Skip to main content
NCBI home page
The Cochrane Database of Systematic Reviews logoLink to The Cochrane Database of Systematic Reviews
. 2017 Apr 28;2017(4):CD007344. doi: 10.1002/14651858.CD007344.pub2

L‐ornithine‐L‐aspartate for hepatic encephalopathy

Wenming Yuan 1, Jing Li 1,✉, Lin Xu 1, Mingming Zhang 2, Zhenchan Lu 3, Shejun Feng 4, Ling Wang 1
PMCID: PMC6478143

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the beneficial and harmful effects of L‐ornithine‐L‐aspartate on patients with hepatic encephalopathy.

Background

Hepatic encephalopathy is a common complication of hepatic cirrhosis and significantly impacts quality of life (Ferenci 2002). The clinical manifestation of hepatic encephalopathy includes psychiatric abnormality ranging from sleep disturbance, disorientation, somnolence to unconsciousness, and neurological signs ranging from asterixis, altered reflexes, loss of reflexes to coma. The characterization of hepatic encephalopathy is based on the changes of clinical manifestation and laboratory features after exclusion of other causes of mental status changes. Currently, the severity of hepatic encephalopathy is classified by two common and useful grading systems ‐ the West Haven criteria grading hepatic encephalopathy from I to IV (Ferenci 2002) and the Glasgow Coma Scale qualifying neurologic impairment (Teasdale 1974).

The pathogenesis of hepatic encephalopathy is not absolutely clear, but there are some assumptions to contribute to the development of hepatic encephalopathy from the data of animal studies, such as ammonia hypothesis, false neurotransmitter hypothesis, and gamma amino‐butyric acid (GABA)/benzodiazepine neurotransmitter hypothesis (Fischer 1971; Schafer 1982; Albrecht 2006).

Based on the above hypotheses, the current interventions of hepatic encephalopathy include supportive care, correction of the precipitating causes, dietary restrictions, and pharmacological therapies, such as nonabsorbable disaccharides, dopaminergic agonists, branched‐chain amino acids, and benzodiazepine receptor antagonists (Bianchi 1993; Als‐Nielsen 2003; Als‐Nielsen 2004a; Als‐Nielsen 2004b; Als‐Nielsen 2004c). However, pharmacological therapies have not shown convincing evidence in improving hepatic encephalopathy based on the results of recent Cochrane systematic reviews. Nonabsorbable disaccharides and branched‐chain amino acids had no beneficial effect on hepatic encephalopathy in trials with low risk of bias. There is also no significant statistically beneficial effect on mortality (Als‐Nielsen 2004a; Als‐Nielsen 2003). Dopaminergic agonists showed no significant beneficial effect on patients with hepatic encephalopathy (Als‐Nielsen 2004b). Benzodiazepine receptor antagonists only seemed to improve hepatic encephalopathy in the short term, without significant benefit on recovery or survival (Als‐Nielsen 2004c).

Ammonia is the most important neurotoxin responsible for the neuropsychiatric syndrome, and the reduction of the plasma concentration is considered as a primary target in the therapy of hepatic encephalopathy. L‐ornithine‐L‐aspartate can dissolve into ornithine and aspartate acid in vivo, both of which could increase the removal of blood ammonia by stimulating the urea and glutamine synthesis (Gebhardt 1997). The current data from the randomised control trials suggest that L‐ornithine‐L‐aspartate is somewhat more effective than placebo in improving the mental state of hepatic encephalopathy. However, the sample size of these trials was small and the qualities of these trials should be appraised (Kircheis 1997; Feher 1997; Stauch 1998).

We found two meta‐analyses published as abstract in 2000 and as full‐text in 2006, both of which have claimed that L‐ornithine‐L‐aspartate could improve the hepatic encephalopathy compared with placebo (Delcker 2000; Pilar 2006b). No Cochrane systematic review has been performed to assess the beneficial or harmful effects of L‐ornithine‐L‐aspartate on hepatic encephalopathy.

Objectives

To assess the beneficial and harmful effects of L‐ornithine‐L‐aspartate on patients with hepatic encephalopathy.

Methods

Criteria for considering studies for this review

Types of studies

We will include all randomised clinical trials regardless of country of origin, language of publication, or publication status. We will also search for ongoing trials. If we identify trials with cross‐over design, then we will include data from the first period of the trial in order to avoid the carry‐over of the effects of the intervention given in the first period into a subsequent period (Higgins 2008). We will exclude trials in which patients were allocated by a quasi‐random method, i.e., day of birth or date of admission, when considering benefits, but such studies as well as observational studies will be considered regarding harm.

Types of participants

All patients with subclinical or overt hepatic encephalopathy in connection with acute and chronic liver disease as well as fulminant hepatic failure will be included, regardless of the aetiology of liver disease or factors precipitating the hepatic encephalopathy.

Types of interventions

We will include trials that compare:

  • L‐ornithine‐L‐aspartate versus placebo or no intervention.

  • L‐ornithine‐L‐aspartate versus nonabsorbable disaccharides.

  • L‐ornithine‐L‐aspartate versus other potential beneficial interventions for hepatic encephalopathy (i.e., dopaminergic agonists, branched‐chain amino acids, benzodiazepine receptor antagonists, or antibiotics).

Trials will be included regardless of dose, duration, or mode of administration. Additional interventions will be allowed if received equally by all groups of the trial.

Types of outcome measures

Primary outcome measures

  1. Mortality at the maximum follow‐up of individual trials.

  2. Number of patients without improvement of hepatic encephalopathy, using the definitions of individual trials at maximum follow‐up. Improvement is defined as partial or complete resolution of clinical or subclinical symptoms of hepatic encephalopathy and assessed by clinical grading, Portal‐systemic encephalopathy index, psychometrical testing, or electrophysiological testing.

Secondary outcome measures

  1. Score of mental state. The mental state is graded on a 0 to 4 scale of severity according to the West Haven criteria (Ferenci 2002). The 0 score represents the subclinical hepatic encephalopathy.

  2. Venous plasma ammonia concentrations.

  3. Number and type of adverse events. Adverse events are defined as any untoward medical occurrence not necessarily having a causal relationship with the treatment, but resulting in a dose reduction or discontinuation of treatment (ICH‐GCP 1996).

  4. Quality of life.

Search methods for identification of studies

We will search The Cochrane Hepato‐Biliary Group Controlled Trials Register (Gluud 2008), the Cochrane Central Register of Controlled Trials in The Cochrane Library, OVID MEDLINE, EMBASE, Science Citation Index Expanded, three Chinese databases (the Chinese Biomedical Database, Chinese Science and Technique Journals Database, and the China National Knowledge Infrastructure database), ongoing trials as well as grey literature, using the preliminary search strategies proposed in Appendix 1. All databases will be searched from the start to present. The reference lists of eligible articles will be hand‐searched.

Data collection and analysis

Selection of trials The selection on eligible trials and the evaluation on the methodological quality of included trials will be undertaken independently by Wenming Yuan and Lin Xu. Discrepancies and disagreement will be discussed until consensus is reached, if not, then Jing Li will serve as an arbitrator. Excluded studies will be listed in the table of excluded studies with the reason for their exclusion.

Data extraction Wenming Yuan and Lin Xu will independently extract the data from the included trials. If the information in the eligible for inclusion trials is not enough or is unclear, then we will contact to the authors of the publications. We will design an extraction sheet that will include the following information for data entry: A. Trial characteristics: study ID, source. B. Patient characteristics: number of patients randomised to each arm, mean or median age, gender, aetiology and stage of hepatic encephalopathy, baseline of precipitating cause and length of follow‐up. C. Intervention characteristics: type and dose of each group, duration of therapy, mode of administration, and additional interventions. D. Methodology: method of randomisation, allocation concealment, blinding, and number of patients with follow‐up. E. Outcomes: all outcomes will be extracted from each trial.

Methodological quality The review authors (Wenming Yuan and Lin Xu) will assess the methodological quality of the trials independently, without masking of the trial names. The authors will follow the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) and the Cochrane Hepato‐Biliary Group Module (Gluud 2008). Due to the risk of biased overestimation of intervention effects in randomised trials with inadequate methodological quality (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008), we will look at the influence of methodological quality of the trials on the results by evaluating the methodological components described below. If information is not available in the published trial, we will contact the authors in order to assess the trials correctly.

Generation of the allocation sequence ‐ Yes, adequate, sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards and throwing dice are adequate if performed by an independent adjudicator. ‐ Unclear, the trial is described as randomised but the method of sequence generation was not specified. ‐ No, inadequate, the sequence generation method is not, or may not be, random. Quasi‐randomised studies, those using dates, names, or admittance numbers in order to allocate patients are inadequate and will be excluded for the assessment of benefits but not for harms.

Allocation concealment ‐ Yes, adequate, allocation was controlled by a central and independent randomisation unit, opaque and sealed envelopes or similar, so that intervention allocations could not have been foreseen in advance of, or during, enrolment. ‐ Unclear, the trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment. ‐ No, inadequate, if the allocation sequence was known to the investigators who assigned participants or if the study was quasi‐randomised. Quasi‐randomised studies will be excluded for the assessment of benefits but not for harms. Blinding ‐ Yes, adequate, the trial was described as double blind and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial. ‐ Unclear, the trial was described as double blind, but the method of blinding was not described, so that knowledge of allocation was possible during the trial. ‐ No, not performed, the trial was not double blind, so that the allocation was known during the trial. Incomplete outcome data ‐ Yes, adequate, the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals. ‐ Unclear, the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated. ‐ No, inadequate, the number or reasons for dropouts and withdrawals were not described. Selective outcome reporting ‐ Yes, adequate, pre‐defined, or clinically relevant and reasonably expected outcomes are reported on. ‐ Unclear, not all pre‐defined, or clinically relevant and reasonably expected outcomes are reported on or are not reported fully, or it is unclear whether data on these outcomes were recorded or not. ‐ No, inadequate, one or more clinically relevant and reasonably expected outcomes were not reported on; data on these outcomes were likely to have been recorded. Any other bias ‐ Yes, adequate, the trial appears to be free of other components that could put it at risk of bias. ‐ Unclear, the trial may or may not be free of other components that could put it at risk of bias. ‐ No, inadequate, there are other factors in the trial that could put it at risk of bias, e.g., no sample size calculation made, early stopping, industry involvement, academic bias, or an extreme baseline imbalance.

Trials with adequate generation of allocation sequence, adequate allocation concealment, adequate blinding, adequate handling of incomplete outcome data, no selective outcome reporting, and without other bias risks will be considered low‐bias risk trials. Trials with one or more unclear or inadequate quality component will be considered high‐bias risk trials. However, we are aware that in a large number of reviews, such optimal division of trials may not be possible.

In addition, we will register whether analyses in the included trials were based on the intention‐to‐treat principle and whether sample size calculation was performed. Statistical analysis Statistical analysis will be conducted following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). All analysis will be performed following the intention‐to‐treat method, including all randomised patients regardless of loss of follow‐up. If patients have missing outcome data, the last reported observed response will be included (Hollis 1999). The statistical heterogeneity among results of different trials will be explored by the chi‐square test with significance set at P value < 0.1. The percentage of variation between trial results that is due to heterogeneity rather than chance will be measured by I2 (Higgins 2003). Dichotomous outcomes will be expressed as relative risks (RR) with 95% confidence intervals (CI). Continuous outcomes will be expressed as weighted mean difference (WMD) with 95% CI. A fixed‐effect model will be used for combination of the individual results if there is no significant heterogeneity among the included trials; otherwise, the random‐effects model will be used.

Possible sources of heterogeneity will be explored by performing sensitivity analysis without the low bias risktrials or subgroup analysis based on the grade of hepatic encephalopathy or treatment regimens.

Funnel plot asymmetry will be used to assess the existence of bias if more than nine trials are included (Egger 1997).

Acknowledgements

Peer Reviewers: LL Gluud, Denmark; P Stenbøg, Denmark.

Contact Editor: C Gluud, Denmark.

Appendices

Appendix 1. Search Strategies

Database Time span of search Search strategy
The Cochrane Hepato‐Biliary Group Controlled Trials Register The date when the search is performed. (ornit* and aspart*) and 'hepatic encephalopath*'
Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library Latest issue. #1 ornit* in All Text #2 MeSH descriptor Ornithine explode all trees #3 aspart* in All Text #4 MeSH descriptor Aspartic Acid explode all trees #5 (#1 or #2) and (#3 or #4) #6 cirrhosis in All Text #7 Encephalopath* in All Text #8 MeSH descriptor Hepatic Encephalopathy explode all trees #9 #6 or #7 or #8 #10 #5 and #9
OVID MEDLINE 1980 to the date the search is performed. #1 Randomized controlled trial pt. #2 Controlled clinical trial.pt. #3 exp Randomized controlled trial/ #4 exp Random allocation/ #5 exp Double‐blind method/ #6 exp Single‐blind method/ #7 clinical trial.pt. #8 exp clinical trial/ #9 (clin$ adj25 trial$).ti,ab. #10 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 #11 singl$ or doubl$ or tripl$ or trebl$).ti,ab. #12 (blind$ or mask$).ti,ab. #13 #11 and #12 #14 exp Placebos/ #15 placebo$.ti,ab. #16 random$.ti,ab. #17 #14 or #15 or #16 #18 #10 or #13 or #17 #19 animals/ not humans/ #20 #18 not #19 #21 exp Ornithine/ #22 exp Aspartic Acid/ #23 #21 and #22 #24 (ornit$ and aspart$).ti,ab. #25 #23 or #24 #26 exp Hepatic Encephalopathy/ #27 Encephalopathy.ti,ab. #28 cirrhosis.ti,ab. #29 #26 or #27 or #28 #30 #20 and #25 and #29
EMBASE 1980 to the date the search is performed. #1 Controlled study/ #2 Randomized Controlled trial/ #3 double blind procedure/ #4 single blind procedure/ #5 cross over procedure/ #6 drug comparision/ #7 placebos/ #8 random*.ti, ab. #9 crossover.ti,ab. #10 cross‐over.ti, ab. #11placebo*.ti,ab. #12 ((doubl* or singl* or tripl* or trebl*) adj5 (blind* or mask*)).ti, ab. #13 (comparative adj25 trial*).ti,ab. #14 (clinical adj25 trial*).ti,ab. #15 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 #16 nonhumans/ #17 animals/ not (humans/ and animals/) #18 #16 or #17 #19 #15 not #18 #20 'aspartic acid'/ #21 'ornithine'/ #22 #20 and #21 #23 ornit*.ti, ab. #24 aspart*.ti, ab. #25 #23 and #24 #26 #22 or #25 #27 'hepatic encephalopathy'/ #28 encephalopath*.ti, ab. #29 #27 or #28 #30 #19 and #26 and #29
Science Citation Index Expanded 1945 to the date the search is performed. #1 TS=(ornit* and aspart*) #2 TS=(hepatic encephalopath*) #3 #1 and #2 #4 TS=(random* OR blind* OR placebo* OR meta‐analys?s OR systamtic review*) #5 #3 and #4
Open in a new tab

Group Controlled Trials Register

What's new

Date Event Description
28 April 2017 Amended The editorial group responsible for this previously published document have withdrawn it from publication.
Open in a new tab

Contributions of authors

Wenming Yuan drafted the protocol. Lin Xu and Ling Wang collected the material for the Background section of the review. Jing Li contributed to the development of the Methodology section of the protocol of the review. Mingming Zhang advised on and assisted in the language of the protocol of the review. Zhenchan Lu and Shejun Feng advised on the preparation of the protocol. All authors approved of the final version of the protocol.

Declarations of interest

None known.

Notes

This protocol has been withdrawn as it has been updated and replaced by the new protocol by Stokes CS, Goh ET, Vilstrup H, Morgan MY, Gluud LL. L‐ornithine L‐aspartate for people with cirrhosis and hepatic encephalopathy. Cochrane Database of Systematic Reviews 2016, Issue 10. Art. No.: CD012410. DOI: 10.1002/14651858.CD012410. The review is expected by the end of the 2017.

Withdrawn from publication for reasons stated in the review

References

Additional references

  1. Albrecht J, Norenberg MD. Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 2006;44(4):788‐94. [DOI] [PubMed] [Google Scholar]
  2. Als‐Nielsen B, Koretz RL, Kjaergard LL, Gluud C. Branched‐chain amino acids for hepatic encephalopathy. Cochrane Database of Systematic Reviews 2003, Issue 1. [DOI: 10.1002/14651858.CD001939] [DOI] [PubMed] [Google Scholar]
  3. Als‐Nielsen B, Gluud LL, Gluud C. Nonabsorbable disaccharides for hepatic encephalopathy. Cochrane Database of Systematic Reviews 2004, Issue 2. [DOI: 10.1002/14651858.CD003044.pub2] [DOI] [PubMed] [Google Scholar]
  4. Als‐Nielsen B, Gluud LL, Gluud C. Dopaminergic agonists for hepatic encephalopathy.. Cochrane Database of Systematic Reviews 2004, Issue 4. [DOI: 10.1002/14651858.CD003047.pub2] [DOI] [PubMed] [Google Scholar]
  5. Als‐Nielsen B, Gluud LL, Gluud C. Benzodiazepine receptor antagonists for hepatic encephalopathy. Cochrane Database of Systematic Reviews 2004, Issue 2. [DOI: 10.1002/14651858.CD002798.pub2] [DOI] [PubMed] [Google Scholar]
  6. Bianchi GP, Marchesini G, Fabbri A, Rondelli A, Bugianesi E, Zoli M, et al. Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy, A randomized cross‐over comparison. Journal of internal medicine 1993;233(5):385‐92. [DOI] [PubMed] [Google Scholar]
  7. Delcker AM, Jalan R, Comes G. L‐ornithine‐l‐aspartate vs placebo in the treatment of hepatic encephalopathy: a meta‐analysis of randomised placebo‐controlled trials using individual data. Hepatology 2000;32(4 Pt 2):310A. [Google Scholar]
  8. Egger M, Davey‐Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ 1997;315(7109):629‐34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Feher J, Lang I, Gogl A, Varga L, Varga L, Tompos G, et al. Effect of ornithine‐aspartate infusion on elevated serum ammonia concentration in cirrhotic patients ‐ Results of a randomized, placebo‐controlled double‐blind multi‐centre trial. Medical Science Monitor 1997;3(5):669‐73. [Google Scholar]
  10. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy‐definition, nomenclature, diagnosis, and quantification: final report of the Working Party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002;35(3):716‐21. [DOI] [PubMed] [Google Scholar]
  11. Fischer, JE, Baldessarini, RJ. False neurotransmitters and hepatic failure. Lancet 1971;298(7715):75‐80. [DOI] [PubMed] [Google Scholar]
  12. Gebhardt R, Beckers G, Gaunitz F, Haupt W, Jonitza D, Klein S, et al. Treatment of cirrhotic rats with L‐ornithine‐L‐aspartate enhances urea synthesis and lowers serum ammonia levels. J Pharmacol Exp Ther 1997;283(1):1‐6. [PubMed] [Google Scholar]
  13. Gluud C, Nikolova D, Klingenberg SL, Whitfield K, Alexakis N, Als‐Nielsen B, et al. Cochrane Hepato‐Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)). The Cochrane Library 2008, Issue 3. Art. No.: LIVER.
  14. Higgins JP, Thompson SG, Deeks JJ, Altman D. Measuring inconsistency in meta‐analyses. BMJ 2003;327(7414):557‐60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Higgins JPT, Green S, (editors). Cochrane Handbook for Systematic Reviews of Intervention 5.0.0 [updated February 2008 ]. The Cochrane Collaboration, 2008. [Google Scholar]
  16. Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ 1999;319(7211):670‐4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. ICH harmonised tripartite guideline. Guideline for good clinical practice E6 (R1). Geneva: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. June 10 1996. Available: www.ich.org/LOB/media/MEDIA482.pdf (accessed 2008 May 15). [Google Scholar]
  18. 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 1997;25(6):1351‐60. [DOI] [PubMed] [Google Scholar]
  19. Kjaergard LL, Villumsen J, Gluud C. Reported methodological quality and discrepancies between small and large randomized trials in meta‐analyses. Ann Intern Med 2001;135(11):982‐989. [DOI] [PubMed] [Google Scholar]
  20. Moher D, Pham B, Jones A, Cook D J, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta‐analyses?. Lancet 1998;352(9128):609‐13. [DOI] [PubMed] [Google Scholar]
  21. Schafer DF, Jones EA. Hepatic encephalopathy and the gamma‐aminobutyric‐acid neurotransmitter system. Lancet 1982;319(8262):18‐20. [DOI] [PubMed] [Google Scholar]
  22. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408‐12. [DOI] [PubMed] [Google Scholar]
  23. 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(5):856‐64. [DOI] [PubMed] [Google Scholar]
  24. Teasdale G, Jennett B. Assessment of coma and impaired consciousness, A practical scale. Lancet 1974;304(7872):81‐4. [DOI] [PubMed] [Google Scholar]
  25. Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman DG, Gluud C, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta‐epidemiological study. BMJ 2008;336(7644):601‐5. [DOI] [PMC free article] [PubMed] [Google Scholar]

References to other published versions of this review

  1. Pilar L, Mercado R. L‐ornithine aspartate among cirrhotic patients with hepatic encephalopathy: does it make a difference?. Journal of Gastroenterology & Hepatology 2006;21(1 Suppl):41A. 16706810 [Google Scholar]
  2. Pilar L, Mercado R. L‐ornithine aspartate among cirrhotic patients with hepatic encephalopathy: dose it make a difference?. Philippine Journal of Gastroenterology 2006;2:87‐94. [Google Scholar]

Articles from The Cochrane Database of Systematic Reviews are provided here courtesy of Wiley

RESOURCES