What evidence supports the use of L-ornithine-L-aspartate in hepatic encephalopathy?

Evidence Supporting L-Ornithine-L-Aspartate in Hepatic Encephalopathy

L-ornithine-L-aspartate (LOLA) is recommended as an adjunctive therapy for patients with acute-on-chronic liver failure (ACLF) who have overt hepatic encephalopathy, though the quality of supporting evidence is very low. 1

Mechanism of Action

LOLA works as a substrate for the urea cycle and stimulates enzymatic activity in residual hepatocytes, leading to:

• Increased urea excretion
• Improved ammonia detoxification
• Reduction in hyperammonemia, a key pathophysiological factor in hepatic encephalopathy

Clinical Evidence

Guidelines Recommendations

Current clinical guidelines provide the following recommendations regarding LOLA:

• The 2023 Critical Care Medicine guidelines suggest using LOLA in critically ill ACLF patients with overt hepatic encephalopathy (conditional recommendation, very low quality of evidence) 1
• The 2014 EASL/AASLD guidelines note that IV LOLA can be used as an alternative or additional agent to treat patients nonresponsive to conventional therapy (GRADE I, B, 2) 1
• The guidelines specifically state that oral supplementation with LOLA is ineffective 1

Route of Administration

The evidence shows important distinctions based on route of administration:

• Intravenous LOLA: An RCT on patients with persistent hepatic encephalopathy demonstrated improvement in psychometric testing and postprandial venous ammonia levels 1
• Oral LOLA: Guidelines state oral supplementation is ineffective 1, though some research studies show contradictory findings

Research Evidence

A 1998 placebo-controlled double-blind study of oral LOLA (18g daily) in patients with cirrhosis and stable chronic hepatic encephalopathy showed:

• Improved Number Connection Test performance times (p<0.01)
• Reduced fasting (p<0.01) and postprandial (p<0.05) venous blood ammonia concentrations
• Improved mental state grade (p<0.05) and Portosystemic Encephalopathy Index (p<0.01)
• Good safety profile with no reported adverse events 2

A 2019 meta-analysis of randomized controlled trials found:

• Evidence of benefit across a range of clinical presentations
• Improvement in mental state grade in overt hepatic encephalopathy
• Improvement in minimal hepatic encephalopathy assessed by psychometric testing
• Consistent lowering of fasting blood ammonia
• Comparable or superior efficacy to non-absorbable disaccharides or probiotics in network meta-analyses 3

Treatment Algorithm for Hepatic Encephalopathy

1. First-line treatment: Lactulose (25-30 mL every 1-2 hours until at least two soft bowel movements per day, then maintenance of 30-45 mL orally every 6-8 hours) 4

2. For recurrent episodes: Add rifaximin 550 mg twice daily after the second episode 4

3. For treatment-resistant cases:

   • Ensure proper lactulose dosing and rifaximin adherence
   • Consider adding IV LOLA (30 g/day) 4
   • Consider branched-chain amino acids (0.25 g/kg/day orally) 4

Important Caveats and Limitations

• A 2009 critical analysis noted that while LOLA reduces hyperammonemia, studies were small with short follow-up periods and some had low methodological quality 5
• The 2023 guidelines note that the panel was "very uncertain" about the findings supporting LOLA due to the very low quality of evidence 1
• LOLA is more frequently used for treatment of hepatic encephalopathy outside the United States 1
• Animal studies suggest LOLA may be beneficial in liver devascularized rats 1, but this cannot be directly extrapolated to humans

Practical Considerations

• LOLA should be considered as an adjunctive therapy, not as a replacement for established first-line treatments
• IV administration appears to be more effective than oral administration based on current guidelines
• LOLA may be particularly useful in cases where standard therapy with lactulose and rifaximin has not produced adequate response
• Cost and availability may be limiting factors in some healthcare settings

In conclusion, while there is evidence supporting the use of LOLA in hepatic encephalopathy, particularly via the IV route, it should be positioned as an adjunctive therapy for patients who have not responded adequately to standard treatments with lactulose and rifaximin.