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Meta-Analysis
. 2018 May 15;5(5):CD012410.
doi: 10.1002/14651858.CD012410.pub2.

L-ornithine L-aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis

Ee Teng Goh  1 , Caroline S Stokes, Sandeep S Sidhu, Hendrik Vilstrup, Lise Lotte Gluud, Marsha Y Morgan
Affiliations
Meta-Analysis

L-ornithine L-aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis

Ee Teng Goh et al. Cochrane Database Syst Rev. .

Abstract

Background: Hepatic encephalopathy is a common complication of cirrhosis and has high associated morbidity and mortality. The condition is classified as overt if it is clinically apparent or minimal if only evident though psychometric testing. The exact pathogenesis of this syndrome is unknown although ammonia is thought to play a key role. L-ornithine L-aspartate has ammonia-lowering properties and may, therefore, benefit people with cirrhosis and hepatic encephalopathy.

Objectives: To evaluate the beneficial and harmful effects of L-ornithine L-aspartate versus placebo, no intervention, or other active interventions in people with cirrhosis and hepatic encephalopathy.

Search methods: We undertook electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS and Science Citation Index Expanded to December 2017 and manual searches of meetings and conference proceedings; checks of bibliographies; and corresponded with investigators and pharmaceutical companies.

Selection criteria: We included randomised clinical trials, irrespective of publication status, language, or blinding. We included participants with cirrhosis who had minimal or overt hepatic encephalopathy or who were at risk for developing hepatic encephalopathy. We compared: L-ornithine L-aspartate versus placebo or no intervention; and L-ornithine L-aspartate versus other active agents such as non-absorbable disaccharides, antibiotics, probiotics, or branched-chain amino acids.

Data collection and analysis: Two review authors, working independently, retrieved data from published reports and correspondence with investigators and pharmaceutical companies. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta-analyses and presented the results as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed bias control using the Cochrane Hepato-Biliary Group domains; we evaluated the risk of publication bias and other small trial effects in regression analyses; conducted subgroup and sensitivity analyses; and performed Trial Sequential Analyses. We determined the quality of the evidence using GRADE.

Main results: We identified 36 randomised clinical trials, involving at least 2377 registered participants, which fulfilled our inclusion criteria including 10 unpublished randomised clinical trials. However, we were only able to access outcome data from 29 trials involving 1891 participants. Five of the included trials assessed prevention, while 31 trials assessed treatment. Five trials were at low risk of bias in the overall assessment of mortality; one trial was at low risk of bias in the assessment of the remaining outcomes.L-ornithine L-aspartate had a beneficial effect on mortality compared with placebo or no intervention when including all trials (RR 0.42, 95% CI 0.24 to 0.72; I2 = 0%; 19 trials; 1489 participants; very low quality evidence), but not when the analysis was restricted to the trials at low risk of bias (RR 0.47, 95% CI 0.06 to 3.58; 4 trials; 244 participants). It had a beneficial effect on hepatic encephalopathy compared with placebo or no intervention when including all trials (RR 0.70, 95% CI 0.59 to 0.83; 22 trials; 1375 participants; I2 = 62%; very low quality evidence), but not in the one trial at low risk of bias (RR 0.96, 95% CI 0.85 to 1.07; 63 participants). The analysis of serious adverse events showed a potential benefit of L-ornithine L-aspartate when including all randomised clinical trials (RR 0.63, 95% CI 0.45 to 0.90; 1 trial; 1489 participants; I2 = 0%; very low quality evidence), but not in the one trial at low risk of bias for this outcome (RR 0.83, 95% CI 0.15 to 4.65; 63 participants). The Trial Sequential Analyses of mortality, hepatic encephalopathy, and serious adverse events found insufficient evidence to support or refute beneficial effects. Subgroup analyses showed no difference in outcomes in the trials evaluating evaluating the prevention or treatment of either overt or minimal hepatic encephalopathy or trials evaluating oral versus intravenous administration We were unable to undertake a meta-analysis of the three trials involving 288 participants evaluating health-related quality of life. Overall, we found no difference between L-ornithine L-aspartate and placebo or no intervention in non-serious adverse events (RR 1.15, 95% CI 0.75 to 1.77; 14 trials; 1076 participants; I2 = 40%). In comparison with lactulose, L-ornithine L-aspartate had no effect on mortality (RR 0.68, 95% CI 0.11 to 4.17; 4 trials; 175 participants; I2 = 0%); hepatic encephalopathy (RR 1.13, 95% CI 0.81 to 1.57); serious adverse events (RR 0.69, 95% CI 0.22 to 2.11); or non-serious adverse events (RR 0.05, 95% CI 0.01 to 0.18). In comparison with probiotics, L-ornithine L-aspartate had no effect on mortality (RR 1.01, 95% CI 0.11 to 9.51); serious adverse events (RR 1.07, 95% CI 0.23 to 4.88); or changes in blood ammonia concentrations from baseline (RR -2.30 95% CI -6.08 to 1.48), but it had a possible beneficial effect on hepatic encephalopathy (RR 0.71, 95% CI 0.56 to 0.90). Finally, in comparison with rifaximin, L-ornithine L-aspartate had no effect on mortality (RR 0.33, 95% CI 0.04 to 3.03; 2 trials; 105 participants); hepatic encephalopathy (RR 1.06, 95% CI 0.57 to 1.96); serious adverse events (RR 0.32, 95% CI 0.01 to 7.42), or non-serious adverse events (RR 0.32, 95% CI 0.01 to 7.42).

Authors' conclusions: The results of this review suggest a possible beneficial effect of L-ornithine L-aspartate on mortality, hepatic encephalopathy, and serious adverse events in comparisons with placebo or no-intervention, but, because the quality of the evidence is very low, we are very uncertain about these findings. There was very low quality evidence of a possible beneficial effect of L-ornithine L-aspartate on hepatic encephalopathy, when compared with probiotics, but no other benefits were demonstrated in comparison with other active agents. Additional access to data from completed, but unpublished trials, and new randomised placebo-controlled, double-blind clinical trials are needed.

PubMed Disclaimer

Conflict of interest statement

ETG: nothing to declare. CSS: nothing to declare. SS: nothing to declare. HV: nothing to declare. LLG: Abbvie, Merck, Norgine (investigator in trials), Novo Nordisk (travel expenses), Norgine (teaching), and Alexion (funding for research). MYM: nothing to declare.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Funnel plot of comparison: 1 L‐ornithine L‐aspartate versus placebo/no intervention, outcome: 1.1 Mortality.
4
4
Mortality: Trial Sequential Analysis (relative risk random‐effects model) including randomised clinical trials comparing L‐ornithine L‐aspartate versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. The pair‐wise meta‐analysis included 19 trials with 1489 participants and found a risk ratio (RR) of 0.42 (95% CI 0.24 to 0.72). The figure shows the Trial Sequential Analysis made with the required information size (also known as the 'heterogeneity adjusted required information size' (DARIS)) defined as the number of participants needed to detect or reject an intervention effect based on the relative risk reduction (RRR) and assumed control risk (ACR). The analysis was made with alpha 3%, power 90%, model‐based diversity (0%), RRR 25%, and ACR 5%.
5
5
Hepatic encephalopathy: Trial Sequential Analysis of hepatic encephalopathy (relative risk random‐effects model). The analysis included randomised clinical trials comparing L‐ornithine L‐aspartate versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. The pair‐wise meta‐analysis included 1375 participants and 22 trials and found a risk ratio (RR) of 0.70 (95% CI 0.59 to 0.83). The figure shows the Trial Sequential Analysis made with the required information size (also known as the 'heterogeneity adjusted required information size' (DARIS)) defined as the number of participants needed to detect or reject an intervention effect based on the relative risk reduction (RRR) and assumed control risk (ACR). The analysis was made with alpha 3%, power 90%, model‐based diversity (78%), RRR 17%, and ACR 40%.
6
6
Serious adverse events: Trial Sequential Analysis (relative risk random‐effects model) including randomised clinical trials comparing L‐ornithine L‐aspartate versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. The pair‐wise meta‐analysis includes 19 trials with 1489 participants and found a RR of 0.63 (95% CI 0.45 to 0.90). The figure shows the Trial Sequential Analysis made with the required information size (also known as the 'heterogeneity adjusted required information size' (DARIS)) defined as the number of participants needed to detect or reject an intervention effect based on the relative risk reduction (RRR) and assumed control risk (ACR). The analysis is made with alpha 3%, power 90%, model‐based diversity (0%), RRR 25%, and ACR 10%.
1.1
1.1. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 1 Mortality.
1.2
1.2. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 2 Mortality, by type of hepatic encephalopathy.
1.3
1.3. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 3 Mortality, by administration method.
1.4
1.4. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 4 Mortality, by publication status.
1.5
1.5. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 5 Hepatic encephalopathy.
1.6
1.6. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 6 Hepatic encephalopathy, by type of hepatic encephalopathy.
1.7
1.7. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 7 Hepatic encephalopathy, by administration method.
1.8
1.8. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 8 Hepatic encephalopathy, by publication status.
1.9
1.9. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 9 Hepatic encephalopathy, completeness status.
1.10
1.10. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 10 Serious adverse events.
1.11
1.11. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 11 Serious adverse events, by type of hepatic encephalopathy.
1.12
1.12. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 12 Serious adverse events, by administration method.
1.13
1.13. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 13 Serious adverse events, by publication status.
1.14
1.14. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 14 Non‐serious adverse events.
1.15
1.15. Analysis
Comparison 1 L‐ornithine L‐aspartate versus placebo/no intervention, Outcome 15 Blood ammonia concentrations.
2.1
2.1. Analysis
Comparison 2 L‐ornithine L‐aspartate versus lactulose, Outcome 1 Mortality.
2.2
2.2. Analysis
Comparison 2 L‐ornithine L‐aspartate versus lactulose, Outcome 2 Hepatic encephalopathy.
2.3
2.3. Analysis
Comparison 2 L‐ornithine L‐aspartate versus lactulose, Outcome 3 Serious adverse events.
2.4
2.4. Analysis
Comparison 2 L‐ornithine L‐aspartate versus lactulose, Outcome 4 Non‐serious adverse events.
2.5
2.5. Analysis
Comparison 2 L‐ornithine L‐aspartate versus lactulose, Outcome 5 Blood ammonia end of treatment.
3.1
3.1. Analysis
Comparison 3 L‐ornithine L‐aspartate versus probiotic, Outcome 1 Mortality.
3.2
3.2. Analysis
Comparison 3 L‐ornithine L‐aspartate versus probiotic, Outcome 2 Hepatic encephalopathy.
3.3
3.3. Analysis
Comparison 3 L‐ornithine L‐aspartate versus probiotic, Outcome 3 Serious adverse events.
3.4
3.4. Analysis
Comparison 3 L‐ornithine L‐aspartate versus probiotic, Outcome 4 Ammonia (change from baseline).
4.1
4.1. Analysis
Comparison 4 L‐ornithine L‐aspartate versus rifaximin, Outcome 1 Mortality.
4.2
4.2. Analysis
Comparison 4 L‐ornithine L‐aspartate versus rifaximin, Outcome 2 Hepatic encephalopathy.
4.3
4.3. Analysis
Comparison 4 L‐ornithine L‐aspartate versus rifaximin, Outcome 3 Serious adverse events.
4.4
4.4. Analysis
Comparison 4 L‐ornithine L‐aspartate versus rifaximin, Outcome 4 Non‐serious adverse events.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD012410

References

References to studies included in this review

Abid 2011 {published data only}
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Blanco Vela 2011c {published and unpublished data}
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Fleig 1999 {published and unpublished data}
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Higuera‐de la Tijera 2017 {published and unpublished data}
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Hong 2003 {published data only}
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Kircheis 1997 {published data only}
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    1. Kircheis G, Nilius R, Held C, Berndt H, Buchner M, Gortelmeyer R, et al. Therapeutic efficacy of L‐ornithine‐L‐aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo‐controlled, double‐blind study. Hepatology (Baltimore, Md.) 1997;25:1351‐60. [PUBMED: 9185752] - PubMed
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Maldonado 2010 {published data only}
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Merz 1987 {unpublished data only}
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Merz 1988a {unpublished data only}
    1. Butterworth RF. L‐ornithine‐L‐aspartate for the treatment of hepatic encephalopathy in cirrhosis: an update on mechanisms of action and therapeutic efficacy (MRZ 90004‐8701). International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting; 2017 Mar 9‐11; New Delhi, India 2017.
Merz 1988b {published and unpublished data}
    1. Butterworth RF. L‐ornithine‐L‐aspartate for the treatment of hepatic encephalopathy in cirrhosis: an update on mechanisms of action and therapeutic efficacy (MRZ 90004‐8701). International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting; 2017 Mar 9‐11; New Delhi, India 2017.
    1. Delcker A, Goertelmeyer R, Comes G. Meta‐analysis L‐ornithine L‐aspartate IV. Unpublished Clinical Study Report: MRZ 90004‐9902 2000.
    1. Delcker AM, Jalan R, Schumacher M, Comes, G. L‐ornithine‐L‐aspartine vs placebo in the treatment of hepatitis encephalopathy: meta‐analysis of randomised placebo‐controlled trials using individual data (MRZ 90004‐8806). Hepatology (Baltimore, Md.) 2000;32(4 Part 2):310A.
Merz 1988c {published and unpublished data}
    1. Butterworth RF. L‐ornithine‐L‐aspartate for the treatment of hepatic encephalopathy in cirrhosis: an update on mechanisms of action and therapeutic efficacy (MRZ 90004‐8701). International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting; 2017 Mar 9‐11; New Delhi, India 2017.
    1. Delcker A, Goertelmeyer R, Comes G. Meta‐analysis L‐ornithine L‐aspartate IV. Unpublished Clinical Study Report: MRZ 90004‐9902 2000.
    1. Delcker AM, Jalan R, Schumacher M, Comes G. L‐ornithine‐L‐aspartine vs placebo in the treatment of hepatitis encephalopathy: meta‐analysis of randomised placebo‐controlled trials using individual data (MRZ 90004‐8807). Hepatology (Baltimore, Md.) 2000;32(4 Part 2):310A.
Merz 1988d {unpublished data only}
    1. Delcker A, Goertelmeyer R, Comes G. Meta‐analysis L‐ornithine L‐aspartate IV. Unpublished Clinical Study Report: MRZ 90004‐9902 2000.
Merz 1989a {published and unpublished data}
    1. Butterworth RF. L‐ornithine‐L‐aspartate for the treatment of hepatic encephalopathy in cirrhosis: an update on mechanisms of action and therapeutic efficacy (MRZ 90004‐8701). International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting; 2017 Mar 9‐11; New Delhi, India 2017.
    1. Delcker A, Goertelmeyer R, Comes G. Meta‐analysis L‐ornithine L‐aspartate IV. Unpublished Clinical Study Report: MRZ 90004‐9902 2000.
    1. Delcker AM, Jalan R, Schumacher M, Comes, G. L‐ornithine‐L‐aspartine vs placebo in the treatment of hepatitis encephalopathy: meta‐analysis of randomised placebo‐controlled trials using individual data (MRZ 90004‐8901). Hepatology (Baltimore, Md.) 2000;32(4 Part 2):310A.
Merz 1989b {unpublished data only}
    1. Butterworth RF. L‐ornithine‐L‐aspartate for the treatment of hepatic encephalopathy in cirrhosis: an update on mechanisms of action and therapeutic efficacy (MRZ 90004‐8701). International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting; 2017 Mar 9‐11; New Delhi, India 2017.
Merz 1992a {unpublished data only}
    1. Butterworth RF. L‐ornithine‐L‐aspartate for the treatment of hepatic encephalopathy in cirrhosis: an update on mechanisms of action and therapeutic efficacy (MRZ 90004‐8701). International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting; 2017 Mar 9‐11; New Delhi, India 2017.
    1. Delcker A, Goertelmeyer R, Comes G. Meta‐analysis L‐ornithine L‐aspartate IV. Unpublished Clinical Study Report: MRZ 90004‐9902 2000.
Merz 1994a {unpublished data only}
    1. Butterworth RF. L‐ornithine‐L‐aspartate for the treatment of hepatic encephalopathy in cirrhosis: an update on mechanisms of action and therapeutic efficacy (MRZ 90004‐8701). International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting; 2017 Mar 9‐11; New Delhi, India 2017.
Merz 1994b {unpublished data only}
    1. Butterworth RF. L‐ornithine‐L‐aspartate for the treatment of hepatic encephalopathy in cirrhosis: an update on mechanisms of action and therapeutic efficacy (MRZ 90004‐8701). International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting; 2017 Mar 9‐11; New Delhi, India 2017.
    1. Delcker A, Goertelmeyer R, Comes G. Meta‐analysis L‐ornithine L‐aspartate IV. Unpublished Clinical Study Report: MRZ 90004‐9902 2000.
Mittal 2011 {published data only}
    1. Mittal VV, Sharma BC, Sharma P, Sarin SK. A randomized controlled trial comparing lactulose, probiotics, and L‐ornithine L‐aspartate in treatment of minimal hepatic encephalopathy. European Journal of Gastroenterology and Hepatology 2011;23:725‐32. [PUBMED: 21646910] - PubMed
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Ndraha 2011 {published data only}
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Nimanong 2010 {published data only}
    1. Nimanong S, Siwaporn C, Sansak I, Tanwandee T, Charatcharoenwitthaya P, Chotiyaputta W, et al. Oral L‐ornithine‐L‐aspartate (LOLA) for patients with overt hepatic encephalopathy treated with lactulose; a randomized, double‐blinded, placebo‐controlled trial [abstract]. Hepatology International 2010;4:35.
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Oruc 2010 {published data only}
    1. Oruc N, Ozturk A, Onal IK, Unal NG, Akdogan M, Yurdaydin C, et al. Therapeutic efficacy of L‐ornithine‐L‐aspartate infusions in patents with cirrhosis and hepatic encephalopathy [abstract]. Journal of Hepatology 2010;52(Suppl 1):S78‐9.
Poo 2006 {published data only}
    1. Poo JL, Gongora J, Sanchez‐Avila F, Aguilar‐Castillo S, Garcia‐Ramos G, Fernandez‐Zertuche M, et al. Efficacy of oral L‐ornithine‐L‐aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose‐controlled study. Annals of Hepatology 2006;5:281‐8. [PUBMED: 17151582] - PubMed
    1. Poo JL, Gongora J, Sanchez‐Avila JF, Aguilar‐Castillo S, Garcia Ramos G, Fernandez‐Zertuche M, et al. Efficacy and safety of L‐ornithine L‐aspartate (LOLA) administration. Open label randomized controlled trial versus lactulose in cirrhotic patients with hyperammoniemic hepatic encephalopathy [abstract]. Journal of Hepatology 2007;46(Suppl 1):S36. - PubMed
Puri 2010 {published data only}
    1. Puri P, Dhingra A, Nandi B, Tiwari A, Grover N, Srivastav S, et al. Treatment of minimal hepatic encephalopathy: a randomized control trial comparing L ornithine L aspartate with placebo [abstract]. Indian Journal of Gastroenterology 2010;29:65.
Schmid 2010 {published data only}
    1. Schmid M, König M, Ferenci P, Gangl A, Peck‐Radosavljevic M. Prospective randomized pilot trial of I.V. L‐ornithine L‐aspartate vs. placebo on postural control in patients with cirrhosis [abstract]. Journal of Hepatology 2008;48(Suppl 2):S123.
    1. Schmid M, Peck‐Radosavljevic M, König F, Mittermaier C, Gangl A, Ferenci P. A double‐blind, randomized, placebo‐controlled trial of intravenous L‐ornithine‐L‐aspartate on postural control in patients with cirrhosis. Liver International 2010;30:574‐82. [DOI: 10.1111/j.1478-3231.2010.02213.x; CN‐00753299] - DOI - PubMed
Sharma 2014 {published data only}
    1. Sharma K, Pant S, Dwivedi M, Misra SP, Misra A, Narang S. Minimal hepatic encephalopathy: effect of rifaximin, probiotics and L‐ornithine L‐aspartate. Journal of Gastroenterology and Hepatology 2012;27:275‐6. [DOI: ; CN‐01029127] - PMC - PubMed
    1. Sharma K, Pant S, Misra S, Dwivedi M, Misra A, Narang S, et al. Effect of rifaximin, probiotics, and L‐ornithine L‐aspartate on minimal hepatic encephalopathy: a randomized controlled trial. Saudi Journal of Gastroenterology 2014;20:225‐32. [PUBMED: 25038208] - PMC - PubMed
Sidhu 2018 {published and unpublished data}
    1. NCT01722578. L‐ornithine L‐aspartate in overt hepatic encephalopathy (HEAL) [Efficacy of Intravenous 'L‐ornithine L‐aspartate' in reversal of overt acute hepatic encephalopathy in patients with liver cirrhosis: a prospective, randomized, double‐blind, placebo controlled trial]. clinicaltrials.gov/ct2/show/NCT01722578 2017.
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Stauch 1998 {published data only}
    1. Stauch S, Kircheis G, Adler G, Beckh K, Ditschuneit H, Gortelmeyer R, et al. Oral L‐ornithine‐L‐aspartate therapy of chronic hepatic encephalopathy: results of a placebo‐controlled double‐blind study. Journal of Hepatology 1998;28:856‐64. [PUBMED: 9625322] - PubMed
Taylor‐Robinson 2017 {published and unpublished data}
    1. Pasha Y, Leech R, Violante IR, Cook N, Crossey MME, Taylor‐Robinson SD. Brain muscle axis during treatment of hepatic encephalopathy with L‐ornithine L‐aspartate. Journal of Clinical and Experimental Hepatology 2017;7(Suppl 1):S5‐6.
Varakanahalli 2017 {published data only}
    1. Varakanahalli S, Sharma BC, Dahale AS. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: a double blind randomized controlled trial of L‐ornithine L‐aspartate vs placebo. Journal of Clinical and Experimental Hepatology 2017;7(Suppl 2):S60‐1. [DOI: ] - PubMed
Zhou 2013 {published data only}
    1. Zhou ZW, Zhong XN, Zhou BY, Xiang JF, Wang RH, Yi J. Ornithine aspartate and naloxone combined therapy for hepatic encephalopathy affects cognitive function, prognosis, and neuropeptide levels. Chinese Journal of Hepatology 2013;21:385‐8. - PubMed

References to studies excluded from this review

Abdo‐Francis 2010 {published data only}
    1. Abdo‐Francis JM, Pérez‐Hernández JL, Hinojosa‐Ruiz A, Hernández‐Vásquez JR. Decreased hospital stay with the use of L‐ornithine L‐ aspartate (LOLA) in patients with hepatic encephalopathy [Disminución de la estancia hospitalaria conel uso de L‐ornitina L‐aspartato (LOLA) enpacientes con encefalopatía hepática]. Revista de Gastroenterología de México 2010;2:135‐41. [PUBMED: 20615780] - PubMed
Acharya 2009 {published data only}
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Aidrus 2015 {published data only}
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Badea 2015 {published data only}
    1. Badea M, Gavrilescu O, Dranga M, Mihai C, Prelipcean CC. Lactulose alone versus lactulose and L‐ornithine L‐aspartate for the prophylaxis of hepatic encephalopathy in acute variceal bleeding: a prospective case control study. Falk Symposium 199 2015:18.
Delcker 2002 {published data only}
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Grover 2017 {published and unpublished data}
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Lim 2010 {published data only}
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McPhail 2013 {published data only}
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Merz 1988e {unpublished data only}
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Merz 1991 {unpublished data only}
    1. Delcker A, Goertelmeyer R, Comes G. Meta‐analysis L‐ornithine L‐aspartate IV. Unpublished Clinical Study Report: MRZ 90004‐9902 2000.
Merz 1992b {unpublished data only}
    1. Delcker A, Goertelmeyer R, Comes G. Meta‐analysis L‐ornithine L‐aspartate IV. Unpublished Clinical Study Report: MRZ 90004‐9902 2000.
Müting 1980 {published data only}
    1. Müting D, Reikowski J. Controlled study of the effect of an orally administered ammonia lowering amino acid (ornithine‐aspartate) on liver and pancreas function in liver cirrhosis patients. Therapiewoche 1980;30:5590‐6.
    1. Reikowski J. Controlled study evaluating the effect of high dose oral ornithineaspartate on hepatic encephalopathy in patients with cirrhosis with or without surgical shunts [Kontrollierte Studie über die Wirkung von hohen Dosen Ornithinaspartate per os auf die Leberentgiftung bei Lebercirrhosen mit und ohne Shuntoperation]. Aminosäuren‐ und Ammoniakstoffwechsel bei Leberinsuffizienz. Grundlagen und therapeutische Folgerungen. Baden‐Baden, Germany: Gerhardt Witzstrock, 1982.
Ndhara 2010 {published data only}
    1. Ndraha S, Hasan I, Simadibrata M. The efficacy of L‐ornithine L‐aspartate granules and normal protein diet in minimal hepatic encephalopathy with malnutrition. Indonesian Journal of Gastroenterology, Hepatology, and Digestive Endoscopy 2010;11:11‐4.
Ong 2011 {published data only}
    1. Ong JP, Oehler G, Kruger‐Jansen C, Lambert‐Baumann J, Younossi ZM. Oral L‐ornithine‐L‐aspartate improves health‐related quality of life in cirrhotic patients with hepatic encephalopathy: an open‐label, prospective, multicentre observational study. Clinical Drug Investigation 2011;31:213‐20. [PUBMED: 21208014] - PubMed
Popa 2015 {published data only}
    1. Popa I, Badea M, Gavrilescu O, Dranga M, Chiosa AM, Didita A, et al. Normix alone vs. normix + L‐ornithine L‐aspartate for the treatment of patients with minimal hepatic encephalopathy. Falk Symposium 199 2015:69.
Rees 2000 {published data only}
    1. Rees CJ, Oppong K, Al Mardini H, Hudson M, Record CO. Effect of L‐ornithine‐L‐aspartate on patients with and without TIPS undergoing glutamine challenge: a double blind, placebo controlled trial. Gut 2000;47:571‐4. - PMC - PubMed
    1. Rees CJ, Oppong K, Al‐Mardini H, Hudson M, Rose J, Record CO. The effect of L‐ornithine L‐aspartate on TIPS patients undergoing glutamine challenge?. In: Record C, Al‐Mardini H editor(s). Advances in Hepatic Encephalopathy & Metabolism in Liver Disease: Proceedings of the 9th International Symposium on Ammonia. Vol. 64, Newcastle upon Tyne (UK): Ipswich Book Company Ltd, 1997:459‐65.
Reikowski 1982 {published data only}
    1. Reikowski J, Müting D. Controlled study evaluating the effect of high dose ornithin‐aspartate on hepatic encephalopathy in cirrhosis with or without surgical shunts [Kontrollierte Studie von die Wirkung von hohen Dosen ornithinaspartat auf die Leberentgiftung bei Leberzirrhosen mit oder ohne Shuntoperation]. In: Holm E editor(s). Aminosäuren‐ und Ammoniakstoffwechsel bei Leberinsuffizienz. Grundlagen und therapeutische Folgerungen. Baden‐Baden (Germany): Witzstrock, 1982.
Staedt 1993 {published data only}
    1. Delcker A, Goertelmeyer R, Comes G. Meta‐analysis L‐ornithine L‐aspartate IV. Meta‐analysis L‐ornithine L‐aspartate IV. Unpublished Clinical Study Report MRZ 90004‐8603.
    1. Staedt U, Leweling H, Gladisch R, Kortsik C, Hagmuller E, Holm E. Effects of ornithine aspartate on plasma ammonia and plasma amino acids in patients with cirrhosis. A double‐blind, randomized study using a four‐fold crossover design. Journal of Hepatology 1993;19:424‐30. [PUBMED: 8151104] - PubMed
Tenda 2012 {published data only}
    1. Tenda ED. Effect of BCAA and LOLA combination as late evening snacks on nutritional status and minimal hepatic encephalopathy in cirrhosis [abstract]. Hepatology Research 2013;7:2185.
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Tiller 2016 {published data only}
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