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Medwave 2016;16(Suppl5):e6795 doi: 10.5867/medwave.2016.6795
¿Aceleran los aminoácidos de cadena ramificada la recuperación de la encefalopatía hepática en pacientes con cirrosis?
Do branched chain amino acids improve hepatic encephalopathy in cirrhosis?
Maximiliano Vergara, Victoria Castro-Gutiérrez, Gabriel Rada
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Abstract

There is controversy about the effectiveness of branched chain amino acids for treatment of hepatic encephalopathy. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified seven systematic reviews including 32 randomized controlled trials, of which 30 address the question of this article. We extracted results, combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded branched chain amino acids might improve hepatic encephalopathy, but they probably lead to little or no effect on mortality.


 
Problem

Hepatic encephalopathy is a brain dysfunction associated to the presence of portal-systemic shunting, generally as consequence of liver insufficiency. The pathogenesis of hepatic encephalopathy is not completely understood, but it is accepted hyperammonaemia plays a central role, so most interventions for this condition are directed to a reduction of ammonia.

It is postulated the plasma ratio of aromatic and branched chain amino acids is altered in this condition, leading to an imbalance in neurotransmitter synthesis and accumulation of false neurotransmitters, which would contribute to hepatic encephalopathy.

Therefore, supplementation with branched chain amino acids could improve hepatic encephalopathy. However, it is unclear whether this is an effective intervention.

Methods

We used Epistemonikos database, which is maintained by screening more than 30 databases, to identify systematic reviews and their included primary studies. With this information, we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

  • Branched chain amino acids probably lead to little or no effect on mortality in hepatic encephalopathy.
  • Branched chain amino acids might improve hepatic encephalopathy, but the certainty of this evidence is low. 
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found seven systematic reviews [1],[2],[3],[4],[5],
[6],[7]  that include 32 trials reported in 61 references 
[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],
[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],
[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],
[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],
[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],
[68]. We excluded two trials evaluating liver transplantation[17],[68] since they did not directly evaluate the question of this summary.

What types of patients were included

In 27 trials, all of the participants had cirrhosis
[8],[13],[16],[20],[21],[24],[26],[30],[31],[32],[36],[39],
[44],[46],[48],[50],[54],[55],[58],[59],[60],[61],[62],[64],
[65],[66],[67], in one trial only 47% of participants had cirrhosis [27] and in three trials patients with portosystemic shunt were also included [55],[56],[67]. For one trial, it was not possible to extract this information from any review. [12]. 

What types of interventions were included

Nine trials administered intravenous branched chain amino acids [8],[13],[30],[31],[32],[36],[46],[50],[56], 18 trials used oral branched chain amino acids [16],[20],[21],[24],
[26],[39],[44],[48],[54],[55],[58],[59],[61],[62],[64],[65],
[66],[67], one trial used oral or intravenous branched chain amino acids according to the condition of the patient [27] and one trial did not specify the route of administration [60]. For one trial, it was not possible to extract this information from any review. [12]. 
One trial used casein as cointervention [54].
All of the trials compared against placebo or standard treatment.

What types of outcomes
were measured

The main outcomes addressed by the different systematic reviews were the following:

  • Hepatic encephalopathy
  • Mortality 

Other outcomes evaluated were: development of ascites, resolution of ascites, gastrointestinal bleeding, resolution of encephalopathy, infections, bilirubin level, length of hospital stay, stay in intensive care unit, postoperative complications, intra-abdominal complications, postoperative pneumonia, operative wound infection, nitrogen balance, re-hospitalisation post liver transplantation,infections, changes in grade of hepatic encephalopathy, side effects (vomiting, diarrhoea), and time on mechanical ventilation.
Summary of findings

The information on the effects of branched chain amino acids in patients with hepatic encephalopathy is based on 23 randomized trials  [8], [13],[16],[20],[21],[24],[26],[27],[30],[31],[32],[36],[39],[44],[46],[48],[50],[56],[58],[59],[60],[61],[62] including 1040 patients. The remaining trials did not provide data about relevant outcomes, or these were not suitable for meta-analysis. All of the trials measure the outcome hepatic encephalopathy and 19 trials (936 patients) measured mortality [8],[13],[16],[20],[21],[26],[27],[30],[32],[36],[39],[44],[46],[48],[50],[56],[58],[61],[62]. The summary of findings is the following:

  • Branched chain amino acids probably lead to little or no effect on mortality in hepatic encephalopathy. The certainty of the evidence is moderate.
  • Branched chain amino acids might decrease hepatic encephalopathy, but the certainty of this evidence is low. 


Other considerations for decision-making

To whom this evidence does and does not apply
  • The evidence presented in this summary applies broadly to any patient with cirrhosis and hepatic encephalopathy.
  • This evidence does not necessarily apply to other conditions associated to hepatic encephalopathy, such as hepatocellular carcinoma or liver surgery.
About the outcomes included in this summary
  • The outcomes selected correspond to those critical for decision making according to the authors of this summary. They also agree with most systematic reviews and clinical guidelines.
Balance between benefits and risks, and certainty of the evidence
  • Considering the level of uncertainty, it is not possible to provide a proper risk/benefit balance. However, considering it is a measure without significant adverse effects, the balance could be favorable.
What would patients and their doctors think about this intervention
  • Patients and clinicians putting more value in an uncertain benefit could be inclined to use this intervention, especially considering this is consistent with the recommendations in the main guidelines.
  • Those giving more importance to the associated costs would probably lean against its use while there is uncertainty.
Resource considerations
  • This is an intervention that adds significant costs, especially if it is associated with some nutritional formula. It is not possible to perform a proper balance between benefits and costs due to the limitations in the certainty of the evidence. If we consider a possible benefit on encephalopathy, but not mortality, it would be a situation where the balance between costs and benefits would be highly dependent of the direct cost of branched chain amino acids in the specific scenario.

Differences between this summary and other sources
  • The conclusions of this summary partially agree with the reviews identified, which generally conclude there is effect on encephalopathy but not in mortality, and that the evidence has limitations so more information is required. For example, the Cochrane review evaluating the specific question [2] reaches to the same conclusion that this summary regarding mortality, but gives greater certainty to the evidence for hepatic encephalopathy. Importantly, this review considered only a proportion of the trials identified in this summary.
  • The conclusions of this summary partially agree with the main guidelines, which recommend the use of this intervention without putting emphasis on the limitations of the existing evidence [69].
Could this evidence change in the future?
  • The probability that future evidence change the conclusions of this summary is high due to the associated uncertainty.
  • There are at least four ongoing trials that could provide new information [70],[71],[72][73].
How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Branched-chain amino acids for treatment of hepatic encephalopathy

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

There is controversy about the effectiveness of branched chain amino acids for treatment of hepatic encephalopathy. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified seven systematic reviews including 32 randomized controlled trials, of which 30 address the question of this article. We extracted results, combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded branched chain amino acids might improve hepatic encephalopathy, but they probably lead to little or no effect on mortality.

Autores: Maximiliano Vergara[1,2], Victoria Castro-Gutiérrez[1,2], Gabriel Rada[2,3,4,5,6]

Filiación:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Programa de Salud Basada en Evidencia, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[4] Departamento de Medicina Interna, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[5] GRADE working group
[6] GRADE working group

E-mail: radagabriel@epistemonikos.org

Correspondencia a:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Lira 63
Santiago Centro
Chile

Citación: Vergara M, Castro-Gutiérrez V, Rada G. Do branched chain amino acids improve hepatic encephalopathy in cirrhosis?. Medwave 2016;16(Suppl5):e6795 doi: 10.5867/medwave.2016.6795

Fecha de publicación: 14/12/2016

Ficha PubMed

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McGhee A, Henderson JM, Millikan WJ Jr, Bleier JC, Vogel R, Kassouny M, et al. Comparison of the effects of Hepatic-Aid and a Casein modular diet on encephalopathy, plasma amino acids, and nitrogen balance in cirrhotic patients. Ann Surg. 1983 Mar;197(3):288-93 | PubMed |

Panella C, Guglielmi F, Laddaga L, Reale L, Polimeno L, DiLeo A. Oral branched-chain amino acids in the treatment of low portosystemic encephalopathy: a long term multicentric trial. Liver and Hormones 1992 Volume 43, Pages 97-106 | Link |

Guarnieri GF, Toigo G, Situlin R, Pozzato G, Faccini L. Muscle biopsy studies on malnutrition in patients with liver cirrhosis: Preliminary results of long-term treatment with a branched-chain amino acid enriched diet. Hepatic Encephalopathy in Chronic Liver Failure, Capocaccia L, Fischer JE, Rossi-Fanelli F (eds). Plenum Press, New York 1984 | CrossRef | Link |

Eriksson LS, Persson A, Wahren J. Branched-chain amino acids in the treatment of chronic hepatic encephalopathy. Gut. 1982 Oct;23(10):801-6 | PubMed |

Qiu Y, Zhu X, Wang W, Xu Q, Ding Y. Nutrition support with glutamine dipeptide in patients undergoing liver transplantation. Transplant Proc. 2009 Dec;41(10):4232-7 | CrossRef | PubMed |

Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35 | CrossRef | PubMed |

Won Young Tak. Branched-chain Amino Acid (BCAA) on Progression of Advanced Liver Disease (BRAVE) | Link |

Keiding S. Effects of Branched-Chain Amino Acids on Muscle Ammonia Metabolism in Patients With Cirrhosis and Healthy Subjects | Link |

Torre A. Branched chain aminoacid supplementation in patients with liver cirrhosis | Link |

Córdoba J. Effects of proteins in patients with cirrhosis and prior hepatic encephalopathy. ClinicalTrials.gov identifier: NCT00955500 | Link |

Edición Julio 2022
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