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

Goh, Ee Teng; Stokes, Caroline S.; Sidhu, Sandeep Singh; Vilstrup, Hendrik; Gluud, Lise Lotte; Morgan, Marsha Y.

doi:10.1002/14651858.cd012410.pub2

Cited by 79 publications

(78 citation statements)

References 100 publications

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“…Although there was a significant reduction in ammonia in the drug arm, no differences in survival were observed, possibly because of the relatively low sample size. In a meta‐analysis of L‐ornithine L‐aspartate for prevention and treatment of HE that included 1,489 patients, L‐ornithine L‐aspartate administration was associated with a relative reduction in mortality compared to placebo (relative risk, 0.42; 0.24‐0.72), suggesting that ammonia lowering may improve survival of patients with cirrhosis with AD . The data showing that an increase in ammonia levels between day 5 and admission was associated with an increased risk of death and with worsening of HE provide support for the argument that ammonia should be a therapeutic target.…”

Section: Discussionmentioning

confidence: 86%

Prognostic Role of Ammonia in Patients With Cirrhosis

et al. 2019

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Ammonia is thought to be central to the pathogenesis of hepatic encephalopathy (HE), but its prognostic role in patients with cirrhosis and acute decompensation is unknown. The aims of this study were to determine the relationship between ammonia levels and severity of HE and its association with organ dysfunction and short‐term mortality. We identified 498 patients from two institutions as part of prospective observational studies in patients with cirrhosis. Plasma ammonia levels were measured on admission and Chronic Liver Failure‐Sequential Organ Failure Assessment criteria were used to determine the presence of organ failures. The 28‐day patient survival was determined. Receiver operating characteristic analysis was used to identify the cutoff points for ammonia values, and multivariable analysis was performed using the Cox proportional hazard regression model. The 28‐day mortality was 43.4%. Plasma ammonia correlated with severity of HE (P < 0.001), was significantly higher in nonsurvivors (93 [73‐121] versus 67 [55‐89] µmol/L, P < 0.001), and was an independent predictor of 28‐day mortality (hazard ratio, 1.009, P < 0.001). An ammonia level of 79.5 µmol/L had sensitivity of 68.1% and specificity of 67.4% for predicting 28‐day mortality. An ammonia level of ≥79.5 µmol/L was associated with a higher frequency of organ failures (liver [P = 0.004], coagulation [P < 0.001], kidney [P = 0.004], and respiratory [P < 0.001]). Lack of improvement in baseline ammonia at day 5 was associated with high mortality (70.6%). Conclusion: Ammonia level correlates with not only the severity of HE but also the failure of other organs and is an independent risk factor for mortality; lack of improvement in ammonia level is associated with high risk of death, making it an important biomarker and a therapeutic target.

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Section: Discussionmentioning

confidence: 86%

Prognostic Role of Ammonia in Patients With Cirrhosis

et al. 2019

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“…In contrast, Alvares-da-Silva et al reported no significant differences between oral LOLA administration (for 60 days) and placebo in the mental state and neuropsychological tests in MHE patients [99], but the therapy was useful in preventing further episodes of OHE. In summary, the administration of LOLA has shown improvement in the mental state and a decrease in the blood ammonia concentration in LC patients with OHE or CHE [100,101]. However, further studies considering the degree of hepatocellular damage and the stage of HE are necessary.…”

Section: Other Ammonia-lowering Drugsmentioning

confidence: 87%

“…The treatment by LOLA (in oral and intravenous forms) for covert HE and HE has been recently developed in European countries, although it is not available in the United States and Japan. In clinical trials, intravenous administration of LOLA showed a significant effect by reducing HE grade, decreasing venous blood ammonia concentration, and improving psychomotor function in patients with MHE and OHE compared to placebo [97][98][99][100]. A large scale study by Sidhu et al reported that five days of intravenous LOLA (30 g daily), as an add-on therapy with lactulose (30-120 mL through a nasogastric tube or orally and/or lactulose enema) and ceftriaxone (2 g twice daily), can significantly improve the grade of HE over days 1-4, but not on day 5 compared to placebo [98].…”

Section: Other Ammonia-lowering Drugsmentioning

confidence: 99%

Therapeutic Strategies and Current Management for Hepatic Encephalopathy in Liver Cirrhosis

Suzuki¹,

Kato²,

Takikawa³

2019

obm hg

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Hepatic encephalopathy (HE) is a neuropsychiatric syndrome with a wide spectrum of symptoms and one of the serious complications seen in patients with acute and chronic liver disease or spontaneous portal-systemic shunting. HE is usually classified into three types according to the underlying cause (A, B, and C). Some recent discussions suggest a fourth type (D) to exclusively include HE patients with acute-on-chronic liver failure. HE has also been classified into coma grades I to IV according to the West Haven criteria, while the International Society for Hepatic Encephalopathy and Nitrogen Metabolism has proposed two distinct categories: covert HE (includes minimal HE, which is identified solely through psychometric or neurological tests and coma grade I) and overt HE (coma grade II-IV). Although modern therapeutic approaches based on clinical evidence have gradually improved the outcomes of cirrhotic patients with HE, recurrent or resistant HE is still common and the prognosis in patients with severe liver dysfunction is still poor. In this article, we discuss the therapeutic strategies and current management, except for liver transplantation and interventional procedures for portal-systemic shunting, in cirrhotic patients with HE.

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“…However, the use of LOLA for the prevention/prophylaxis of OHE in cirrhosis has not, to date, been a major source of concern and there are no published reports of systematic reviews/meta-analyses of trials dedicated to the efficacy of LOLA for OHE prevention. Sporadic reports are limited in number to small sub-groups of very low numbers of trials and patients but results so far are inconsistent (Goh et al 2018;Thumburu et al 2017). Given this paucity of available data and as a basis for planned research in this area, the present systematic review with meta-analysis was undertaken in order to review the evidence base in support of a beneficial effect of LOLA for OHE prevention/prophylaxis in patients with cirrhosis.…”

Section: Introductionmentioning

confidence: 99%

Beneficial effects of L-ornithine L-aspartate for prevention of overt hepatic encephalopathy in patients with cirrhosis: a systematic review with meta-analysis

Butterworth

2019

Metab Brain Dis

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The present systematic review with meta-analysis was undertaken to review the evidence base in support of a beneficial effect of L-ornithine L-aspartate (LOLA) for the prevention/prophylaxis of overt hepatic encephalopathy (OHE) in patients with cirrhosis. Using appropriate keywords and electronic and manual searches together with established inclusion/exclusion criteria, six randomized controlled trials (RCTs) for a total of 384 patients were identified five of which were of high quality and low risk of bias according to Jadad-Cochrane criteria. Treatment with LOLA resulted in significant reductions in the risk of progression to OHE in MHE patients (3 studies) with RR: 0.23 [95% CI: 0.07, 0.73], p < 0.01. LOLA was also effective for secondary OHE prophylaxis with RR: 0.389 [95% CI: 0.174-0.870] p < 0.002 as well as for primary prophylaxis for OHE following acute variceal bleeding [RR: 0.42 [95% CI: 0.16-0.98] p < 0.03 and for OHE prophylaxis post-TIPSS [RR: 0.30 [95% CI: 0.03-2.66] compared to placebo/no intervention in all cases. OHE prevention/prophylaxis was accompanied by significant reductions of blood ammonia. Both oral and intravenous formulations of LOLA appeared to be effective for the prevention of progression to OHE in patients with MHE. These findings provide the first direct evidence of potential benefit of LOLA for the prevention of OHE in cirrhosis across a range of clinical presentations.

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

Cited by 79 publications

References 100 publications

Prognostic Role of Ammonia in Patients With Cirrhosis

Prognostic Role of Ammonia in Patients With Cirrhosis

Therapeutic Strategies and Current Management for Hepatic Encephalopathy in Liver Cirrhosis

Beneficial effects of L-ornithine L-aspartate for prevention of overt hepatic encephalopathy in patients with cirrhosis: a systematic review with meta-analysis

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