing ornithine and aspartate as substrates for ammonia metabolism, converting ammonia to urea and glutamine, thereby lowering plasma ammonia concentrations that drive hepatic encephalopathy symptoms. 1
Clinical Efficacy: Intravenous LOLA
Acute Treatment Benefits
Faster recovery: When combined with lactulose, IV LOLA (30 g/day) achieves significantly shorter time to symptom recovery (1.92 vs 2.50 days, P=0.002) compared to lactulose alone. 1
Improved encephalopathy grade: Patients treated with lactulose plus IV LOLA had lower grades of hepatic encephalopathy within 1-4 days of treatment, with odds ratios of 2.06-3.04. 1
Ammonia reduction: IV LOLA effectively lowers both fasting and postprandial venous ammonia concentrations more than placebo. 1
Psychometric improvement: Number Connection Test (NCT-A) times improve significantly with IV LOLA treatment in patients with West-Haven grade 1-2 hepatic encephalopathy. 1
Dosing Protocol
The recommended dose is 30 g/day intravenously until clinical improvement occurs. 1 This should be administered as add-on therapy to standard lactulose treatment, not as monotherapy.
Oral LOLA: Not Recommended
Critical caveat: While IV LOLA shows efficacy, oral LOLA supplementation is ineffective for managing overt hepatic encephalopathy and requires further studies to assess its role. 1 Despite one older trial showing some benefit with oral LOLA at 18 g/day, 2 the consensus from more recent guidelines is that oral formulations lack sufficient evidence for routine clinical use. 1
Position in Treatment Algorithm
First-Line Therapy
- Lactulose remains the first-line treatment for overt hepatic encephalopathy (25 mL every 1-2 hours initially, titrated to 2-3 soft stools daily). 1, 3
Second-Line Add-On
- Rifaximin 550 mg twice daily is the preferred add-on therapy to lactulose for preventing recurrent episodes. 1, 3
Third-Line Adjunctive Therapy
- IV LOLA 30 g/day should be considered for persistent hepatic encephalopathy despite lactulose therapy, particularly in West-Haven grade 1-2 patients who need faster recovery or have inadequate response to standard treatment. 1, 3
Evidence Quality Considerations
The 2014 AASLD/EASL guidelines note that data supporting LOLA use are limited, with only one RCT demonstrating improvement in psychometric testing and ammonia levels with IV LOLA in persistent hepatic encephalopathy. 1 However, the more recent 2020 Korean guidelines provide stronger support based on additional RCT evidence showing clinical benefit when combined with lactulose. 1
A 2018 Cochrane review found very low quality evidence for LOLA's benefits, with Trial Sequential Analysis showing insufficient evidence to definitively support or refute its use. 4 The beneficial effects seen in meta-analyses disappeared when restricted to trials at low risk of bias. 4
Despite these limitations, the most recent high-quality RCT (2018) demonstrated clear clinical benefit: IV LOLA as add-on to lactulose and antibiotics significantly improved encephalopathy grade over days 1-4, decreased ammonia levels, and reduced hospital length of stay. 5
Safety Profile
LOLA demonstrates excellent tolerability with no significant adverse events reported in clinical trials. 1, 6, 7 Very good or good tolerability was observed in 97.8% of patients in observational studies. 7
Practical Implementation
When using IV LOLA:
- Administer 30 g/day as continuous or divided infusions 1
- Continue standard lactulose therapy concurrently 1, 5
- Monitor mental status grade daily 5
- Expect clinical improvement within 1-4 days 1, 5
- Consider for patients with West-Haven grade 1-2 encephalopathy who have persistent symptoms despite lactulose 1