Systematic Review
Efficacy of l-Ornithine l-Aspartate for the Treatment of Hepatic Encephalopathy and Hyperammonemia in Cirrhosis: Systematic Review and Meta-Analysis of Randomized Controlled Trials

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Background/objectives

l-Ornithine l-Aspartate (LOLA) is a mixture of two endogenous amino acids with the capacity to fix ammonia in the form of urea and/or glutamine. Its’ efficacy for the treatment of Hepatic Encephalopathy (HE), a known hyperammonemic disorder, remains the subject of debate. This study quantitatively analyzed the efficacy of LOLA in patients with cirrhosis and HE.

Methods

Efficacy was defined as the extent of lowering of blood ammonia and improvement of mental state assessed in clinically overt HE (OHE) by Westhaven criteria or psychometric testing for assessment of Minimal HE (MHE). Appropriate keywords were used for electronic and/or manual searches of databases to identify RCTs for inclusion. Study quality and risk of bias were assessed using the Jadad Composite Scale together with The Cochrane Scoring Tool. Random Effects Models were used to express pooled Risk Ratio (RR) or Mean Difference (MD) with associated 95% Confidence Intervals (CI).

Results

10 RCTs (884 patients) were included. Regression analysis showed no evidence of publication bias or other small study effects. Eight RCTs had low risk of bias by Jadad/Cochrane criteria. Comparison with placebo/no intervention controls revealed that LOLA was significantly more effective for improvement of mental state in all types of HE (RR 1.36 (95% CI 1.10–1.69), p = 0.005), OHE (RR: 1.19, 95% CI of 1.01–1.39, test for overall effect: Z = 2.14, p = 0.03), MHE (RR: 2.15 (1.48–3.14), p < 0.0001) and for lowering of blood ammonia (MD: −17.50 μmol/l (−27.73 to (−7.26)), p = 0.0008). Improvement of mental state was greater in trials with low risk of bias. Heterogeneity was reduced in trials from Europe or with >100 participants. Oral LOLA appeared particularly effective for the treatment of MHE.

Conclusion

LOLA appears to improve mental state and lower ammonia in patients with HE or MHE. Further studies are required in some subgroups of HE and in the era of HE reclassification.

Section snippets

Search Criteria

This involved electronic and manual searches using appropriate keywords as follows: Search strings: (1) Hepatic Encephalopathy (HE), (2) Overt Hepatic Encephalopathy (OHE), (3) Minimal Hepatic Encephalopathy (MHE), (4) l-Ornithine l-Aspartate (LOLA), (5) Intravenous Formulation (iv), (6) oral formulation (oral), (7) cirrhosis, (8) Randomized Controlled Trial (RCT). Search string: (#1 or #2 or #3) and (#4 or #5) and #7 and #8. Medline, PubMed, the Cochrane Controlled Trials Register (2008),

Results

Electronic searches of the databases identified 43 trials with a further 16 from manual searches. Five full-text articles were excluded for reasons of incompatibility of data presentation required for pooling. Following removal of duplicate citations and elimination of published studies in line with eligibility and inclusion/exclusion criteria, a total of 10 trials were included in the final meta-analysis (Figure 1) where sufficient data were available for pooling. Included trials are

Discussion

Hyperammonemia: Results of the present systematic review and meta-analysis significantly extend the findings of a number of individual RCTs namely that LOLA is effective in lowering blood ammonia in patients with cirrhosis. Pooled data from the eight RCTs in which blood ammonia was measured in all patients with HE revealed that blood ammonia was significantly reduced although the degree of reduction was variable from trial-to-trial, the overall effect was statistically significant (MD: −17.50,

Conflicts of Interest

The authors have none to declare.

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