Goh Ee Teng, Stokes Caroline S, Sidhu Sandeep S, Vilstrup Hendrik, Gluud Lise Lotte, Morgan Marsha Y
UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, Rowland Hill Street, Hampstead, London, UK, NW3 2PF.
Cochrane Database Syst Rev. 2018 May 15;5(5):CD012410. doi: 10.1002/14651858.CD012410.pub2.
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.
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.
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.
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.
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.
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; I = 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; I = 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; I = 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; I = 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; I = 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.
肝性脑病是肝硬化的常见并发症，其发病率和死亡率都很高。若临床上明显可见，则该病症被归类为显性肝性脑病；若仅通过心理测试才能发现，则为轻微肝性脑病。尽管认为氨起关键作用，但该综合征的确切发病机制尚不清楚。L-鸟氨酸L-天冬氨酸具有降低氨的特性，因此可能对肝硬化和肝性脑病患者有益。
评估L-鸟氨酸L-天冬氨酸与安慰剂、无干预措施或其他积极干预措施相比，对肝硬化和肝性脑病患者的有益和有害影响。
我们对Cochrane肝胆组对照试验注册库、Cochrane系统评价数据库、医学期刊数据库、荷兰医学文摘数据库、拉丁美洲和加勒比卫生科学数据库以及科学引文索引扩展版进行了电子检索，检索截至2017年12月的数据，并对会议记录和会议论文进行了手工检索；检查了参考文献；并与研究人员和制药公司进行了通信。
我们纳入了随机临床试验，无论其发表状态、语言或是否采用盲法。我们纳入了患有轻微或显性肝性脑病或有发生肝性脑病风险的肝硬化参与者。我们比较了：L-鸟氨酸L-天冬氨酸与安慰剂或无干预措施；以及L-鸟氨酸L-天冬氨酸与其他积极药物，如不吸收双糖、抗生素、益生菌或支链氨基酸。
两位综述作者独立工作，从已发表的报告以及与研究人员和制药公司的通信中检索数据。主要结局为死亡率、肝性脑病和严重不良事件。我们进行了荟萃分析，并将结果表示为风险比（RR）和平均差（MD），并给出95%置信区间（CI）。我们使用Cochrane肝胆组领域评估偏倚控制；我们在回归分析中评估发表偏倚和其他小试验效应的风险；进行亚组分析和敏感性分析；并进行试验序贯分析。我们使用GRADE确定证据质量。
我们识别出36项随机临床试验，涉及至少2377名注册参与者，这些试验符合我们的纳入标准，其中包括10项未发表的随机临床试验。然而，我们仅能从涉及1891名参与者的29项试验中获取结局数据。纳入的试验中有5项评估预防，31项评估治疗。5项试验在总体死亡率评估中偏倚风险较低；1项试验在其余结局评估中偏倚风险较低。与安慰剂或无干预措施相比，当纳入所有试验时，L-鸟氨酸L-天冬氨酸对死亡率有有益影响（RR 0.42，95%CI 0.24至0.72；I² = 0%；19项试验；1489名参与者；极低质量证据），但当分析仅限于偏倚风险较低的试验时则无此效果（RR 0.47，95%CI 0.06至3.58；4项试验；244名参与者）。与安慰剂或无干预措施相比，当纳入所有试验时，L-鸟氨酸L-天冬氨酸对肝性脑病有有益影响（RR 0.70，95%CI 0.59至0.83；22项试验；1375名参与者；I² = 62%；极低质量证据），但在偏倚风险较低的1项试验中则无此效果（RR 0.96，95%CI 0.85至1.07；63名参与者）。对严重不良事件的分析表明，当纳入所有随机临床试验时，L-鸟氨酸L-天冬氨酸可能有益（RR 0.63，95%CI 0.45至0.90；1项试验；1489名参与者；I² = 0%；极低质量证据），但在该结局偏倚风险较低的1项试验中则无此效果（RR 0.83，95%CI 0.15至4.65；63名参与者）。对死亡率、肝性脑病和严重不良事件的试验序贯分析发现，没有足够的证据支持或反驳有益效果。亚组分析表明，在评估显性或轻微肝性脑病的预防或治疗的试验中，或者在评估口服与静脉给药的试验中，结局没有差异。我们无法对涉及288名参与者评估健康相关生活质量的3项试验进行荟萃分析。总体而言，我们发现L-鸟氨酸L-天冬氨酸与安慰剂或无干预措施在非严重不良事件方面没有差异（RR 1.15，95%CI 0.75至1.77；14项试验；1076名参与者；I² = 40%）。与乳果糖相比，L-鸟氨酸L-天冬氨酸对死亡率（RR 0.68，95%CI 0.11至4.17；4项试验；175名参与者；I² = 0%）、肝性脑病（RR 1.13，95%CI 0.81至1.57）、严重不良事件（RR 0.69，95%CI 0.22至2.11）或非严重不良事件（RR 0.05，95%CI 0.01至0.18）均无影响。与益生菌相比，L-鸟氨酸L-天冬氨酸对死亡率（RR 1.01，95%CI 0.11至9.51）、严重不良事件（RR 1.07，95%CI 0.23至4.88）或血氨浓度相对于基线的变化（RR -2.30，95%CI -6.08至1.48）均无影响，但对肝性脑病可能有有益影响（RR 0.71，95%CI 0.56至0.90）。最后，与利福昔明相比，L-鸟氨酸L-天冬氨酸对死亡率（RR 0.33，95%CI 0.04至3.03；2项试验；105名参与者）、肝性脑病（RR 1.06，95%CI 0.57至1.96）、严重不良事件（RR 0.32，95%CI 0.01至7.42）或非严重不良事件（RR 0.32，95%CI 0.01至7.42）均无影响。
本综述结果表明，与安慰剂或无干预措施相比，L-鸟氨酸L-天冬氨酸对死亡率、肝性脑病和严重不良事件可能有有益影响，但由于证据质量极低，我们对这些发现非常不确定。与益生菌相比，有极低质量的证据表明L-鸟氨酸L-天冬氨酸对肝性脑病可能有有益影响，但与其他积极药物相比，未显示出其他益处。需要进一步获取已完成但未发表试验的数据，以及新的随机安慰剂对照双盲临床试验数据。
