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

Abstract

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.

Keywords: HE, Hepatic Encephalopathy; LOLA, l-Ornithine l-Aspartate; OHE, Overt Hepatic Encephalopathy; cirrhosis; hepatic encephalopathy; hepatoprotection; l-ornithine l-aspartate; meta-analysis.

Figure 1

Flowchart indicating key steps (identification, screening, eligibility and final inclusion) of trials included in qualitative and quantitative synthesis (meta-analysis). Of 32 records screened, 17 were excluded since they were published as abstracts, reviews, editorials or book chapters with insufficient data for analysis. Of the 15 eligible full-text articles, an additional 5 were excluded since they included patients with post-TIPS HE considered to be a distinct condition (n = 2) or trials in which the data presentation was incompatible (n = 1) or incomplete (n = 1) for full assessment of trial design, quality or risk of bias.

Figure 2

Cochrane risk of bias summary for the included studies. The (+) symbol indicates low risk, (−) indicates high risk. A blank square represents unclear risk as per Cochrane recommendations.

Figure 3

Forest plots indicating the pooled effect of LOLA versus placebo/no intervention controls for the lowering of blood ammonia in (A) all patients in trials selected according to inclusion/exclusion criteria irrespective of the type of LOLA formulation, (B) and (C) patients selected according to the LOLA formulation (intravenous, oral). LOLA: l-Ornithine l-Aspartate, RR: Risk Ratio, CI: Confidence Interval.

Figure 4

Forest plots indicating the pooled effect of LOLA versus placebo/no intervention controls for the improvement in mental state for all forms of HE in (A) all patients in trials selected according to inclusion/exclusion criteria irrespective of the type of LOLA formulation, (B) and (C) patients selected according to the LOLA formulation (intravenous, oral). LOLA: l-Ornithine l-Aspartate, RR: Risk Ratio, CI: Confidence Interval, HE: Hepatic Encephalopathy.

Figure 5

Forest plot indicating the pooled effect of LOLA versus placebo/no intervention controls for the improvement in mental state for OHE in trials selected according to inclusion/exclusion criteria irrespective of the type of LOLA formulation (intravenous, oral). LOLA: l-Ornithine l-Aspartate, RR: Risk Ratio, CI: Confidence Interval, OHE: Overt Hepatic Encephalopathy.

Figure 6

Forest plots indicating the pooled effect of LOLA versus placebo/no intervention controls for the improvement in mental state for minimal HE in (A) all patients in trials selected according to inclusion/exclusion criteria irrespective of the type of LOLA formulation, (B) and (C) patients selected according to the LOLA formulation (intravenous, oral). LOLA: l-Ornithine l-Aspartate, RR: Risk Ratio, CI: Confidence Interval, MHE: Minimal Hepatic Encephalopathy.

Figure 7

Funnel plots for the meta-analysis data for (A) any mental state improvement (B) minimal hepatic encephalopathy (MHE) improvement and (C) ammonia reduction. In the funnel plots, the Y parameter is the standard error associated with the particular measure and the X-axis is the relative risk (for categorical outcomes) and mean difference (for continuous outcomes). In the figures, both arms of the funnel plots are shown.