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

Existe controversia sobre si los aminoácidos de cadena ramificada son efectivos para el tratamiento de la encefalopatía hepática. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos, identificamos siete revisiones sistemáticas que en conjunto incluyen 32 estudios aleatorizados, de los cuales 30 responden la pregunta de este resumen. Extrajimos los resultados, realizamos un metanálisis y preparamos tablas de resumen de los resultados utilizando el método GRADE. Concluimos que los aminoácidos de cadena ramificada podrían llevar a una mejoría sintomática en la encefalopatía hepática, pero probablemente tienen poco o nulo efecto sobre la mortalidad.


 
Problema

La encefalopatía hepática es una disfunción cerebral asociada a la presencia de un cortocircuito portosistémico, generalmente secundario a insuficiencia hepática. El mecanismo subyacente no es completamente claro, pero se acepta que la hiperamonemia juega un rol central, por lo que la mayoría de las intervenciones para esta condición intentan reducir el amonio.

Existiría también una alteración en la relación entre aminoácidos aromáticos y aminoácidos ramificados, que llevaría a un desbalance en la síntesis de neurotransmisores y a la acumulación de falsos neurotransmisores, lo cual contribuiría a la encefalopatía hepática.

De esta forma, la suplementación con aminoácidos ramificados podría producir una mejoría en la encefalopatía hepática. Sin embargo, no está claro si se trata de una intervención realmente efectiva.

Métodos

Utilizamos la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos, para identificar revisiones sistemáticas y sus estudios primarios incluidos. Con esta información generamos un resumen estructurado, siguiendo un formato preestablecido, que incluye mensajes clave, un resumen del conjunto de evidencia (presentado como matriz de evidencia en Epistemonikos), metanálisis del total de los estudios, tablas de resumen de resultados con el método GRADE, y tabla de otras consideraciones para la toma de decisión.

Mensajes clave

  • Los aminoácidos de cadena ramificada probablemente tienen poco o nulo efecto sobre la mortalidad en la encefalopatía hepática.
  • Los aminoácidos de cadena ramificada podrían acelerar la recuperación en la encefalopatía hepática, aunque la certeza de esta evidencia es baja. 
Acerca del conjunto de evidencia para esta pregunta

Cuál es la evidencia.
Véase matriz de evidencia en Epistemonikos más abajo.

Encontramos siete revisiones sistemáticas [1],[2],[3],[4],[5],[6],[7] que incluyen 32 estudios controlados aleatorizados reportados en 61 referencias [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].
 Excluimos dos estudios [17],[68] que incluían pacientes sometidos a trasplante hepático, por no evaluar de manera directa la pregunta clínica de este resumen.

Qué tipo de pacientes incluyeron los estudios

En 27 estudios la totalidad de los pacientes presentaron cirrosis [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], en un estudio sólo el 47% de los pacientes presentaba cirrosis [27] y en tres estudios también se incluyeron pacientes post shunt portosistémico [55],[56],[67]. Para un estudio no fue posible extraer este dato desde ninguna de las revisiones [12]. 

Qué tipo de intervenciones incluyeron los estudios

En nueve estudios se utilizaron aminoácidos ramificados intravenosos [8],[13],[30],[31],[32],[36],[46],[50],[56], en 18 estudios aminoácidos ramificados orales [16], [20],[21],[24],[26],[39],[44],[48],[54],[55],[58],[59],[61], [62],[64],[65],[66],[67], un estudio utilizó aminoácidos orales o intravenosos según la condición del paciente [27] y un estudio no especificó la vía de administración [60]. Para un estudio no fue posible extraer este dato desde ninguna de las revisiones [12].

Un estudio incluyó caseína como cointervención [54].

Todos los estudios compararon contra placebo o tratamiento estándar.

Qué tipo de desenlaces midieron

Las distintas revisiones sistemáticas evaluaron los siguientes desenlaces principales:

  • Encefalopatía hepática
  • Mortalidad

Otros desenlaces evaluados: aparición de ascitis, resolución de ascitis, sangrado gastrointestinal, resolución de la encefalopatía, infecciones, nivel de bilirrubina, duración de la hospitalización, estadía en unidad de cuidados intensivos, complicaciones postoperatorias, complicaciones intraabdominales, neumonía postoperatoria, infección de herida operatoria, balance nitrogenado, efectos adversos, cambio en encefalopatía hepática, tiempo en ventilación mecánica. 
Resumen de los resultados

La información sobre el efecto de los aminoácidos de cadena ramificada en pacientes con encefalopatía hepática está basada en 23 estudios aleatorizados [8], [13],[16],[20],[21],[24],[26],[27],[30],[31],[32],[36],[39],[44],[46],[48],[50],[56],[58],[59],[60],[61],[62] que incluyen 1040 pacientes. El resto de los estudios no entregó datos sobre los desenlaces relevantes, o estos no pudieron ser incorporados al metanálisis. Todos los estudios midieron el desenlace encefalopatía hepática y 19 estudios (936 pacientes) midieron el desenlace mortalidad [8],[13],[16],[20],[21],[26],[27],[30],[32],[36],[39],[44],[46],[48],[50],[56],[58],[61],[62]. El resumen de los resultados es el siguiente:

  • Los aminoácidos de cadena ramificada probablemente tienen poco o nulo efecto sobre la mortalidad en la encefalopatía hepática. La certeza de esta evidencia es moderada.
  • Los aminoácidos de cadena ramificada podrían acelerar la recuperación en la encefalopatía hepática, aunque la certeza de esta evidencia es baja. 

Otras consideraciones para la toma de decisión

A quién se aplica y a quién no se aplica esta evidencia
  • La evidencia presentada en este resumen se aplica de manera amplia a todos los pacientes con cirrosis hepática y encefalopatía.
  • Esta evidencia no se aplica necesariamente a otros pacientes con encefalopatía hepática, como hepatocarcinoma o cirugías hepáticas, ni a pacientes con otras causas de encefalopatía.
Sobre los desenlaces incluidos en este resumen
  • Los desenlaces seleccionados corresponden a aquellos críticos para la toma de decisión según los autores de este resumen. Coinciden además con aquellos reportados en la mayoría de las revisiones sistemáticas y guías clínicas.
Balance riesgo/beneficio y certeza de la evidencia
  • Debido a la incertidumbre asociada no es posible realizar un adecuado balance riesgo/beneficio. Sin embargo, dado que se trata de una medida sin efectos adversos relevantes, el balance podría ser favorable
Qué piensan los pacientes y sus tratantes
  • Aquellos pacientes y tratantes que pongan mayor valor en un beneficio incierto podrían inclinarse a favor de esta intervención, especialmente considerando que esta conducta coincide con las recomendaciones de las principales guías.
  • Aquellos que pongan mayor valor en los costos asociados probablemente se inclinen en contra de esta mientras no exista mayor certeza
Consideraciones de recursos
  • Se trata de una intervención que agrega costos importantes, en especial si se encuentra asociada a alguna fórmula. No es posible realizar un adecuado balance entre beneficios y costos debido a las limitaciones en la certeza de la evidencia. Si consideráramos un posible beneficio sobre la encefalopatía, pero no sobre mortalidad, se trataría de una situación en la que el balance entre costo y beneficio serían muy dependientes del costo directo de los aminoácidos de cadena ramificada en el escenario específico.
Diferencias entre este resumen y otras fuentes
  • Las conclusiones de este resumen coinciden parcialmente con las revisiones identificadas, las cuales en general concluyen que hay efecto sobre encefalopatía, pero no sobre mortalidad, y que la evidencia tiene limitaciones por lo que se requiere más información. Por ejemplo, la revisión Cochrane que evalúa la pregunta específica [2] llega a la misma conclusión que este resumen sobre la mortalidad, pero le otorga mayor certeza a la evidencia para el desenlace encefalopatía hepática. Es importante destacar que esta revisión consideró sólo una proporción de los estudios identificados en este resumen.
  • Las conclusiones de este resumen concuerdan parcialmente con una de las principales guías, la cual recomienda la utilización de esta intervención sin poner énfasis en las limitaciones de la evidencia existente [69].
¿Puede que cambie esta información en el futuro?
  • La probabilidad que futura evidencia cambie las conclusiones de este resumen es alta debido a la incertidumbre asociada.
  • Existen al menos cuatro estudios en curso que podrían aportar nueva información [70],[71],[72][73].
Cómo realizamos este resumen

Mediante métodos automatizados y colaborativos recopilamos toda la evidencia relevante para la pregunta de interés y la presentamos en una matriz de evidencia.

Siga el enlace para acceder a la versión interactiva: Aminoácidos ramificados para el tratamiento de la encefalopatía hepática

Notas

Si con posterioridad a la publicación de este resumen se publican nuevas revisiones sistemáticas sobre este tema, en la parte superior de la matriz se mostrará un aviso de “nueva evidencia”.  Si bien el proyecto contempla la actualización periódica de estos resúmenes, los usuarios están invitados a comentar en Medwave o contactar a los autores mediante correo electrónico si creen que hay evidencia que motive una actualización más rápida.

Luego de crear una cuenta en Epistemonikos, al guardar las matrices recibirá notificaciones automáticas cada vez que exista nueva evidencia que potencialmente responda a esta pregunta. El detalle de los métodos para elaborar este resumen están descritos aquí: http://dx.doi.org/10.5867/medwave.2014.06.5997.

La Fundación Epistemonikos es una organización que busca acercar la información a quienes toman decisiones en salud, mediante el uso de tecnologías. Su principal desarrollo es la base de datos Epistemonikos (www.epistemonikos.org).

Los resúmenes de evidencia siguen un riguroso proceso de revisión por pares interno.

Declaración de conflictos de intereses
Los autores declaran no tener conflictos de intereses con la materia de este artículo.

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.

 

Existe controversia sobre si los aminoácidos de cadena ramificada son efectivos para el tratamiento de la encefalopatía hepática. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos, identificamos siete revisiones sistemáticas que en conjunto incluyen 32 estudios aleatorizados, de los cuales 30 responden la pregunta de este resumen. Extrajimos los resultados, realizamos un metanálisis y preparamos tablas de resumen de los resultados utilizando el método GRADE. Concluimos que los aminoácidos de cadena ramificada podrían llevar a una mejoría sintomática en la encefalopatía hepática, pero probablemente tienen poco o nulo efecto sobre la mortalidad.

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

Affiliation:
[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] The Cochrane Collaboration

E-mail: radagabriel@epistemonikos.org

Author address:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Lira 63
Santiago Centro
Chile

Citation: 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

Publication date: 14/12/2016

PubMed record

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  52. Michel H, Pomier-Layrargues G, Duhamel O, Lacombe B, Cuilleret G, Bellet-Hermann H. Intravenous infusion of ordinary and modified amino-acid solutions in the management of hepatic encephalopathy (controlled study, 30 patients). Gastroenterology 1980;79:1038. | Link |
  53. Pomier-Layrargues G, Duhamel O, Lacombe B, Cuilleret G, Bellet H, Michel H. Intravenous infusion of ordinary and modified amino-acid solutions in the management of hepatic encephalopathy. Liver 1981;1:140 | Link |
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  56. Ceriati F, Cavicchioni C, Marino IR, De Luca G, Puglionisi A. Management of hepatic encephalopathy in cirrhotic patients after derivative surgery [Trattamento dell’encefalopatia epatica nei pazienti cirrotici sottoposti ad intervento chirurgico derivativo]. Acta Medica Romana 1985;23(1):69–76. | Link |
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  60. Sievert W, Gibson PR, Colman JC, Kronborg I, Crawford DH, Keogh J, et al. Energy and amino acid supplements in a malnourished patients with cirrhosis: a randomised controlled trial. 50th Annual Meeting American Association for the Study of Liver Disease (Published in: . Hepatology. 1999;30(Supp 4):434A. 1999 | Link |
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  64. 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 |
  65. 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 |
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Egberts EH, Schomerus H, Hamster W, Jürgens P. Branched chain amino acids in the treatment of latent portosystemic encephalopathy. A double-blind placebo-controlled crossover study. Gastroenterology. 1985 Apr;88(4):887-95. | PubMed |

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Michel H, Bories P, Aubin JP, Pomier-Layrargues G, Bauret P, Bellet-Herman H. Treatment of acute hepatic encephalopathy in cirrhotics with a branched-chain amino acids enriched versus a conventional amino acids mixture. A controlled study of 70 patients. Liver. 1985 Oct;5(5):282-9 | PubMed |

Michel H, Pomier-Layrargues G, Aubin JP, Bories P, Mirouze D, Bellet-Herman H. Treatment of hepatic encephalopathy by infusion of a modified amino acid solution: results of a controlled study in 47 cirrhotic patients. In: Capocaccia L, Fischer JE, Rossi-Fanelli F editor(s). Hepatic Encephalopathy in Chronic Liver Failure. New York: Plenum Press, 1984:301–10. | Link |

Michel H, Pomier-Layrargues G, Duhamel O, Lacombe B, Cuilleret G, Bellet-Hermann H. Intravenous infusion of ordinary and modified amino-acid solutions in the management of hepatic encephalopathy (controlled study, 30 patients). Gastroenterology 1980;79:1038. | Link |

Pomier-Layrargues G, Duhamel O, Lacombe B, Cuilleret G, Bellet H, Michel H. Intravenous infusion of ordinary and modified amino-acid solutions in the management of hepatic encephalopathy. Liver 1981;1:140 | Link |

Christie ML, Sack DM, Pomposelli J, Horst D. Enriched branched-chain amino acid formula versus a casein-based supplement in the treatment of cirrhosis. JPEN J Parenter Enteral Nutr. 1985 Nov-Dec;9(6):671-8 | PubMed |

Sieg A, Walker S, Czygan P, Gärtner U, Lanzinger-Rossnagel G, Stiehl A, et al. Branched-chain amino acid-enriched elemental diet in patients with cirrhosis of the liver. A double blind crossover trial. Z Gastroenterol. 1983 Nov;21(11):644-50 | PubMed |

Ceriati F, Cavicchioni C, Marino IR, De Luca G, Puglionisi A. Management of hepatic encephalopathy in cirrhotic patients after derivative surgery [Trattamento dell’encefalopatia epatica nei pazienti cirrotici sottoposti ad intervento chirurgico derivativo]. Acta Medica Romana 1985;23(1):69–76. | Link |

Puglionisi A, Ceriati F, Marino IR, Cavicchioni C, De Luca G, Roncone A, et al. Prophylaxis of hepatic encephalopathy after porta-caval anastomosis using branched chain amino acid mixtures. In: Capacaccio L, Fischer JE, Rossi-Fanelli F editor(s). Hepatic Encephalopathy in Chronic Liver Failure. New York: Plenum Press, 1984:345–50 | Link |

Ichikawa T, Naota T, Miyaaki H, Miuma S, Isomoto H, Takeshima F, Nakao K. Effect of an oral branched chain amino acid-enriched snack in cirrhotic patients with sleep disturbance. Hepatol Res. 2010 Oct;40(10):971-8 | CrossRef | PubMed |

Simko V. Long-term tolerance of a special amino acid oral formula in patients with advanced liver disease. Nutrition Reports International 1983;27(4):765–73 | Link |

Sievert W, Gibson PR, Colman JC, Kronborg I, Crawford DH, Keogh J, et al. Energy and amino acid supplements in a malnourished patients with cirrhosis: a randomised controlled trial. 50th Annual Meeting American Association for the Study of Liver Disease (Published in: . Hepatology. 1999;30(Supp 4):434A. 1999 | Link |

Humbert P, Pintó A, Johnston S, Fábrega C, Planas R, Boix J, et al. Effect of oral administration of branched-chain amino acids for the treatment of nutrition disturbances and for the prophylaxis of encephalopathy in cirrhotic patients [Efecto de la administración oral de aminoácidos ramificados en el tratamiento de los trastornos nutricionales y en la prevención de la encefalopatía de pacientes cirróticos.]. Gastroenterología y Hepatología 1989;12(1): 9–13. | Link |

Nakaya Y, Okita K, Suzuki K, Moriwaki H, Kato A, Miwa Y, et al. BCAA-enriched snack improves nutritional state of cirrhosis. Nutrition. 2007 Feb;23(2):113-20 | PubMed |

Nakaya Y, Okita K, Kato A, Miwa Y, Suzuki K, Moriwaki H. Randomized trial of branched chain amino acid rich supplement against carbohydrate-rich snacks as a late evening snack in patients with liver cirrhosis (Abstract). Hepatology 2005;42 Suppl 1(4):699A–700A. | Link |

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 | 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 | CrossRef | Link |

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

July 2022, Vol 22, Issue 6
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Association of biomarkers and severity of COVID-19: A crosssectional study

Systematization of initiatives in sexual and reproductive health about good practices criteria in response to the COVID-19 pandemic in primary health care in Chile

Clinical, psychological, social, and family characterization of suicidal behavior in Chilean adolescents: a multiple correspondence analysis

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