GASTROENTEROLÓGICA LATINOAMERICANA Terlipresina e hiponatremia en pacientes cirróticos con
Vol 46 Nº4 año 2016 ISSN: 2469-1119
Las manifestaciones gastrointestinales de la hemangiomato-
MO 284 hemorragia variceal. Predictores y significación clínica
332 sis neonatal difusa en un niño: reporte de un caso
Julio Berreta, Mónica Marino, Daniel Kociak, Adrián Balducci, Julio Argonz, Gustavo Romero
Milena Rios Santos, Luciana Rodrigues Silva, Roberto Sapolnik, Cibele Dantas Ferreira Marques, João Eugênio Machado Teixeira Dias
Páncreas exócrino-endócrino. Menopausia y tratamiento con
291 estradiol. Análisis mediante el “Pancreatograma”
Figura 4. Múltiplas lesões hemangiomatosas em intestino ressecado.
Osvaldo M Tiscornia, Simmy Bank, Fabiana N López Mingorance, María B Di Carlo, Graciela Otero, Selene Rodríguez, Patricia G Tiscornia-Wasserman, Gustavo A Negri
300
Sorafenib para el tratamiento de la recurrencia de hepatocarcinoma post trasplante hepático: experiencia sudamericana
310
Evaluación con manometría de alta resolución de una cohorte de pacientes con antecedentes de estenosis esofágica por la ingesta de cáusticos
Hemorragia digestiva grave por lesión “símil Dieulafoy”
a la toma de biopsias gástricas: reporte de un caso 337 posterior y revisión bibliográfica
Federico Piñero, Sebastián Marciano, Margarita Anders, Federico Orozco Ganem, Alina Zerega, Josemaría Menéndez, Manuel Mendizábal, Matías Tisi Baña, Octavio Gil, Solange Gerona, Eduardo de Santibañes, Ricardo Mastai, Adrián Gadano, Marcelo Silva
Priscila R Armijo, Fernando PP Vicentine, Fernando AM Herbellar, Marco G Patti
La prolongación en el tiempo del tránsito oro-cecal está
al sobrecrecimiento bacteriano en el síndrome de 314 asociado intestino irritable. Estudio realizado en un centro terciario en Brasil
Cristiane Kibune Nagasako, Sônia Letícia Silva Lorena, Célia Regina Pavan, Michelle Viviane Sá dos Santos Rondon, Ciro Garcia Montes, Maria Aparecida Mesquita
Manuel Mahler, Natalia Causada Calo, Sebastián Durán, Diana Nieto Acevedo, María Julieta Argüero, Ramiro González Sueyro, Víctor Abecia Soria, Emilio Varela, Mariano Marcolongo
Revisión de la enfermedad inflamatoria intestinal durante el
RE 340 embarazo y la lactancia Sergio Pablo Huernos
Consenso y Guías Argentinas para la Vigilancia, Diagnóstico
CO 350 y Tratamiento del Hepatocarcinoma
Eduardo Fassio, Guillermo Mazzolini y la Asociación Argentina para el Estudio de las Enfermedades del Hígado
Microbiota intestinal humana - Una historia de vida: del
a la edad adulta (Riviera Maya, México - Junio 26, RD 375 nacimiento 2015) Luis Bustos Fernández, Henry Cohen, Francisco Guarner, Aldo Maruy, Keira Leon, Jaime Ramírez-Mayans, Vera Sdepanian, Yvan Vandenplas
Resección de la unión gastroesofágica + reconstrucción en
una nueva alternativa para el tratamiento de la acalasia Cistoadenoma seroso pancreático: diagnóstico y manejo CC 322 Y-de-Roux: recidivada CB 383 terapéutico Johanna Mabel Kiese, Federico Cuenca-Abente, Laura Filippa, Alejandro Faerberg, Javier Ithurralde-Argerich, Diego Ferro, Pablo Fernández-Marty
Excreción metanógena en la pseudoobstrucción intestinal
327 crónica: respuesta terapéutica Luis Soifer
Sociedad Argentina de Gastroenterología
Lucas Souto Nacif, Rubens Macedo Arantes, Rodrigo Bronze Martino, Wellington Andraus, Luiz Carneiro D’ Albuquerque
Prevención de cáncer colorrectal (CCR): de piedra y high
CE 386 definition
José María Sanguinetti
Órgano oficial
Sociedad de Gastroenterología del Uruguay
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ACTA GASTROENTEROL LATINOAM - DICIEMBRE 2013;VOL ACTA 43:Nº4 GASTROENTEROL LATINOAM - DICIEMBRE 2013;VOL 43:Nº4
Órgano oficial Órgano oficial Órgano oficial
Sociedad Argentina de Gastroenterología
Sociedad Argentina de Gastroenterología
Edita: Sociedad Argentina de Gastroenterología, Ciudad Autónoma de Buenos Aires. Argentina. EDITOR EN JEFE
EDITOR EN JEFE COMITÉ CONSULTOR
José Luis Fernández
José Luis Fernández Fernando Arroyo (Ecuador)
EDITOR EN JEFE
COMISIÓN COMITÉ DIRECTIVA CONSULTOR SAGE - PERÍODO 2013
COMISIÓN DIRECTIVA COMISIÓN DIRECTIVA SAGE - PERÍODO 2013 SGU - BIENIO 2013-2015
Fernando PRESIDENTE
Arroyo (Ecuador)PRESIDENTE PRESIDENTE Eduardo Gutierrez Galiana REVISORES NACIONALES Alfredo García Alfredo García León Barúa (Perú)
León Barúa (Perú)COMITÉ EDITORIAL 1 VICEPRESIDENTE VICEPRESIDENTE VICEPRESIDENTE Julio C. Bai Vázquez Julio C. Bai Horacio Henry Cohen (Uruguay) Henry Cohen (Uruguay) AnaAsadur AdetTchekmedyian Luis M. Bustos Fernández Luis M. Bustos Fernández Rodolfo E. Corti Hospital de Gastroenterología Rodolfo E. Corti 2 VICEPRESIDENTE Mario Barugel Juan C. Chiocca Juan (Argentina) Juan C. Chiocca (Argentina) Juan Andrés De Paula Andrés De Paula María Antonieta Pessolano SECRETARIO SECRETARIO Dr. Carlos Bonorino Udaondo, CABA. Basso Sergio Huernos Adrián Gadano Adrián Gadano Sergio Huernos Eran Goldin (Israel) Eran Goldin (Israel) Sandra SECRETARIA Laura Quintana Rubén Terg Rubén Terg Roman Bigliardi PROSECRETARIA PROSECRETARIA Roberto Groszmann (EE.UU.) Roberto Groszmann (EE.UU.) TESORERO Cairo Rosana Argento Rosana Argento Fernando COMITÉ EDITORIAL Claudio Iglesias SECRETARIA Vicente GutiérrezSECRETARIA (Argentina) Vicente Gutiérrez (Argentina) COMITÉ EDITORIAL
er
do.
Mariela GarcíaBolino Muñoz Carolina
María Cristina Cañero Velasco
TESORERA Mariela García MuñozTESORERA SECRETARIA DE ACTAS Alejandro Jmelnitzky (Argentina) Alejandro JmelnitzkyMarcela (Argentina) Judith Doweck Judith Doweck Alicia Pérez Medeiros Carballido
Gastroenterología Diagnóstica y Terapéutica CORRECTOR David Kravetz (EE.UU.) (GEDyT), Hernán Sassi CABA. Hernán Sassi CORRECTOR
Oscar Laudanno (Argentina)
Josefina Etchevers
VOCALES TITULARES
VOCALES TITULARES Cecilio Cerisoli SUPLENTE PREFERENCIALES
Carolina Roberto Fischer Santos Lucero (Argentina) Carolina Fischer Artigas Escudero Fernando Chirdo www.latingrafica.com.ar Carolina Pedro Bolino Hospital Italiano de Buenos Aires, CABA. Pedro Llorens (Chile) Llorens (Chile) Martha RibeiroCarolina Bolino Karina ColliaDaniel Peralta Daniel Peralta PROGRAMACIÓN NACIONAL PUBLICIDAD PUBLICIDAD Fernando Magnanini (Argentina) Fernando Magnanini (Argentina) LuisÁlvaro Colombato Fiorini VOCALES SUPLENTES VOCALES SUPLENTES Jorge Olmos Establecer contacto con Establecer contacto con Víctor Pérez (Argentina) Víctor Pérez (Argentina) Javier Valentini Valentini Rodolfo CortiJavier PROGRAMACIÓN INTERNACIONAL
[email protected] Hospital de Clínicas General San
[email protected] Martín, Ma. Ines Delli Quadri Ma. Galiana Ines Delli Quadri Horacio Gutiérrez Federico Cuenca Abente Alejandro Pulpeiro (Argentina) Alejandro Pulpeiro (Argentina) Tel. 4864-8716 Tel. 4864-8716 Universidad de Buenos Aires, CABA. Raquel González Raquel González COMISIÓN FISCAL Cecilia Curvale PRESIDENTE Humberto Reyes (Chile) Humberto Reyes (Chile) CONSULTOR EX–PRESIDENTE Javier Barreiro CONSULTOR EX–PRESIDENTE Martín Olmos Jorge Daruich Claudio Bilder Claudio Bilder Eduardo Schiffrin (Argentina) Eduardo Schiffrin (Argentina) IMPRESIÓN
IMPRESIÓN Roberto Santos Lucero (Argentina)
Kravetz (EE.UU.) VOCALES Augusto PROTESORERO Sebastián Carrica Rosa Cruells Ubaldo Gualdrini Ubaldo Gualdrini Mariano Cartier Oscar Laudanno (Argentina) Patricia Gaggero David PROTESORERO
www.latingrafica.com.ar
Hospital Bernardino Rivadavia, CABA. Hugo Tanno (Argentina)
Lisandro Pereyra
Jorge Valenzuela (Chile)
Guido Villa Gómez (Bolivia) Hospital Alemán, CABA.
CONSULTOR
Roberto Zeilicoff (Argentina)
Julio César Bai Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, CABA. SECCIÓN IMÁGENES
Roberto Mazure PÁGINA WEB
Gabriela Longarini SECRETARIA
Mariela García Muñoz PRODUCCIÓN Y EDICIÓN
Raúl Groizard DISEÑO Y ARMADO DIGITAL
Candela Córdova CORRECTOR
Hernán Sassi
JuanINTEGRANTES Andrés De Paula Carlos Batalla CONSEJO ASESOR DE SAGE Luis Durand Guido AnnuitiClaudio Bilder Claudio Bilder Jorge Valenzuela (Chile) Horacio Vázquez Horacio Vázquez Nora Fernández SUPLENTES Roberto Mazure Cecilia Torres Roberto Mazure Guido Villa Gómez (Bolivia) José L. Fernández Luis Viola José Figuera Luis Viola Alfredo GarcíaRicardo Mastai Ethel Szafer Roberto Zeilicoff (Argentina) Ricardo Mastai Andrea González Nicolás González Carlos González del Solar Estanislao Gómez Ubaldo Gualdrini Martín Guidi Silvia Gutiérrez Hui Jer Hwang Juan Lasa María Eugenia Linares CONSEJO ASESOR DE SAGE Hugo Tanno (Argentina)
ISSN 0300-9033 COMISIÓN DIRECTIVA SGU - BIENIO 2013-2015 PRESIDENTE
Eduardo Gutierrez Galiana 1er VICEPRESIDENTE
Asadur Tchekmedyian Carlos Miguel Lumi 2 VICEPRESIDENTE Pablo Luna María Antonieta Pessolano Fernando Man SECRETARIA Laura Quintana Mariano Marcolongo TESORERO Mastai Ricardo Claudio Iglesias Eduardo Mauriño SECRETARIA DE ACTAS Guillermo Mendez Alicia Pérez Medeiros VOCALES Muñoz Alberto Rosa Cruells Fabio PatriciaNachman Gaggero Alejandro Nieponice SUPLENTE PREFERENCIALES Artigas Escudero Marina Orsi Martha Ribeiro Silvia Pedreira PROGRAMACIÓN NACIONAL María Marta Piskorz Álvaro Fiorini Graciela Salis PROGRAMACIÓN INTERNACIONAL Horacio Gutiérrez Galiana Alicia Sambuelli COMISIÓN FISCAL Edgardo Smecuol PRESIDENTE JavierSoifer Barreiro Luis INTEGRANTES Laura Sole Carlos Batalla Silvia Guido Susana Annuiti Soler Eduardo Sosa SUPLENTES Cecilia Tanno Torres Hugo José Figuera María del Carmen Toca Ethel Szafer Lucio Uranga Carlos Vaccaro María Inés Vaccaro Walter Vasen Federico Villamil Luis Viola Marta Wagener Daniel Wainstein David Zagalsky Hugo Zandalazini do.
REVISORES INTERNACIONALES
Herbert Burgos Henry Cohen Nicolás González Angel Lanas Xavier Llor Carolina Olano Julio Carlos Pereira Lima
Mario Reis Alvares da Silva José M. Remes-Troche Roque Saenz Asadur Jorge Tchekmedyian Marcelo Vela Elena Verdú
Acta Gastroenterol Latinoam - Vol 45 - Sup Nº 2 - Congreso Argentino de Gastroenterología y Endoscopía Digestiva - Septiembre 2015
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ACTA GASTROENTEROL LATINOAM - DICIEMBRE 2016;VOL 46:Nº 4
ACTA GASTROENTEROL LATINOAM - DICIEMBRE 2013;VOL 43:Nº4 ACTA GASTROENTEROL LATINOAM - DICIEMBRE 2013;VOL 43:Nº4
Órgano oficial Órgano oficial
Sociedad Sociedad Argentina Argentina de de Gastroenterología Gastroenterología COMISIÓN DIRECTIVA COMITÉ CONSULTOR SAGE - PERÍODO COMITÉ 2016 CONSULTOR
EDITOR EN JEFE EDITOR EN JEFE
JoséFernández Luis Fernández José Luis PRESIDENTE
Fernando (Ecuador) Fernando Arroyo Arroyo (Ecuador)
Silvia C. Pedreira León Barúa León(Perú) Barúa (Perú) Julio Julio C. BaiC. Bai Henry (Uruguay) Henry Cohen Cohen (Uruguay) Rodolfo E. Corti VICEPRESIDENTE Rodolfo E. Corti Juan C. Chiocca (Argentina) Juan Andrés De Paula Juan C. Chiocca (Argentina) Juan Andrés De Paula Sonia Niveloni Adrián Gadano Eran Goldin (Israel) Adrián Gadano Eran Goldin (Israel) RubénRubén Terg Terg Groszmann (EE.UU.) SECRETARIA RobertoRoberto Groszmann (EE.UU.) COMITÉ EDITORIAL COMITÉ EDITORIAL
Laura I. Solé
SECRETARIA SECRETARIA
Mariela Mariela GarcíaGarcía MuñozMuñoz
Gutiérrez (Argentina) VicenteVicente Gutiérrez (Argentina) Alejandro Jmelnitzky (Argentina) Alejandro Jmelnitzky (Argentina)
PROSECRETARIA CORRECTOR David Kravetz (EE.UU.) CORRECTOR Raquel A. González David Kravetz (EE.UU.) Hernán Sassi Hernán Sassi
Oscar Laudanno (Argentina) Oscar Laudanno (Argentina)
TESORERA
COMISIÓN DIRECTIVA COMISIÓN DIRECTIVA SGU - PERÍODOCOMISIÓN 2015-2016 DIRECTIVA
COMISIÓN DIRECTIVA COMISIÓN DIRECTIVA SAGE - PERÍODO 2013 SAGE - PERÍODO 2013 PRESIDENTE PRESIDENTE
SGU - BIENIO 2013-2015 SGU - BIENIO 2013-2015
PRESIDENTE PRESIDENTE PRESIDENTE Eduardo Gutierrez Galiana Alfredo García Eduardo Gutierrez Galiana Alfredo García Asadur Jorge Tchekmedyian VICEPRESIDENTE VICEPRESIDENTE Luis er M. Bustos
1er VICEPRESIDENTE 1er VICEPRESIDENTE
Asadur Tchekmedyian Fernández Asadur Tchekmedyian 1 VICEPRESIDENTE Luis M. Bustos Fernández 2 VICEPRESIDENTE 2 VICEPRESIDENTE Antonieta Pessolano Claudio Iglesias María María SECRETARIO Antonieta Pessolano SECRETARIO Huernos SECRETARIA SergioSergio Huernos SECRETARIA Quintana 2do VICEPRESIDENTE Laura Laura Quintana do.
do.
PROSECRETARIA PROSECRETARIA
María Antonieta Argento RosanaRosana Argento TESORERA TESORERA
TESORERO Pessolano TESORERO
Claudio Claudio IglesiasIglesias
SECRETARIA Doweck JudithJudith Doweck
SECRETARIA DE ACTAS SECRETARIA DE ACTAS
PROTESORERO
VOCALES
Alicia Pérez Medeiros Pérez Medeiros Luciana Nicoloff Alicia VOCALES PROTESORERO
Ubaldo Gualdrini Ubaldo Gualdrini TESORERO VOCALES TITULARES VOCALES TITULARES
Rosa Cruells Rosa Cruells Patricia Gaggero Patricia Gaggero
SUPLENTE PREFERENCIALES AliciaFischer Perez Medeiros (Argentina) SUPLENTE PREFERENCIALES RobertoRoberto Santos Santos Lucero Lucero (Argentina) Carolina Carolina Fischer Escudero ArtigasArtigas Escudero Carolina Bolino Pedro Llorens (Chile) Martha Ribeiro Carolina Bolino Pedro Llorens (Chile) Martha Ribeiro SECRETARIA DE ACTAS DanielDaniel PeraltaPeralta PROGRAMACIÓN NACIONAL PUBLICIDAD Fernando Magnanini (Argentina) PROGRAMACIÓN NACIONAL PUBLICIDAD Cecilia Torres Fernando Magnanini (Argentina) PROTESORERA VOCALES SUPLENTES Establecer contacto ÁlvaroÁlvaro FioriniFiorini VOCALES SUPLENTES Establecer contacto con con Víctor(Argentina) Pérez (Argentina) Javier Valentini PROGRAMACIÓN INTERNACIONAL Víctor Pérez María Carolina Bolino Javier Valentini
[email protected] PROGRAMACIÓN INTERNACIONAL
[email protected] VOCALES Ma. Ines Quadri Delli Quadri Horacio Horacio Gutiérrez Galiana Ma. Ines Delli Gutiérrez Galiana Alejandro (Argentina) Tel. 4864-8716 Alejandro PulpeiroPulpeiro (Argentina) Tel. 4864-8716 González Javier Barreiro COMISIÓN FISCAL RaquelRaquel González COMISIÓN FISCAL VOCALES TITULARES Humberto Reyes (Chile) PRESIDENTE GuidoEX–PRESIDENTE Annuiti PRESIDENTE Humberto Reyes (Chile) CONSULTOR CONSULTOR EX–PRESIDENTE Barreiro Javier Javier Barreiro María Eugenia Linares Eduardo Schiffrin (Argentina) Claudio Bilder Claudio Suplentes Bilder preferenciales Eduardo Schiffrin (Argentina) INTEGRANTES IMPRESIÓN IMPRESIÓN
www.latingrafica.com.ar Adriana R. Zelter www.latingrafica.com.ar
Diego Fernández Hugo (Argentina) Tanno (Argentina) Hugo Tanno Omar R. Miravalle Jorge Valenzuela Jorge Valenzuela (Chile)(Chile)
Guido Villa Gómez (Bolivia)
Guido Villa Gómez (Bolivia) VOCALES SUPLENTES
Mariel Iriarte Paola Adami Viviana Valcarce
(Argentina) RobertoRoberto ZeilicoffZeilicoff (Argentina)
CONSULTOR EX-PRESIDENTE Ángel Nadales CONSEJO ASESOR DE SAGE Ángel Nadales Luis M. Bustos Fernández Alfredo García Claudio Bilder Horacio Vázquez
INTEGRANTES
CarlosCarlos BatallaBatalla Ethel Szafer Annuiti Claudio GuidoGuido Annuiti Claudio BilderBilder Álvaro Fiorini Horacio Vázquez SUPLENTES Horacio Vázquez SUPLENTES Mónica Noble Roberto Mazure Roberto Mazure CeciliaCecilia TorresTorres Luis Viola José Figuera Luis Viola José Figuera Ethel Szafer Ricardo Mastai PROGRAMACIÓN NACIONAL Ethel Szafer Ricardo Mastai CONSEJO ASESOR DE SAGE CONSEJO ASESOR DE SAGE
Eduardo Gutiérrez Galiana PROGRAMACIÓN INTERNACIONAL Horacio Gutiérrez Galiana COMISIÓN FISCAL Miembros titulares Rosario Terra Laura Delgado Álvaro Piazze Suplentes preferenciales Artigas Escudero José Figuera Carlos Batalla
Acta Gastroenterológica Latinoamericana es el órgano oficial de la Sociedad Argentina de Gastroenterología (SAGE) y la Sociedad de Gastroenterología del Uruguay (SGU). Propiedad intelectual Nº 231736. Las opiniones y afirmaciones expresadas en artículos, editoriales u otras secciones de Acta Gastroenterológica Latinoamericana corresponden a los respectivos autores. Ni el Comité Editorial de la publicación ni la Sociedad Argentina de Gastroenterología se hacen cargo de ellas. S 2
Acta Gastroenterol Latinoam - Vol 45 - Sup Nº 2 - Congreso Argentino de Gastroenterología y Endoscopía Digestiva - Septiembre 2015
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ÍNDICE
MANUSCRITOS ORIGINALES
CASOS CLÍNICOS
ACTA GASTROENTEROL LATINOAM - DICIEMBRE 2016:VOL 46:Nº4
Terlipresina e hiponatremia en pacientes cirróticos con hemorragia variceal. Predictores y significación clínica Julio Berreta, Mónica Marino, Daniel Kociak, Adrián Balducci, Julio Argonz, Gustavo Romero
284
Páncreas exócrino-endócrino. Menopausia y tratamiento con estradiol. Análisis mediante el “Pancreatograma” Osvaldo M Tiscornia, Simmy Bank, Fabiana N López Mingorance, María B Di Carlo, Graciela Otero, Selene Rodríguez, Patricia G Tiscornia-Wasserman, Gustavo A Negri
291
Sorafenib para el tratamiento de la recurrencia de hepatocarcinoma post trasplante hepático: experiencia sudamericana Federico Piñero, Sebastián Marciano, Margarita Anders, Federico Orozco Ganem, Alina Zerega, Josemaría Menéndez, Manuel Mendizábal, Matías Tisi Baña, Octavio Gil, Solange Gerona, Eduardo de Santibañes, Ricardo Mastai, Adrián Gadano, Marcelo Silva
300
Evaluación con manometría de alta resolución de una cohorte de pacientes con antecedentes de estenosis esofágica por la ingesta de cáusticos Priscila R Armijo, Fernando PP Vicentine, Fernando AM Herbellar, Marco G Patti
310
La prolongación en el tiempo del tránsito oro-cecal está asociado al sobrecrecimiento bacteriano en el síndrome de intestino irritable. Estudio realizado en un centro terciario en Brasil Cristiane Kibune Nagasako, Sônia Letícia Silva Lorena, Célia Regina Pavan, Michelle Viviane Sá dos Santos Rondon, Ciro Garcia Montes, Maria Aparecida Mesquita
314
Resección de la unión gastroesofágica + reconstrucción en Y-de-Roux: una nueva alternativa para el tratamiento de la acalasia recidivada Johanna Mabel Kiese, Federico Cuenca-Abente, Laura Filippa, Alejandro Faerberg, Javier Ithurralde-Argerich, Diego Ferro, Pablo Fernández-Marty
322
Excreción metanógena en la pseudoobstrucción intestinal crónica: respuesta terapéutica Luis Soifer
327
Las manifestaciones gastrointestinales de la hemangiomatosis neonatal difusa en un niño: reporte de un caso Milena Rios Santos, Luciana Rodrigues Silva, Roberto Sapolnik, Cibele Dantas Ferreira Marques, João Eugênio Machado Teixeira Dias
332
Hemorragia digestiva grave por lesión “símil Dieulafoy” posterior a la toma de biopsias gástricas: reporte de un caso y revisión bibliográfica Manuel Mahler, Natalia Causada Calo, Sebastián Durán, Diana Nieto Acevedo, María Julieta Argüero, Ramiro González Sueyro, Víctor Abecia Soria, Emilio Varela, Mariano Marcolongo
337
281
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ÍNDICE
REVISIÓN
Revisión de la enfermedad inflamatoria intestinal durante el embarazo y la lactancia Sergio Pablo Huernos
340
CONSENSO
Consenso y Guías Argentinas para la Vigilancia, Diagnóstico y Tratamiento del Hepatocarcinoma Eduardo Fassio, Guillermo Mazzolini y la Asociación Argentina para el Estudio de las Enfermedades del Hígado
350
REUNIÓN DE EXPERTOS
Microbiota intestinal humana - Una historia de vida: del nacimiento a la edad adulta (Riviera Maya, México - Junio 26, 2015) Luis Bustos Fernández, Henry Cohen, Francisco Guarner, Aldo Maruy, Keira Leon, Jaime Ramírez-Mayans, Vera Sdepanian, Yvan Vandenplas
375
COMUNICACIÓN BREVE
Cistoadenoma seroso pancreático: diagnóstico y manejo terapéutico Lucas Souto Nacif, Rubens Macedo Arantes, Rodrigo Bronze Martino, Wellington Andraus, Luiz Carneiro D’ Albuquerque
383
CARTA AL EDITOR
Prevención de cáncer colorrectal (CCR): de piedra y high definition José María Sanguinetti
386
u
INDEX
ORIGINAL ARTICLES
282
ACTA GASTROENTEROL LATINOAM - DICIEMBRE 2016:VOL 46:Nº4
Terlipressin and hyponatremia in cirrhotic patients with variceal bleeding. Predictors and clinical significance Julio Berreta, Mónica Marino, Daniel Kociak, Adrián Balducci, Julio Argonz, Gustavo Romero
284
Menopause and Estradiol Treatment. Analysis by the “Pancreatogram” Osvaldo M Tiscornia, Simmy Bank, Fabiana N López Mingorance, María B Di Carlo, Graciela Otero, Selene Rodríguez, Patricia G Tiscornia-Wasserman, Gustavo A Negri
291
Sorafenib for recurrent hepatocellular carcinoma after liver transplantation: a South American experience Federico Piñero, Sebastián Marciano, Margarita Anders, Federico Orozco Ganem, Alina Zerega, Josemaría Menéndez, Manuel Mendizábal, Matías Tisi Baña, Octavio Gil, Solange Gerona, Eduardo de Santibañes, Ricardo Mastai, Adrián Gadano, Marcelo Silva
300
High resolution manometry evaluation of a series of patients with previous caustic stricture of the esophagus Priscila R Armijo, Fernando PP Vicentine, Fernando AM Herbellar, Marco G Patti
310
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INDEX
CASE REPORTS
ACTA GASTROENTEROL LATINOAM - DICIEMBRE 2016:VOL 46:Nº4
Prolonged orocecal transit time is associated with small intestinal bacterial overgrowth in irritable bowel syndrome in a tertiary referral hospital in Brazil Cristiane Kibune Nagasako, Sônia Letícia Silva Lorena, Célia Regina Pavan, Michelle Viviane Sá dos Santos Rondon, Ciro Garcia Montes, Maria Aparecida Mesquita
314
Resection of the gastroesophageal junction + Roux-en-Y reconstruction: a new alternative for the treatment of recurrent achalasia Johanna Mabel Kiese, Federico Cuenca-Abente, Laura Filippa, Alejandro Faerberg, Javier Ithurralde-Argerich, Diego Ferro, Pablo Fernández-Marty
322
Methanogenic excretion in chronic intestinal pseudo-obstruction. Therapeutic response Luis Soifer
327
Gastrointestinal manifestations of diffuse neonatal hemangiomatosis in child: a case report Milena Rios Santos, Luciana Rodrigues Silva, Roberto Sapolnik, Cibele Dantas Ferreira Marques, João Eugênio Machado Teixeira Dias
332
Severe upper gastrointestinal bleeding due to “Dieulafoy´s-like” lesion of the stomach after biopsy samples: a case report and review of the literature Manuel Mahler, Natalia Causada Calo, Sebastián Durán, Diana Nieto Acevedo, María Julieta Argüero, Ramiro González Sueyro, Víctor Abecia Soria, Emilio Varela, Mariano Marcolongo
337
REVIEW
Pregnancy and breastfeeding in inflammatory bowel disease Sergio Pablo Huernos
340
CONSENSUS
Argentinean Consensus and Guidelines for Surveillance, Diagnosis and Treatment of Hepatocellular Carcinoma Eduardo Fassio, Guillermo Mazzolini y la Asociación Argentina para el Estudio de las Enfermedades del Hígado
350
EXPERTS MEETING
Human gut microbiota - A lifetime history: from birth to adulthood (Riviera Maya, Mexico - June 26th, 2015) Luis Bustos Fernández, Henry Cohen, Francisco Guarner, Aldo Maruy, Keira Leon, Jaime Ramírez-Mayans, Vera Sdepanian, Yvan Vandenplas
375
BRIEF COMMUNICATION
Pancreatic serous cystadenoma: diagnostic and therapeutic management Lucas Souto Nacif, Rubens Macedo Arantes, Rodrigo Bronze Martino, Wellington Andraus, Luiz Carneiro D’ Albuquerque
383
LETTER TO THE PUBLISHER
Prevention of colorectal cancer (CCR): of stone and high definition José María Sanguinetti
386
283
Terlipresina e hiponatremia en pacientes cirróticos con hemorragia variceal. Predictores y significación clínica Julio Berreta,1 Mónica Marino,2 Daniel Kociak,1 Adrián Balducci,1 Julio Argonz,3 Gustavo Romero2 Servicio de Terapia Intensiva. Sección de Hepatología. 3 Servicio de Endoscopía. Hospital de Gastroenterología “Dr Carlos Bonorino Udaondo”, Ciudad Autónoma de Buenos Aires, Argentina. 1 2
Acta Gastroenterol Latinoam 2016;46:284-290 Recibido: 21/09/2016 / Aprobado: 23/11/2016 / Publicado en www.actagastro.org el 01/01/2017
Resumen
En los últimos 5 años se comunicó que hay riesgo de generar hiponatremia en los pacientes cirróticos con hemorragia por várices esofágicas (HVE) tratados con terlipresina. Objetivo. Encontrar los predictores para el desarrollo de hiponatremia en estos pacientes y los cambios evolutivos vinculables a la misma. Métodos. Se analizaron 60 pacientes cirróticos con HVE entre marzo de 2012 y enero de 2015 tratados con terlipresina y ligadura endoscópica. Se consideró hiponatremia al descenso en la natremia mayor que 5 mEq/L hasta 1 día después de finalizado el tratamiento. Los enfermos fueron agrupados en: 1) cohorte A: los que no desarrollaron hiponatremia, y 2) cohorte B: los que desarrollaron hiponatremia. Se enfrentaron 24 variables de ingreso clínicas y de laboratorio, y 4 variables evolutivas en ambas cohortes a fin de detectar predictores de hiponatremia y posibles consecuencias evolutivas. Resultados. La cohorte A fue integrada por 43 pacientes, en tanto 17 pertenecieron a la cohorte B. Entre las variables al ingreso, la natremia ≥ que 137,5 mEq/L y la pertenencia a la clase A de Child-Pugh se asociaron con evolución a hiponatremia (p = 0,0001 y 0,0485, respectivamente). Analizados por regresión logística solo la natremia
Correspondencia: Julio Berreta Caseros 2061. Ciudad Autónoma de Buenos Aires, Argentina Tel./Fax. 4821-7569. Correo electrónico:
[email protected]
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basal ≥ 137,5 mEq/L fue predictora independiente de evolución a hiponatremia. Las variables evolutivas no fueron diferentes en ambas cohortes. Conclusiones. La natremia basal mayor o igual que 137,5 mEq/L es predictora independiente de desarrollo de hiponatremia durante el tratamiento con ligadura endoscópica y terlipresina. La hiponatremia observada no modificó la evolución. Palabras claves. Hemorragia digestiva por várices esofágicas, hiponatremia, terlipresina.
Terlipressin and hyponatremia in cirrhotic patients with variceal bleeding. Predictors and clinical significance Summary
In the past 5 years it was reported that treatment with terlipressin in cirrhotic patients with esophageal variceal bleeding (EVB) may cause hyponatremia. Objective. to find predictors of hyponatremia in cirrhotic patients with EVB treated with terlipressin and endoscopic ligation. Methods. since january 2013 to march 2015, 60 cirrhotic patients were admitted because of EVB and treated with terlipressin plus endoscopic ligation. Hiponatremia was defined as a decrease of serum sodium concentration greater than 5 mEq/L until 1 day after terlipressin treatment was concluded. Thus 2 cohorts were formed. Cohort A: patients who did not develop hyponatremia, and cohort B: patients who developed hyponatremia. 24 clinical and analytic variables present at admission, and 4 evolutive variables were statistically confronted each other in both cohorts in order to identify predictors of developing hyponatremia during treatment, and changes in evolution related to it. Results. cohort A was composed for 43 patients,
Terlipresina e hiponatremia en pacientes cirróticos con hemorragia variceal
while 17 made up the cohort B. Among the variables on admission, the natremia at admission ≥ 137.5 mEq/L, and Child-Pugh A were significantly associated with hyponatremia development (p = 0.0001 and 0.0485 respectively). In multivariate analysis only the natremia ≥ 137.5 mEq/L was independent predictor. The outcome was not different in the both cohorts. Conclusions. A serum sodium level of 137.5 mEq/L or greater at admission is independent predictor of hyponatremia development in cirrhotic patients with esophageal variceal bleeding treated with endoscopic ligation plus terlipressin. The level of hyponatremia reached in our study did not change the results. Key words. Gastrointestinal bleeding esophageal varices, hyponatremia, terlipressin.
La glipresina (terlipresina) es un fármaco ampliamente utilizado para el tratamiento de la hemorragia por várices esofágicas (HVE) y es recomendada como una de las drogas de primera línea asociada a la ligadura endoscópica para el tratamiento de esta complicación de la cirrosis.1-4 La terlipresina es una prodroga de la vasopresina que una vez inyectada por vía endovenosa tiene un rápido efecto vasoconstrictor sistémico y esplácnico y luego se metaboliza por peptidasas a vasopresina, responsable de su acción prolongada.5-6 Este fármaco ejerce su acción vasoconstrictora por efecto agonista sobre los receptores V1 de vasopresina en el músculo liso vascular, produciendo una reducción del flujo de entrada a la vena porta que se traduce en una reducción de la presión portal5 y variceal, extendiéndose esta última hasta una hora.7 La terlipresina también estimula los receptores V2 que se hallan en las células tubulares renales, lo que da cuenta de su efecto antidiurético a través del aumento de la expresión de acuaporina 2.8-9 El incremento de la actividad de los receptores V2 mediado por la terlipresina se considera responsable de la producción de hiponatremia por reabsorción de agua libre de electrolitos hacia la circulación sanguínea. Diversos estudios han evaluado el descenso de la natremia en pacientes cirróticos con hemorragia variceal tratados con terlipresina describiendo reducciones en el rango de 5 mEq/l o mayores en el 22,8 al 70%, y reducciones en más 10 meq/L en 12,6 al 38% de los pacientes.10-12 Las manifestaciones neurológicas se han referido en estos trabajos a aquellos pacientes en los que la natremia descendió más que 10 mEq/L respecto a la del ingreso. La reciente reunión de consenso de Baveno VI4 ha recomendado monitorear la natremia en los pacientes con hemorragia variceal tratados con terlipresina. No existen
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hasta el momento series en América que hayan evaluado esta complicación. El objetivo de este trabajo fue evaluar, en pacientes cirróticos con HVE tratados con ligadura endoscópica y terlipresina la prevalencia de hiponatremia, y las variables clínicas y de laboratorio al ingreso del paciente que se asocian con esta complicación, identificar los predictores independientes para su desarrollo y evaluar su impacto evolutivo. Material y métodos
Desde una base de datos iniciada en 2001 en el Hospital de Gastroenterología Dr Carlos Bonorino Udaondo, se analizó en forma retrospectiva a todos los pacientes con cirrosis hepática ingresados por HVE y que fueron tratados con terlipresina y ligadura endoscópica entre marzo de 2012 y enero de 2015. Se consideró HVE a todo episodio de hemorragia digestiva alta manifestada por la presencia de hematemesis y/o melena cuando la endoscopía digestiva alta realizada dentro de las 24 hs mostró: 1) visualización del sangrado de una várice, considerado en este caso sangrado activo; 2) coágulo fresco sobre la superficie de la várice; 3) tapón de fibrina sobre la várice; y 4) sangre fresca en estómago en presencia de várices esofágicas sin otra lesión que pueda justificar el sangrado.1 Se refirió como fracaso de la terapéutica hemostática inicial a la presencia de uno o más de los siguientes hechos: 1) hemorragia variceal persistente constatada por el endoscopista luego de finalizada la terapia inicial con terlipresina y ligadura endoscópica, en presencia de signos clínicos de sangrado persistente, 2) imposibilidad de elevar la presión arterial sistólica 20 mm Hg o de mantenerla en un valor de 80 mm Hg o mayor a pesar de una correcta reanimación con fluidos y hemoderivados en ausencia de shock séptico o cardiogénico. Para el caso en que se hubiere detenido la hemorragia en las primeras 6 horas, se consideró resangrado a la presencia de: 1) nueva hematemesis de sangre fresca, 2) inestabilidad hemodinámica y caída de la presión sistólica 20 mm Hg o más, que se repite en una medición efectuada una hora después y a pesar de una correcta reanimación con fluidos.13 La reanimación inicial con fluidos se efectuó con suero fisiológico y albúmina al 20%, y glóbulos rojos, procurando mantener una concentración de hemoglobina en sangre [Hb] alrededor de 8 g%.14 Los planes de hidratación una vez conseguido el control hemostático y la estabilidad hemodinámica se efectuaron con criterio de restricción moderada de volumen intentando balances neutros. Se tomó como normal al Acta Gastroenterol Latinoam 2016;46(4):284-290
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Terlipresina e hiponatremia en pacientes cirróticos con hemorragia variceal
valor de natremia entre 135 y 145 mEq/L. Se consideró hiponatremia atribuible al tratamiento, a un descenso de la natremia superior a 5 mEq/L en relación al basal hasta un día después de finalizado el mismo. De este modo se constituyeron 2 cohortes: 1) Cohorte A: formada por aquellos pacientes cuya natremia no descendió o cuyo descenso no superó los 5 mEq/L respecto al valor basal; y 2) Cohorte B: formada por los pacientes que desarrollaron hiponatremia con un descenso mayor que 5 mEq/L respecto al basal durante el tratamiento y hasta un día después. Con el fin de identificar variables al ingreso que pudieran predisponer al desarrollo de hiponatremia durante el tratamiento se analizaron en ambas cohortes: edad, sexo, etiología alcohólica o no alcohólica, clase de Child-Pugh, score de MELD (Model for End-Stage Liver Disease), [Hb], recuento de plaquetas, kalemia, valores de bilirrubina total, alanino aminotransferasa (ALAT), aspartato aminotransferasa (ASAT), fosfatasa alcalina, albuminemia, RIN, KPTT, urea, creatinina, glucemia, [Na] sérica basal, frecuencia cardíaca, presión arterial media, presencia o no de ascitis, sangrado variceal activo al momento de la endoscopía, y éxito o fracaso hemostático inicial. El valor de natremia basal se dicotomizó al valor seleccionado por la curva ROC que mejor discriminó la evolución hacia hiponatremia, e ingresó al análisis como el valor basal mayor o igual así seleccionado. Además, se evaluó como posible variable asociada a desarrollo de hiponatremia a la duración del tratamiento con terlipresina. Para evaluar posibles cambios evolutivos asociados a hiponatremia se enfrentaron las siguientes variables en ambas cohortes: mortalidad intrahospitalaria, resangrado, requerimiento de transfusiones y presencia de encefalopatía. La terlipresina se suministró según el siguiente protocolo: bolo de 2 mg endovenoso previo a la endoscopía diagnóstica-terapéutica realizada antes de 4 horas a partir del ingreso del paciente al hospital, seguida por bolos de 2 mg siempre endovenosos cada 4 horas hasta el control del sangrado, y luego por bolos de 1 mg cada 4 horas por 3 a 5 días. Los criterios de exclusión para el tratamiento con terlipresina en nuestro hospital son: edad menor de 17 años, portador de insuficiencia cardíaca, o de cardiopatía hipertensiva con valores de presión arterial sistólica al ingreso de 150 mm Hg o mayores, arteriopatía periférica, enfermedad cerebrovascular y embarazo. Métodos estadísticos
Se utilizó el software estadístico G – Stat 2.0.1 (Departamento de Biometría GlaxosmithKline - Universidad de Barcelona). 286
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Para evaluar el descenso de natremia en el total de los pacientes, y en cada una de las 2 cohortes en particular, se utilizó el test t de Student para muestras apareadas. Para encontrar el punto de corte de natremia al ingreso que mejor discriminó desarrollo hacia hiponatremia durante el tratamiento se utilizó la curva Reciever Operator Characteristics (ROC) tomando el desarrollo de hiponatremia como estado de naturaleza y valor de natremia basal como variable testeada. Para evaluar asociación entre variables cuantitativas en ambas cohortes se utilizaron los test t de Student para muestras independientes y de Mann Whitney (rangos medios de Wilcoxon). Para evaluar asociación entre variables cualitativas en ambas cohortes se utilizó el test de Chi2 y cuando éste presentó una limitación técnica para su uso se utilizó el test no paramétrico exacto de Fisher. Las variables cuantitativas y cualitativas de ingreso, que en el análisis univariado tuvieron asociación significativa con evolución a hiponatremia durante el tratamiento, se evaluaron mediante regresión logística con el fin de detectar predictores independientes de evolución a hiponatremia en esta situación. El valor de natremia basal ingresó dicotomizado como mayor o igual al punto de corte que mejor discriminó hiponatremia. Un valor de p < 0,05 se consideró estadísticamente significativo. Resultados
Entre marzo de 2012 y enero de 2015 sesenta pacientes con cirrosis hepática ingresados con diagnóstico de HVE fueron tratados con terlipresina y ligadura endoscópica de acuerdo al protocolo mencionado. La edad mediana de los enfermos fue de 54 años (rango: 28-77), 46 hombres (77%), 32 (53,3%) de etiología alcohólica, 6 (10%) pertenecían a la clase A de Child-Pugh, 33 (60%) a la clase B y 18 (30%) a la clase C. Las características clínicas y de laboratorio basales se listan en la Tabla 1. La duración del tratamiento con terlipresina fue de 3,6 ± 1,3 días. De los 60 pacientes tratados con terlipresina y ligadura endoscópica, 43 tuvieron un descenso de la [Na] sérica que no superó los 5 mEq/L durante el tratamiento y hasta 1 día después, integrando la cohorte A (no hiponatremia). La [Na] sérica basal fue de 134 ± 6 mEq/L (rango: 117-145). Los 17 pacientes restantes, que experimentaron un descenso de la natremia mayor que 5 mEq/L en igual tiempo, integraron la cohorte B (hiponatremia), en ellos la [Na] sérica basal fue de 141 ± 5 mEq/L (rango: 129-149). En 15 de éstos la natremia basal fue normal y 2 tuvieron valores menores que 135 mEq/L. En el total de los paciente sometidos a ligadura endoscópica y terlipresina la natremia descendió 3,7 ± 4,8 mEq/L (p < 0,0001). En la Figura 1 A se grafica la evolu-
Terlipresina e hiponatremia en pacientes cirróticos con hemorragia variceal
ción de la natremia en cada paciente de la cohorte A. En la Figura 1 B se hace lo propio con aquella correspondiente a los pacientes de la cohorte B.
Figure 1. A: Modificación de la natremia en los pacientes de la cohorte A desde su ingreso hasta el menor valor durante el tratamiento con terlipresina y hasta 1 día después. B: Modificación de la natremia en los pacientes de la cohorte B en igual circunstancia.
Tabla 1. Se listan las variables presentes al ingreso (60) y sus valores. [Hb]: hemoglobina. FC: frecuencia cardíaca. TAM: presión arterial media. ALAT: aspartato aminotransferasa. ALAT: alanina aminotransferasa mEq: miliequivalente. DE: desvío estándar.
Etiología (alcohólica / no alcohólica) Child-Pugh (A / B / C) n (%)
54 (28-77) 32 / 28 6 (10%) / 36 (60%) / 18 (30%) 15,1 ± 7,2
RIN (media ± DE)
1,5 ± 0,4
Bilirrubina total mg % (media ± DE)
3,5 ± 5,9
ASAT UI/L (media ± DE)
75,1 ± 60,5
ALAT UI/Ln (media ± DE)
40,5 ± 20
Fosfatasa alcalina UI / L (media ± DE)
119,3 ± 95
Uremia (mg %) (media ± DE)
140
46 /14
Meld (media ± DE)
Albuminemia (g %) (media ± DE)
145
[Na] sérico (mEq/L)
Sexo (M/F)
A
150
135 130 125 120
2,4 ± 0,9
115
51,7 ± 34,3
Glucemia (mg %) (media ± DE)
151 ± 66
Creatinina (mg %) (media ± DE)
1,1 ± 0,9
Hemoglobina (g %) (media ± DE)
8,9 ± 2,1
Plaquetas / mm3 (media ± DE)
103466 ± 50700
Natremia (mEq/L) (media ± DE)
135,8 ± 6,5
Ascitis n (%)
37 (61,7)
Kalemia (mEq/L) (media ± DE)
4,2 ± 0,9
KPTT (s) (media ± DE)
42,7± 16,9
FC basal / minuto (media ± DE)
88,5 ± 20,1
TAM (mmHg) (media ± DE)
70,3 ± 7,2
Sangrado activo n (%)
23 (38,3)
Fracaso hemostático inicial n (%)
10 (16,7)
Un descenso de la [Na] sérica superior a 10 mEq/L respecto del basal se objetivó en 5 pacientes (29,4%) de los pacientes en la cohorte B. En este subgrupo la natremia basal fue 143,6 ± 5,1 mEq/L (rango: 138-149), y el valor más bajo de [Na] sérica durante la evolución fue 125 mEq/L. Ninguno de ellos tuvo manifestaciones neurológicas atribuibles a la hiponatremia. La cohorte B tuvo más pacientes en clase A de ChildPugh, 4 (23,5%) vs 2 (4,6%) p = 0,0485, y mayor natremia basal que la cohorte A (141 ± 5 mEq/L vs 134 ± 6 mEq/L, p = 0,003). En las demás variables de ingreso no hubo variación de significación entre ambas. Todos los valores de las variables de ingreso y sus diferencias en ambas cohortes se listan en la Tabla 2.
[Na] basal
menor [Na] Cohorte A
B
150 145 140 [Na] sérico (mEq/L)
Edad (años) mediana (rango)
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135 130 125 120 115
[Na] basal
menor [Na] Cohorte B
La curva ROC construida a partir de la [Na] sérica al ingreso como variable testeada y del desarrollo de hiponatremia por el tratamiento como estado de naturaleza, con un área bajo la curva (AUC) de 0,797, mostró que el valor de natremia basal ≥ 137,5 mEq/L fue el que mejor discriminó la evolución a hiponatremia con sensibilidad de 0,82 y especificidad de 0,72 para predecirla (Figura 2). Acta Gastroenterol Latinoam 2016;46(4):284-290
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La [Na] sérica ≥ 137,5 mEq/L se asoció con desarrollo de hiponatremia durante el tratamiento (p = 0,0001) (Tabla 3). Tabla 2. Se listan las diferencias cuantitativas y cualitativas en las variables de ingreso en ambas cohortes, y el nivel de significación de la diferencia. FC: frecuencia cardíaca. TAM: presión arterial media. Rec plaq: recuento de plaquetas. Creat: creatinina. Bil: bilirrubina. ALAT: aspartato aminotransferasa. ALAT: alanina aminotransferasa. FAL: fosfatasa alcalina. mEq: miliequivalente. min: minuto. [Na]: natremia. [K]: kalemia. DE: desvio estándar.
Tabla 3. Asociación entre natremia al ingreso ≥ 137,5 mEq/L y desarrollo de hiponatremia durante el tratamiento, Chi p = 0,0001.[Na]: natremia. Desarrollo de hiponatremia Sí
No
Total
[Na] basal ≥ n (%)
Sí
14 (82,4)
12 (27,9)
26
137,5 mEq/L n (%)
No
3 (17,6)
31 (72,1)
34
17 (100)
43 (100)
60
Total
Tabla 4. Variables evolutivas en ambas cohortes. UGR: unidades de glóbulos rojos. DE: desvío estándar.
Cohorte A No hiponatremia
Cohorte B hiponatremia
n pacientes (%)
43 (71,6)
17 (28,3)
Edad (años) mediana (rango)
54 (28-77)
54 (37-67)
0,8245
Sexo
Femenino n (%)
9 (20,9)
5 (29,4)
0,4840
n pacientes (%)
43 (1,6)
17 (28,3)
Masculinos n (%)
34 (79,1)
12 (70,6)
A n (%)
2 (4,6)
4 (23,5)
0,0485
Mortalidad n (%)
5 (11,6)
1 (5,9)
0,4486
B n (%)
26 (60,5)
10 (58,8)
0,9069
7 (16,3)
2 (11,8)
0,6539
C n (%)
15 (34,9)
3 (17,7)
0,1892
Resangrado n (%)
Alcohólica n (%)
24 (55,8)
8 (47,1)
0,5402
No alcohólica n (%)
19 (44,2)
9 (52,9)
1,3 ± 2,1
1,1 ± 1,5
0.6839
MELD basal (media ± DE)
16 ± 7,5
12,9 ± 5,8
0,1301
(UGR) (media ± DE)
[Hb] basal (g/dL) (media ± DE)
8,6 ± 2,3
9,6 ± 1,8
0,0788
Encefalopatía n (%)
12 (27,9)
3 (17,6)
0.4082
Rec. plaq. basal (/mm) (media ± DE)
109933 ± 54933
87117 ± 35550
0,1175
Bil. total basal (mg/dL) (media ± DE)
3,9 ± 5,9
2,9 ± 6,0
0,6795
ASAT basal (U/L) (media ± DE)
71,7 ± 54,9
83,6 ± 74,1
0,4956
ALAT basal (U/L) (media ± DE)
38,4 ± 19
45,6 ± 21,9
0,2074
FAL basal (U/L) (media ± DE)
109,9 ± 80,8
142,6 ± 123,1
0,23489
[K+] basal (mEq/L) (media ± DE)
4,3 ± 0,9
4 ± 0,7
0,2881
[albúmina] basal (g/dL) (media ± DE)
2,4 ± 0,5
2,6 ± 0,7
0,2006
RIN basal (media ± DE)
1,6 ± 0,3
1,4 ± 0,4
0,1349
KPTT (s) (media ± DE)
44,3 ± 17,5
38,3 ± 14,1
0,2253
Urea basal (mg/dL) (media ± DE)
56 ± 38,4
41,1 ± 18,3
0,1348
Creat. basal (mg/dL) (media ± DE)
1,1 ± 1,0
0,8 ± 0,3
0,2387
Glucemia basal (mg/dL) (media ± DE)
160 ± 74,7
131 ± 39,3
0,1556
FC basal/min (media ± DE)
90 ± 19,2
84,8 ± 22,1
0,3729
TAM basal (mmHg) (media ± DE)
70,8 ± 5,9
69,2 ± 9,9
0,4391
[Na+] basal (mEq/L) (media ± DE)
134 ± 6
141 ± 5
0,003
Sangrado activo n (%)
14 (32,6)
9 (52,9)
0,1434
Fracaso hemostático inicial n (%)
7 (16,3)
3 (17,6)
0,8981
Ascitis n (%)
30 (69)
7 (41,2)
0,3194
Etiología
p
Variables evolutivas
Cohorte A No hiponatremia
Cohorte B hiponatremia
p
Transfusiones
Figure 2. La curva ROC, construida a partir de los valores de natremia al ingreso de los pacientes y del desarrollo de hiponatremia durante el tratamiento con un AUC de 0,797, refirió al valor basal ≥ 137,5 mEq / L como el que mejor discriminó la evolución hacia la hiponatremia. Cada marca sobre la curva representa un valor de natremia medido en mEq/L. 1
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Sensibilidad
Child
288
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0 0
1- especificidad
1
Terlipresina e hiponatremia en pacientes cirróticos con hemorragia variceal
Las variables de ingreso que correlacionaron con el desarrollo de hiponatremia durante el tratamiento fueron: la clase A de Child-Pugh y la [Na] sérica basal ≥ 137,5 mEq/L. Ambas fueron incluidas en el análisis de regresión logística, resultando la [Na] sérica basal ≥ 137,5 mEq/L la única que calificó como predictor independiente de evolución a hiponatremia con un OR (IC 95%) de 12,1 (2,9-49,6). La duración del tratamiento con terlipresina fue de 3,4 ± 1,1 días en la cohorte A, y 4,1 ± 1,7 días en la cohorte B (p = 0,0605). Durante la evolución no se observaron diferencias significativas en mortalidad hospitalaria, resangrado, requerimiento de transfusiones y presentación de encefalopatía en ambas cohortes (Tabla 4). No se presentaron manifestaciones neurológicas atribuibles a hiponatremia. Discusión
El presente trabajo suma evidencia al hecho de que los pacientes cirróticos con HVE tratados con terlipresina presentan una reducción de la [Na] sérica. La hiponatremia por este tratamiento ocurrió en 28,3% de nuestros pacientes. Como en otras publicaciones, nuestro estudio evidencia una fuerte asociación entre los valores basales mayores de natremia al ingreso y el desarrollo de hiponatremia durante el tratamiento. La pertenencia a clase A de Child-Pugh también tuvo en el análisis univariado una significativa asociación con evolución a hiponatremia durante el tratamiento con terlipresina. La regresión logística mostró que la clase A de Child-Pugh pierde su valor predictivo cuando se incorpora al análisis multivariado el valor de natremia de 137,5 mEq/L o más al momento de ingreso del enfermo al hospital. Esta última es entonces predictor independiente de evolución a hiponatremia durante el tratamiento con esta droga. La prevalencia comunicada de hiponatremia en esta situación es muy dispar y la proporción de pacientes que en nuestra serie la desarrolló (28,3%) es intermedia entre quienes no la mencionan15 o la refieren en 3 a 6% de los pacientes tratados16-17 y aquellos que la describen en el 41 a 70% de los casos.10-12 Se comunicó una asociación directa entre la evolución a hiponatremia y la eficacia de la terlipresina en el control del sangrado, y que esta complicación asociada al tratamiento de la HVE no es indicadora de pronóstico desfavorable12 como sí lo es en el paciente cirrótico en otras circunstancias.18-19 El primer trabajo que evaluó esta complicación en un número relevante de pacientes con HVE constató hiponatremia en el 67% de 58 enfermos tratados con terli-
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presina. Los pacientes incluidos en ese estudio presentaban características de mayor gravedad que los de nuestra serie, dado que ya habían fracasado o resangrado luego de recibir somatostatina más tratamiento endoscópico, y requirieron un número mayor de transfusiones de glóbulos rojos que los de nuestro grupo. Además, estos autores refieren a la solución de dextrosa 5% en agua como uno de los fluidos de reanimación.12 Todo esto podría tener relación con la elevada proporción con que se presentó esta complicación. Nuestros pacientes no provenían de un fracaso hemostático previo y recibieron reanimación con suero fisiológico, albúmina, plasma cuando se lo consideró necesario, y con glóbulos rojos, intentando mantener la [Hb] en sangre en 7 a 8 g %. Las manifestaciones neurológicas asociadas a la hiponatremia fueron referidas en la literatura en aquellos pacientes en los que la natremia descendió más de 10 mEq/L respecto a la de ingreso. Esto ocurrió en 3 de 21,12 1 de 40,10 y en 5 de 16 pacientes.11 En nuestra serie 5 pacientes tuvieron un descenso de la natremia superior a 10 mEq/L respecto al ingreso; en ellos la natremia basal fue 143,6 ± 5,1 mEq/L y el valor más bajo alcanzado fue de 125 mEq/L. Ninguno de ellos tuvo manifestaciones neurológicas atribuibles a hiponatremia. En los tres trabajos que comunicaron hiponatremia asociada al tratamiento con terlipresina entre 41 y 70% de la población expuesta, ésta se asoció en el análisis univariado con los siguientes parámetros de ingreso: mayor [Na] sérica, menor score de MELD, menos antecedentes de encefalopatía hepática, de diabetes melitus y de uso de diuréticos, menor bilirrubina sérica, menor score de Child-Pugh, menor valor de RIN, menor índice de masa corporal, menor valor de creatinina. La mayor duración del tratamiento con terlipresina también se asoció a hiponatremia. El análisis multivariado entre los tres trabajos seleccionó como predictores independientes de evolución hacia hiponatremia a la presencia al ingreso de: mayor valor de natremia, menor score de MELD, menor edad, menor score de Child-Pugh, y durante el tratamiento a su mayor duración. Es de destacar que el predictor independiente común en todos éstos fue el mayor valor de la natremia al ingreso.10-12 En nuestro trabajo, la natremia al ingreso ≥ 137,5 mEq/L fue el único predictor independiente de evolución a hiponatremia OR: 12,1 (IC 95%: 2,9-49,6). Se ha sugerido que el descenso de la natremia generado por la terlipresina sería mayor a menor grado de ocupación de los receptores V2 en los túbulos renales, Acta Gastroenterol Latinoam 2016;46(4):284-290
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Terlipresina e hiponatremia en pacientes cirróticos con hemorragia variceal
permitiendo que la droga administrada estimule la retención de agua libre de solutos.12 El nivel de vasopresina circulante es mayor en los cirróticos descompensados que en los compensados y20-21 la elevada secreción de vasopresina no mediada por la osmolaridad plasmática es uno de los mecanismos responsables de la retención de agua en cirróticos.18, 23 Esto daría argumento al hecho de que la natremia desciende más en pacientes con natremia previa normal y está acorde con la baja prevalencia de hiponatremia reportada durante el tratamiento del síndrome hepatorenal con terlipresina y albúmina.22 Conclusión: El único predictor independiente de hiponatremia en cirróticos con HVE tratados con ligadura endoscópica y terlipresina fue el mayor valor de la natremia al ingreso, dicotomizado como una natremia basal de 137,5 mEq/L o mayor. El grado de hiponatremia observado no modificó los resultados de la terapéutica, no hallándose diferencias entre ambas cohortes en mortalidad intrahospitalaria, resangrado, número de transfusiones requeridas, ni encefalopatía. No observamos manifestaciones neurológicas que pudieran atribuirse a la hiponatremia.
Referencias 1. de Franchis R. Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol 2000; 33: 846-852. 2. Abraldes JG, Bosch J. The treatment of acute variceal bleeding. J Clin Gastroenterology 2007; 41: S312-S317. 3. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W; Practice Guidelines Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007; 46: 922-938. 4. de Franchis R. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015; 63: 743-752. 5. Escorsell A, Bandi JC, Moitinho E, Feu F Garcia-Pagan JC, Bosch J, Rodes J. Time profile of the haemodynamic effects of terlipressin in portal hypertension. J Hepatol 1997; 26: 621-627. 6. Merkel C, Gatta A, Bolognesi M, Finucci G, Battaglia G, Angeli P, Zuin R. Hemodynamic changes of systemic, hepatic, and splenic circulation following triglycyl-lysine-vasopressin administration in alcoholic cirrhosis. Dig Dis Sci 1988; 33: 1103-1109. 7. Romero G, Kravetz D, Argonz J, Bildozola M, Suárez A, Terg R. Terlipressin is more effective in decreasing variceal pressure than portal pressure in cirrhotic patients. J Hepatol 2000; 32: 419-425. 8. Machova´ A. Antidiuretic activity of terlipressin (triglycyl-lysine vasopressin) - role of pressure natriuresis. Physiol Res 1992; 41: 121-127.
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9. Krag A, Bendtsen F, Pedersen EB, Holstein-Rathlou NH, Møller S. Effects of terlipressin on the aquaretic system: evidence of antidiuretic effects. Am J Physiol Renal Physiol 2008; 295: F1295-F1300. 10. Yim SY, Seo YS, Jung CH, Kim TH, Kim ES, Keum B, Kim JH, An H, Yim HJ, Yeon JE, Jeen YT, Lee HS, Chun HJ, Byun KS, Um SH, Kim CD, Ryu HS. Risk Factors for Developing Hyponatremia During Terlipressin Treatmen: A Retrospective Analyses in Variceal Bleeding. J Clin Gastroenterol 2015; 49: 607-612. 11. Kang YJ, Bae EJ, Hwang K, Jeon DH, Jang HN, Cho HS, Chang SH, Park DJ. Initial serum sodium concentration determines the decrease in sodium level after terlipressinadministration in patients with liver cirrhosis. Springerplus 2013; 2: 519. 12. Solà E, Lens S, Guevara M, Martín-Llahí M, Fagundes C, Pereira G, Pavesi M, Fernández J, González-Abraldes J, Escorsell A, Mas A, Bosch J, Arroyo V, Ginès P. Hiponatremia in patients treated with terlipressin for severe gastrointestinal bleeding due to portal hypertension. Hepatology 2010; 52: 1783-1790. 13. Berreta J, Kociak D, Romero G, Balducci A, Amaya R, Argonz J. Endoscopic versus endoscopic plus octreotide treatment for acute variceal bleeding. Benefit according to severity at admission. Acta Gastroenterol Latinoam 2013; 43: 89-97. 14. de Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005; 43: 167-176. 15. Abid S, Jafri W, Hamid S, Salih M, Azam Z, Mumtaz K, Shah HA, Abbas Z. Terlipressin vs. octreotide in bleeding esophageal varices as an adjuvant therapy with endoscopic band ligation: a randomized double-blind placebo-controlled trial. Am J Gastroenterol 2009; 104: 617-623. 16. Escorsell A, Ruiz del Arbol L, Planas R, Albillos A, Bañares R, Calès P, Pateron D, Bernard B, Vinel JP, Bosch J. Multicenter randomized controlled trial of terlipressin versus sclerotherapy in the treatment of acute variceal bleeding: the TEST study. Hepatology 2000; 32: 471-476. 17. Feu F, Ruiz del Arbol L, Bañares R, Planas R, Bosch J. Doubleblind randomized controlled trial comparing terlipressin and somatostatin for acute variceal hemorrhage. Variceal Bleeding Study Group. Gastroenterology 1996; 111: 1291-1299. 18. Lehrich RW, Ortiz-Melo DI, Patel MB, Greenberg A. Role of vaptans in the management of hyponatremia. Am J Kidney Dis 2013; 62: 364-376. 19. Biggins SW, Rodriguez HJ, Bacchetti P, Bass NM, Roberts JP, Terrault NA. Serum sodium predicts mortality in patients listed for liver transplantation. Hepatology 2005; 41: 32-39. 20. San-e Ishikawa, Schrier R. Pathogenesis of hyponatremia: the role of arginine vasopressin. En: Gines P, Arroyo V, Rodes J, Schrier R. Ascites and renal dysfunction in liver disease. Pathogenesis, diagnosis, and treatment. 2a edition. ed: Blackwell Publishing 2005: 305-314. 21. Bichet D, Szatalowicz V, Chaimovitz C, Schrier RW. Role of vasopressin in abnormal water excretion in cirrhotic patients. Ann Intern Med 1982; 96: 413-417. 22. Nazar A, Pereira GH, Guevara M, Martin-Llahi M, Pepin MN, Marinelli M, Solá E, Baccaro ME, Terra C, Arroyo V, Ginès P. Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology 2010; 51: 219-226.
Menopause and Estradiol Treatment. Analysis by the “Pancreatogram” Osvaldo M Tiscornia,1, 2 Simmy Bank,3 Fabiana N López Mingorance,1, 2 María B Di Carlo,2 Graciela Otero,1 Selene Rodríguez,1 Patricia G Tiscornia-Wasserman,1, 4 Gustavo A Negri1, 2 Programa de Estudios Pancreáticos, Hospital de Clínicas, UBA. Ciudad Autónoma de Buenos Aires, Argentina. Departamento de Bioquímica Clínica, Hospital de Clínicas, FFyB, INFIBIOC, UBA. Ciudad Autónoma de Buenos Aires, Argentina. 3 Deparment of Gastroenterology of Long Island Jewish Medical Center (LIJ). USA. 4 Deparment of Cytopathology, Columbia University. USA. 1 2
Acta Gastroenterol Latinoam 2016;46:291-299 Recibido: 05/01/2016 / Aprobado: 06/06/2016 / Publicado en www.actagastro.org el 01/01/2016
Summary
The aim of the present undertaken was to analyze, by means of the “pancreatogram”, the changes induced by estradiol in a group of non-obese healthy women (n = 15) in the menopause stage (mean age 57) in comparison with a control group (n = 18) of all ages (mean 46). This exam allows an encompassing view of both the exocrine and endocrine pancreas and of their interactions.The main evaluation was done with the 2hs cumulative values of glycemia, insulin, amylase, isoamylase, lipase and calcium. The menopause group was reevaluated after one month of estradiol treatment (estrogen stage) at the dose of 0,625 mg/day. Unexpectedly 75% of the menopause women revealed an impaired glucose tolerance test, this reflected by the glycemia/insulin index figures. The estrogen stage and the one performed following a free hormonal treatment period (post-treatment stage), disclosed a progressive significant decline of the glycemia values associated to unmodified insulin ones. This finding reflects an enhanced sensitivity response to the endocrine hormone. Coupled to the latter are associated the isolated respective values
Correspondencia: Fabiana López Mingorance J E Uriburu 1044 - 1º piso. Dto 15. Ciudad Autónoma de Buenos Aires, Argentina Tel: 4823-1843. Cel: 15 5404 9779 Correo electrónico:
[email protected]
on the lipasemia fall and of calcemia rising. Coherent with these results are those observed with the index figures of lipase/ insulin and lipase/calcium. Undoubtedly estradiol enhances both insulin and calcium secretion. Suggestively, these effects were more marked following a short arrest period of estradiol administration. This fact seemingly allowing to infer that in certain circumstances it would be advisable to choose an intermittent therapeutic option. Key words. Menopause, estradiol, oral glucose tolerance test.
Páncreas exócrino-endócrino. Menopausia y tratamiento con estradiol. Análisis mediante el “Pancreatograma” Resumen
El objetivo del presente emprendimiento fue el de analizar, por medio del “Pancreatograma”, los cambios inducidos por el estradiol en un grupo de mujeres no-obesas, sanas (n = 15) en estadío menopáusico (edad promedio 46 años). El aquí propuesto examen faculta el lograr una visión global abarcativa tanto de los componentes exocrino y endocrino del páncreas y el de la interacción entre ambas. La valoración se centró en los valores acumulativos de 2hs de todos los parámetros: glucosa, insulina, amilasa, isoamilasa, lipasa y calcio (estadío pre-tratamiento). El grupo menopáusico fue reevaluado luego de un mes de tratamiento con estradiol en dosis de 0,625 mg/día (estadío estrogénico). Inesperadamente el 75% de las mujeres menopáusicas revelaron una respuesta intolerante de la glucosa, ello bien reflejado por el índice glucosa/insulina. Este estadío, y el desarrollado siguiendo a un período libre de terapia hormonal (estadío post-tratamiento) Acta Gastroenterol Latinoam 2016;46(4):291-299
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pusieron de manifiesto una progresiva significativa declinación de los valores glucémicos asociados a niveles invariables de la insulina, ello indicando una incrementada sensibilidad de respuesta de la hormona endocrina. Esto acoplado a una depresión de la lipasemia y a una elevación de la calcemia. Coherente con estos resultados son los observados en los índices lipasa/insulina y lipasa/calcio. Indudablemente el estradiol estimula los valores secretorios de la insulina y del calcio. Fue muy sugestivo que estos efectos fueran más ostensibles siguiendo a un corto periodo de arresto de la terapéutica hormonal. Esto permite inferir que, en ciertas circunstancias, sería aconsejable adoptar un tratamiento intermitente de la hormona femenina. Palabras claves. Menopausia, estradiol, prueba de tolerancia oral a la glucosa. Abbreviations CCK: cholecystokinin. SHBG: serum-hormone-binding-globulin. NIDDM: non-insulin-dependent diabetes mellitus. BMI: body-mass index. CV: cumulative Value. Pr. Estr. St.: Pre Estradiol Stage. Estr. St.: Estradiol Stage. Post. Estr. St.: Post- Estradiol- Stage. Lip: lipase. Ca: calcium. Ins: insulin. Gly: glycemia. Amy: amylase. HISS: hepatic insulin sensitizing substance. MISS: meal-induced-insulin-sensitization. AMISS: absence of meal induced insulin sensitization.
Several decades of involvement in the evaluation of the exocrine pancreas gradually convinced us that it could constitute a practical advance in this field to design a new, easy to perform, non-invasive test able to offer both an encompassing view of the exocrine and endocrine pancreas and of their interactions.1-3 In order to fulfill the above purpose we considered that the classical oral glucosetolerance test might be an appropiate method to start with. It was also our conviction that this exam could be perfected by adding to the classical determinations in blood of glucose and insulin those of total amylase, pancreatic isoamylase, lipase and calcium. We baptized the new procedure as the “Pancreatogram”. 292
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Previous data provided support to this approach. The main ones being those pivoting on insulin, primarily on its trophic and functional influences upon the “pancreon” units that are exerted mainly paracrinically. Concerning the latter, the changes worthy of emphasis are the divergent influences of stimulation and inhibition, respectively, upon the synthesis and secretion of amylase and lipase.1-5 We have hypothesized that, by evaluating the base line and the post “Pancretogram” parameters values, one might be able to get a trustworthy assessment of both the exocrine and endocrine pancreas and of their interrelationship. Another background knowledge that was taken into account, especially due to its linking to the present undertaking, is that both the “pancreon” units and the Langerhansislets, as well as the hepatocytes, possess estrogen receptors.6-10 Furthermore, that an intrapancreatic “estrogenic tone” interact with the rest of the neuro-endocrine agents that control the trophism and the secretory capacity of the gland. In that sense, a series of findings of our group support this contention.11-13 One of them is observed analyzing the secretin-induced exocrine pancreatic secretion of healthy men and women above and below the 45 year old age. This study put in evidence that women over this time limit secreted significantly less water and bicarbonate than men. Another report, complementary of the preceding one,12 showed that the above differences could be erased by the administration of estradiol for a month. In the same line of thought, we also reported, in male rats, that a two-week estradiol treatment elicited a significant potentiation of all basal bile-pancreatic secretion parameters.13 This exocrine secretory change associated, histologically, to a hypertrophy of the Langerhans islets´ beta cells and a marked zymogene granules depletion of the acinar pancreocytes. Out of the above findings we inferred an estradiolevoked enhancement of the beta cell insulin secretion. We speculated further that the histological and functional changes might result, on one hand, of a direct effect of insulin, and, on the other, of an interrelationship of this hormone with well known neuro-hormonal factors such as acetylcholine and CCK.14 Linked to the above observations is the clinical-functional feature characterized by a marked secretin-evoked exocrine pancreas hydrelatic hypersecretion. We have put this in evidence in a group of diseases in which are associated, in the liver and pancreas, histological changes of ductular hyperplasia. The entities were those of biliary and alcoholic cirrhosis and hemochromatosis.2 But the fact to be emphasized, that keeps relation with the
Menopause and Estradiol Treatment. Analysis by the “Pancreatogram”
present report, is the finding of a relative hyperestrogenism resulting from an accentuated peripheral conversion of plasma testosterone and androstenedione to estrogen, phenomenon that is potentiated by chronic alcoholism. In that sense it should be pointed out that ethanol is an agent that increases the number of estrogen receptors in both liver and pancreas.8, 14-16 In respect to the modifications of the estrogenic and of the androgenic tone in different physiological conditions, one to be considered is that of the old men who usually show a fourfold higher levels of estradiol than older women. It should be recalled that in men testosterone is secreted almost exclusively by the testis. Other androgens and some estrogens also come from adrenal secretion and/or the peripheral conversion of precursors. Undoubtedly testicular androgen secretion declines with age. Concerning the increase of estradiol plasma concentration in ageing males this is due partly to its reduced metabolic clearance rate and partly to an increase in peripheral aromatization of androgens.17 In the experimental field one cannot but to make reference to the contribution of the Houssay group in an effort to elucidate the involvement of the sex hormones in the physiology of exocrine-endocrine pancreas. Houssay18 was one that drew attention to the relation of sex hormones to glucose tolerance. Indeed, in his 1951 review he noted that estrogen given to partially pancreatectomized rats reduced the 6-month incidence of diabetes. Subsequently, his group,19-25 making appeal to the 95 % pancreatectomized rat model, showed that the frecuency of diabetes was higher in males than in females. Besides, that in male rats castration reduced the incidence of diabetes, whereas, in females, inducement of diabetes was substantially increased by ovariectomy. Also, that the protective effect of estrogen was associated with hypertrophy and hyperplasia of both the “pancreon” units and of the Langerhan islets. Furthermore, that the implantation of estrogen pellets in the pancreas was associated with islet regeneration, particularly in the area of the implant. All the above findings undoubtedly pointing to a direct influence of estrogen upon the pancreatic gland. An observation coherent with the preceding facts is the demonstration that the islets cells coming from rats receiving estradiol for 21 days secrete greater amounts of insulin in respect to those coming from control animals.24 In the same line of the above results are those of Basabe et al.25 Indeed, they showed that long-term administration of estradiol (4 μg/day) for 7 months to ovariectomized rats reduced blood sugar levels by increasing blood insulin values.
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The reports above commented and the results of this presentation leave no doubt that estradiol plays a significant role in the physiology of both the “pancreon” units and the Langerhan islets. Before entering into the details of the present undertaking we have considered appropriated to underscore the contrasting evidences, in respect to the preceding ones that result when androgen tone predominates. Thus, when women show a low level of serum-hormone-bindingglobulin (SHBG) which in fact reflects an increase of free testosterone, they usually show signs of insulin resistance and with it visceral obesity and tendency to develop NIDDM, hypertension and cardiovascular disease.26-33 A feature to point out is that, in the hyperandrogenic women the insulin sensitivity in the liver is preserved but reduced in the periphery. An interesting fact, that is pertinent to the findings of the present report, is that the above changes are alleviated by the estrogen administration. Besides that, the female sex hormone improves the glucose metabolism through a depression of the hepatic glucose output. 26-33 Another dilemma to be resolved is that of the estradiol-induced enhancement of the insulin responses and, by contrast, those of depression associated by a rising of the testosterone level.26-33 Subjects and methods
Fifteen apparently healthy women, all of them, except two, in spontaneous menopause, were selected from the Clinical Hospital Menopause Clinic. The average age of this Menopause Group was 57.46-56 Their mean body-mass index (BMI) was 23. They were non-smokers and nonalcoholics. None was taking medications known to affect lipid metabolism, nor did they receive sex steroids within the previous 3 months. Post-menopausal status was confirmed by measurements of gonadotropin levels (FSH > 50 IU/ml), (mean 79,1 IU/ml). The post-menopausal women had amenorrhea for > 2 year and estradiol level < 20 μg/ml. Each was free of medical illness, including diabetes. The study protocol conformed to the guidelines of the World Medical Association Declaration of Helsinki, and to those of the Ethics Committee of the Hospital de Clínicas “José de San Martín”. As in this report the analysis of the modifications observed in the “Pancreatogram” play a pivotal role, in the Table 1 is pinpointed, taking essentially into account the blood glucose and insulin values, what was the criteria chosen to include a patient either in a normal, impaired or definite diabetic group. Acta Gastroenterol Latinoam 2016;46(4):291-299
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Table 1. Plasma Glucose Cutpoints Values (fasting and 2-h post Pancreatogram) that define normal glucose metabolism, “impaired” tolerance and diabetes mellitus. Fasting
2-h Post-load
2-h Cumulative value (CV)
Normal
< 110 mg/dl (6.1 mmol/l)
< 140 mg/dl (7.8 mmol/l)
< 500 mg
Impaired
≥ 110 mg/dl (6.1 mmol/l) and < 126 mg/dl (7.0 mmol/l)
≥ 140 mg/dl (7.8 mmol/l) and < 200 mg/dl (11.1 mmol/l)
> 500 mg and < 800 mg
Diabetes Mellitus
≥ 126 mg/dl (7.0 mmol/l)
200 mg/dl (11.1 mmol/l)
> 800 mg
Procedures: Subjects were attended at the “Pancreatic Studies Program” following a 12 hours overnight fast. Height and weight were measured and a general history was obtained including dietary habits, alcohol consumption and family history of diabetes and heart disease. With the patient semi recumbent a cannula was inserted into an antecubital vein. Blood was taken for basal measurement of plasma glucose,34 insulin by an inmunoenzymatic method, total amylase35 and pancreatic isoamylase previous inhibition of salivary amylase with wheat gluten; lipase by the Lehmann method36 and calcemia by a standard laboratory method. Subsequently, an oral glucolin solution (75 g diluted in 350 ml of tap water) was given by mouth. Blood samples at 30, 60 and 120 minutes were drawn and the same determinations above described were repeated. Other parameters besides those that have been already stated were, i.e, the “Cumulative Value”(CV) (adding fasting value plus those of the post-glucose challenge samples) (Table 2). In addtion, a series of indexes were analyzed, such as: glucose/insulin, amylase/isoamylase, lipase/ insulin and lipase/calcium. The above quotients were calculated with the respective parameters´ values of each sample, fasting and post-glucose testing, including those of the respective “CV”. In this group of 15 patients we evaluated the effects of one month of estradiol treatment. Also, the eventual modifications of the “pancreatogram”, following a twomonth free treatment period. Thus, in order to evaluate the results, a “Pre.Estradiol Stage” (Pr.Estr.St.), an “Estradiol Stage” (Estr. St.) for one month and, following a two-month free treatment period, a “Post- EstradiolStage” (Post. Estr. St.) were considered and evaluated comparatively. The findings of the “Menopause Group” were compared with those of a “Control Group” The latter was 294
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constituted by eighteen healthy subjects of all ages (mean 46, range 37-64 yr.) 13 females and 5 men that were subjected to the same “Pancreatogram” above described. The statistical analysis was performed essentially with the Student “t” test. When appropiate, the non-parametric Mann-Whitney test was also applied. A p value of less than 0.05 was considered as significant. Table 2. Analysis of the Control Group of the “Pancreatogram” 2-h Cumulative Values CV Indexes, upper and lower. Cutpoint values of each parameter. Parameters
× ± SEM
Upper
Lower
Glycemia
404 ± 9.7
500
300
Panc. isoamylase
203 ± 9.9
350
60
Amylase
393 ± 9.9
650
150
Lipase
416 ± 43.9
800
60
Calcium
34.80 ± 0.85
40
27
Insulin
253 ± 26
450
50
Glyc/Ins
1.82 ± 0.18
3.22
0.42
Lip/Ins
2.11 ± 0.38
5.07
0.0
Lip/Ca
12.0 ± 1.26
22.34
1.60
Amyl/Ins
2.03 ± 0.19
3.85
0.0
Indexes
Results
The first finding to emphasize is that 75% of the “Menopause Group” disclosed, unexpectedly, an “impaired glucose tolerance test” (Tables 1-4). The “Menopause Group” showed in the three Stages analyzed significantly higher glycemia values in respect to those of the “Control Group”. Surprisingly the difference was ostensibly less notorious in the Post. Estr. St. This is primarily reflected in the significant fall of the CV of this stage in respect to those of the Pr.Estr. St. (Table 3). Concerning insulin (Table 3) its value in the three stages of the “Menopause Group” do not differ from those of the Control Group. It is worthy of emphasis that the blood insulin values of the Control Group are similar to those recently reported in Turkey.38 In respect to pancreatic isoamylase (Table 2), this enzyme shows a slight, non significant progressive rise going from the Pr. Estr. St. to the Post.Estr. St. When the
Menopause and Estradiol Treatment. Analysis by the “Pancreatogram”
analysis is restricted to the evaluation of the CV this is put in evidence in the Post. Estr. St. a significant higher level than in the Control Group. A feature opposite to the above one is displayed by lipase (Table 3). Indeed this parameter reveals in the CV a significant lower value in the Post.Estr.St. in respect to those of the Pr. Estr. St. In respect to calcemia (Table 3) estradiol treatment induces a significant rise. This is reflected by the CV level which is significantly higher than those of the Pr.Estr. St. and the Control Group. Total amylase is in fact the only parameter that does not reveal estradiol-induced changes (Table 3). The analysis of the different isolated parameters (Table 3) and all their indexes (Table 4) allow confirmation
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Concerning the sex hormone-evoked modifications of the calcemia and of its related indexes, mainly those of Ins/Ca and of Lip/Ca might also be an expression of an enhanced insulin receptor sensitivity and, as a result of that, of an augmented hormone-evoked intracellular calcium release. In respect to the absence, as expected, of a definitive augmented amylase response following estradiol administration, a finding that would be coherent with an increased sex hormone-induced pancreocytes insulin receptor sensitivity, this is probably well explained by the recent observation that in isolated pancreatic acini estradiol causes a doubling of the intracellular amount of amylase and trypsin but does not affect the secretion of these digestive enzymes into the culture medium.39 Furthermore
Table 3. 2hs cumulative value (CV) of the "AOGTT" parameters in the different stages of the Experimental Series. Analysis of Estradiol treatment effects on Menopausal Women. Each subject analyzed as her own control and comparison with a control group. Glycemia Contr. Pre Estr. St. Estr. St. Post. Estr. St.
Expo. Ser.
Amylasemia Contr.
*** 667 ± 27.06 404 ± 9.7
*** 626 ± 31.89 †† *** 577 ± 21.99
Expo. Ser.
Iso-Amyl Contr.
478 ± 50.40 393 ± 29.2
492 ± 49.06
483 ± 38.87
Expo. Ser.
Lipasemia Contr.
220 ± 12.50 203 ± 17.10
235 ± 18.90 * 262 ±17.70
Expo. Ser.
Calcemia Contr.
580 ± 58.10 472 ± 69.5
668 ± 185 ††† 377 ± 35.20
Expo. Ser.
Insulinemia Contr.
35.64 ± 1.04 34,80 ± 0.85
†† ** 39.16 ± 0.71 37.06 ± 0.70
Expo. Ser. 257 ± 31
253 ± 26
255 ± 20.40
267 ± 24.50
Control (n=18). Experimental series (n=15). Values are mean ± SEM Statistical analysis by the "t" Student test. Indexes calculated with the 2 hs CV. † Difference between either the Estr. St or the Post Estr St with the baseline (Pre. Est. St). * Difference with the control series. * p < 0.05;**† p < 0.01;*** p < 0.001 † p < 0.05; †† p < 0.01; ††† p < 0.001
of the above changes associated with estradiol treatment. Thus, the Gly/Ins index shows a progressive value fall in all the different samples during the Estr. St. and the Post. Estr. St. in respect to those of the baseline. This change being more ostensibly clear in the CV results (Table 3). The same phenomenon is displayed by the Lip/Ca index (Table 4). These findings putting in evidence a sex-hormone-induced improved sensitivity of the insulin receptor both in the peripheral tissues (muscle and adipose) and in the exocrine pancreocytes.
in other studies in whole rats treated with supplementary dosis of estradiol, their isolated acini showed an elevated amylase content but a reduced secretion rate.39 The latter is in fact in accord with the Blevins et al40, 41 findings in the sense that estradiol treatment induces a decrease of CCK receptors on the cell surface. From the above observations one might infer that the lack of an expected rising of the amylasemia values subsequent to estradiol administration would be the result of an indirect phenomenon, essentially of a decrease of the acinar cell reponsiveness to CCK. Acta Gastroenterol Latinoam 2016;46(4):291-299
295
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Table 4. Different Indexes of the "Pancreatogram". Analysis of the Estradiol-Induced effects on Menopausal Women (Experimental Series). Comparison with a control group. Glyc/Ins Contr.
Post. Estr. St.
Expo. Ser.
Contr.
*** 3.10 (± 0.35)
Pre Estr. St. Estr. St.
Lip/Ins
1.85 (± 0.19)
*** 2.74 (± 0.27)
Lip/Ca
Expo. Ser.
Contr.
2.46 (± 0.26)
† 2.02 (± 0.21) ††† 1.44 (± 0.20)
Contr.
* 16.77 (± 1.95)
2.42 (± 0.24) 2.10 (± 0.38)
Expo. Ser.
Amyl/Isoamyl
12.09 (± 1.23)
16.53 (± 4.90) ††† 9.89 (± 1.05)
Expo. Ser. 2.26 (± 0.16)
2.07 (± 0.18)
2.20 (± 0.19) 1.81 (± 1.88)
Control (n=18). Experimental series (n=15). Values are mean ± SEM. Statistical analysis by the "t" Student test. Indexes calculated with the 2 hs CV. † Difference between either the Estr. St or the Post Estr St with the base line (Pre. Est. St). * Difference with the Control Series † p < 0.05; †† p < 0.01; ††† p < 0.001 * p < 0.05; **† p < 0.01;*** p < 0.001
Discussion
The first fact to be emphasized resulting of the present undertaking is that the performing of the “Pancreatogram” here proposed discloses, rather unexpectedly, that 75% of a group of healthy non-obese menopause women reveal an impaired glucose tolerance test. This finding associated to normal, except fasting, post-oral glucoseinduced blood insulin values. Interestingly, this group during the Estr. St., and surprisingly even more notoriously in the Post. Estr. St., showed an improvement of the “Pancreatogram” parameters. For example, the Gly/ Ins decreased to a level non-significant from that of the control series. The here observed association of events is well explained according to our view by the report of Spencer et al.42 Indeed, they have pointed out, after analyzing a group of subjects closely similar to the one of our series, that this clinical –endocrinologic condition is associated with a decline of insulin secretion and followed by a progressive increase in insulin resistance and hepatic insulin throughput, i.e., less insulin is taken up by the liver. According to this group, the essential physiological action of the estradiol replacement is that of an increase in both insulin sensitivity and secretion and hepatic insulin uptake. A feature emphasized by Spencer et al.42 is that oral estradiol therapy in post-menopausal women increases hepatic but not peripheral sensitivity, and that the lower296
Acta Gastroenterol Latinoam 2016;46(4):291-299
ing of glycemia figures results from an estrogen-induced reduction in glucagon secretion and sensitivity. In a few words, that the estrogen effects are less counteracted by glucagon, primarily at the liver. In addition, that the improvement in insulin secretion in response to estrogen replacement is a relatively long-term effect resulting from the islets´beta cells hypertrophy and hyperplasia. In synthesis, that the lack of overall changes in the insulin concentration is consequence of the fact that, its estradiol-induced pancreatic secretion is compensated by a simultaneous enhancement of its hepatic uptake. According to Spencer et al,42 the estradiol-evoked insulin secretion is primary and the increased insulin uptake by the liver is a secondary effect. In regard to the above observations, it is appropiate to add those of Anderson et al.26 This group reported an improvement of glucose metabolism and plasma lipids in postmenopausal with NIDDIM after replacement therapy with estradiol. What they emphasize is that, these diabetic women were hyperandrogenic in comparison with non-diabetic women and that after estradiol substitution, SHBG increased 4-fold, whereas free testosterone decreased. According to these authors, hyperandrogenicity, as indicated by low SHBG values, is a powerful independent risk factor for the development of NIDDM, hypertension, and cardiovascular disease. Furthermore, that a low SHBG is associated closely with visceral obe-
Menopause and Estradiol Treatment. Analysis by the “Pancreatogram”
sity. Indeed, women with central body fat distribution have low levels of SHBG and increased free testosterone in parallel with insulin resistance. Visceral obesity is a risk factor for cardiovascular disease, stroke and NIDDM. Low SHBG concentration and visceral obesity may have additive effects on insulin resistance. Thus, increased androgenicity in women may cause insulin resistance. On the other hand, there are several pieces of evidence that insulin resistance, or rather hyperinsulinemia, may lead to hyperandrogenism. In effect, it has been shown that hyperinsulinemia increases androgen output from the ovary and may suppress SHBG production in the liver. That hyperandrogenicity induces insulin resistance and glucose intolerance is in agreement with the results of Anderson et al,26 because elevated SHBG levels induced by estrogen administration, alleviating hyperandrogenicity, were followed, at least partly, by an improved glucose tolerance. It should be pointed out that, insulin sensitivity is preserved in the liver but reduced in the periphery in hyperandrogenic women. In addition to alleviating androgen effects on muscle, estrogen regulates insulin-induced glucose transport via translocation of glucose transporter. In the mechanism for the improvement of glucose homeostasis to the preceding effects should be added those of the estradiol-induced depression of hepatic glucose output. As a collateral digression it should be mentioned that in a series of papers several interesting properties of estradiol and testosterone has been added. Thus, as the latter causes immunosuppression, estrogen does enhance immune function. The above facts explains the philosophical elaboration that whereas males, on the one hand, are less likely to have autoimmune diseases or reject organ transplant, on the other might be less able to handle a septic challenge after trauma or hemorrhage. A series of reports, beside those already mentioned in the introduction, provide useful complementary data. One of them is that of Sutter-Dub.43 This author showed, in the isolated perfused pancreas, that estradiol exerts a direct stimulatory effect on the pancreatic islet cells. Another finding coherent with the above is that reported by Kalkhoff and Kim44 in the sense that estrogens reduce glucagon secretion from islets isolated from pregnant rats. Also that of Faure et al.45, 46 in which the increased glucagon concentration induced by ovariectomy in rats was reversed by the administration of estradiol. We are convinced that the findings of our report represent, in fact, the first stage of a metabolic disorder that slowly and progressively leads to the insulin resistance syndrome. Although it has been argued that this can be seen in non-obese individuals, it is accepted that insulin
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resistance most commonly occurs as a result of increasing weight, lack of exercise, aging, diseases or drugs that antagonize the actions of insulin.47 At this stage one cannot but make reference to the original findings of the Canadian school of Lautt.48-51 Indeed, this group, in a series of “in-vivo” and “in-vitro” studies, in the last 15 years have demonstrated that 55% (~66% in humans) of the glucose disposal effect of an I.V. injection of insulin in the fed state, is dependent on the action of a second hormone: “hepatic insulin sensitizing substance” (HISS) which is released from the liver and stimulates glucose uptake in muscle, heart and kidneys. Sensitization of the insulin response by a meal through release of HISS is called meal-induced-insulin-sensitization (MISS). Absence of HISS action results in post-prandial hyperglycemia, hyperinsulinemia, hyperlipidemia, adiposity, increased free radical stress and a cluster of progressive metabolic and cardiovascular dysfunction referred to AMISS (absence of meal induced insulin sensitization). Reduced HISS release accounts for the insulin resistance that occurs with ageing, and is made worse by physical inactivity and diets high in glucose and fat. The Lautt group proved that HISS acts selectively in skeletal muscle, heart and kidneys, but not liver or adipose tissue, to stimulate glucose uptake. In order for insulin to cause the release of HISS, two permissive signals are needed. One signal is delivered via hepatic parasympathetic nerves acting on muscarinic receptors and subsequent activation of nitric oxide synthase and elevated cGMP. The other is chemical signal seen as an approximately 40% elevation in hepatic glutathione. Both signals are needed, as either signal, alone is not sufficient to activate the HISS pathway. The feeding signals decrease with the duration of fasting until by 24 hs HISS release is minor or absent. The MISS process has now been demonstrated in mice, rats, guinea pigs, cats, dogs and humans by independent laboratories. Essentially, then, glucose in the blood causes pulsatile release of insulin, which reaches the liver where reflexively activated parasympathetic nerves and rapidly elevated hepatic glutathione serve as permissive regulators to allow pulses of insulin to stimulate pulsatile releases of HISS. This putative hormone enters the bloodstream and stimulates glucose uptake, primarily into skeletal muscle, doubling the disposal effect of a pulse of insulin. Absence of HISS action results in a major shift in storage of nutrient energy from glycogen in muscle to fat. Absence of HISS action is physiologically and appropriately produced in the fasting state when the hypoglycemic effect of HISS would not be advantageous. Acta Gastroenterol Latinoam 2016;46(4):291-299
297
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In respect to the behavior of the exocrine pancreas component of the “Pancreatogram”, i.e, pancreatic isoamylase and lipase, only the values of the latter give an indication of an estradiol-induced enhancement of the normal influences exerted by the beta cell insulin upon the neighbouring pancreocytes. Indeed, the fall of isolated lipasemia and of the enzyme-linked indexes (Lip/Ins, Lip/Ca) give testimony of the inhibitory influence normally exerted by insulin upon the synthesis and secretion of this exocrine pancreas enzyme. When commenting the results we have elaborated on the mechanism that could explain the lack of influence of estradiol on the secretion of amylase.39-41 As we have pointed out an interesting possibility is that the mechanism that could explain the lack of an expected estradiol-evoked rising of the amylasemia values is the demostration that this sex hormone inhibits secretion of the enzyme through a decrease of the acinar cell responsiveness to ecbolic agents (acetylcholine, CCK , etc.).30, 41 We are convinced that through the repeated performing of our proposed “Pancreatogram” we will be able, in some clinical circumstances, either to confirm or dismiss that a high lipasemia value, associated to coherent changes of the corresponding indexes (Lip/Ins,Lip/Ca), is a reflection of a definite pancreatic lesion or, by contrast, only a result of a functional derangement of the normal exocrine-endocrine interactions. To the above inferences we feel that another one must be added. This centered on our conviction that repeating the proposed test through a long-term period will allow to put in evidence, especially in those patients that have followed an adequate treatment, the regeneration capacity of both the exocrine and endocrine components of the pancreatic gland.53-56 Conclusion
The main basis that give support to the approach of the “Pancreatogram” the “insulo-pancreon-axis” interaction, explain that, when confronting the results of a case, in general just a rapid glimpse of its isolated parameters values allow to conclude without hesitation that the test is either normal or allow to infer a certain abnormality. A feature that deserves to be stressed, well explicited in this case, is the valuable diagnostic support of those physiologic mechanisms of cellular sensitization, primarily involving three indexes, glyc/ins, lip/ins, lip/ca, that are triggered within the “insulo-pancreon” axis.The evolution of the results through time, has shown, in many patients, that the pancreatic gland. Undoubtedly possess an undeniable regeneration capacity. 298
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20. Foglia VG, Schuster N, Rodriguez RR. Sex and diabetes. Endocrinology 1947; 41: 428-434. 21. Lewis JT, Foglia VG, Rodriguez RR. The effects of steroids on the incidence of diabetes in rats after subtotal pancreatectomy. Endocrinology 1950; 46: 111-121. 22. Borelli MI, Cortizo AM, Gagliardino EE, García ME, Gagliardino JJ. Multiple modulators of the glucose-induced net calcium uptake by isolated islets. Acta Physiol Pharmacol Latinoam. 1984; 34: 1-8. 23. Houssay BA, Foglia VG, Rodríguez RR. Production and prevention of some types of experimental diabetes by estrogens or corticosteroids. Acta Endocrinol (Copenh). 1954; 17: 146-164. 24. Rodríguez RR.Influence of estrogens and androgens on the production and prevention of diabetes. In: On the Nature and Treatment of Diabetes. Eds, Wrenshall GA, Leibel BS. New York: Excerpta Medica Foundation; 1965; 288-307. 25. Basabe JC, Chieri RA, Foglia VG. Action of sex hormones on the insulinemia of castrated female rats. Proc Soc Exp Biol Med. 1969; 130: 1159-1161. 26. Andersson B, Mattson L, Hahn L, Marin P, Lapidus L, Holm G, Bengtsson B, Björntorp P. Estrogen replacement therapy decreases hyperandrogenicity and improves glucose homeostasis and plasma lipids in postmenopausal women with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab.1997; 82: 638-643. 27. Barrett-Connor E, Laakso M. Ischemic heart disease risk postmenopausal women. Effects of estrogen use on glucose and insulin levels. Arteriosclerosis 1990; 10: 531-534. 28. Mizushima Y, Wang P, Jarrar D, Cioffi WG, Bland KI, Chadry IH. Estradiol administration after trauma hemorrhage improves cardiovascular and hepatocellular functions in male animals. Ann Surg 2000; 232: 673-679. 29. Remmers DE, Cioffi WG, Bland KI, Angele MK, Chaudry IH. Testosterone: The crucial hormone responsible for depressing myocardial function in males after trauma-hemorrhage Annals of Surgery 1998; 227: 790-799. 30. Jarrar D, Wang P, Knöferl MW, Kuebler JF, Cioffi WG, Bland KI, Chaudry IH. Insight into the mechanism by which estradiol improves organ function after trauma-hemorrhage. Surgery 2000; 188: 246-252. 31. Wichmann MW, Zellweger R, DeMaso CM, Ayala A, Chaudry IH. Arch Surg. 1996; 131: 1186-1192. 32. Remmers DE, Wang P, Cioffi WG, Bland KI, Chaudry IH. Testosterone receptor blockade after trauma-hemorrhage improves cardiac and hepatic functions in males. Am J Physiology 1997; 273: H2919-H2925. 33. Berry SM, Friend LA, Mc Fadden DW, Brodisch R, Krusch DA, Fink AS. Pancretic denervation does not influence glucose-induced insulin response. Surgery 1994; 116: 67-75. 34. Trinder P. Glucemia: Método enzimático. (glucose-oxidasa/peroxidasa). Am Clin Biochem.1969; 6: 24-26. 35. Junge W. Amylase determination. Clin Biochem. 1989; 22: 109-111. 36. Lehmann ES, Tiscornia OM. Valoración de la lipasa en la exploración secretoria pancreática. Método de Bang modificado. Pren. Méd. Arg. 1984; 71: 170-171. 37. Walczewska A, Yu WH, Kavanth S, Mc Cann SM. Estrogen and leptin have differential effects on FSH and LH release in female rats. Proc Soc Exp Biol Med. 1999; 222: 170-177. 38. Sonsuz A, Basaranoglu M, Bilir M, Senturk H, Akin P. Hyperinsulinemia in nondiabetic, both obese and nonobese patients with nonalcoholic hepatitis. Am J Gastroenterol. 2002; 97: 495-496.
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39. Hilgendorf I, Gellersen O, Emmrich J, Mikkat U, Rohwedel J, Krammer HJ, Müller PK, Kruse C.Estradiol has a direct impact on the exocrine pancreas as demonstrated by enzyme and vigilin expression. Pancreatology 2001; 1: 24-29. 40. Blevins GT Jr, Huang HS, Tangoku A, Mckay DW, Rayford PL. Estrogen influence cholecystokinin stimulated pancreatic amylase release and acinar cell membrane cholecystokinin receptors in rat. Life Sci. 1991; 48: 1565-1574. 41. Blevins GT Jr, McCullough SS, Wilbert TN, Isom RM, Chowdhury P, Miller ST. Estradiol alters cholecystokinin stimulus-response coupling in rat pancreatic acini. Am J Physiol. 1998; 275: G993-G998. 42. Spencer CP, Godsland IF, Cooper AJ, Ross D, Whitehead MI, Stevenson JC. Effects of oral and transdermal 17-b-estradiol with cyclical oral norethindrone acetate on insulin sensitivity, secretion and elimination in postmenopausal women. Metabolism 2000; 49: 742-747. 43. Sutter-Dub MT. Preliminary report: Effects of female sex hormones on insulin secretion by the perfused rat pancreas. J Physiol (Paris) 1976; 72: 795-800. 44. Kalkhoff RK, Kim HJ.Effects of pregnancy on insulin and glucagon secretion by perfused rat pancreatic islets. Endocrinology.1978; 102: 622-631. 45. Faure A, Sutter-Dub MT, Sutter BC. Ovarian-adrenal interactions in regulation of endocrine pancreatic function in the rat. Diabetología 1983; 24: 122-127. 46. Faure A, Billaudel B, Sutter BC. Adrenal interference of insulin secretion after 14 days of estradiol treatment in female rats. Diabetología 1984; 26: 76-80. 47. Everson SA, Goldberg DE, Helmrich SP, Lakka TA, Lynch JW, Kaplan GA, Salonen JT. Weight gain and the risk of developing insulin resistance syndrome. Diabetes Care 1998; 21: 1637-1643. 48. Xie H, Lautt WW. Insulin resistance caused by hepatic cholinergic interruption and reversal by acetylcholine administration. Am J Physiol 1996, 271: E587 – E592. 49. Lautt WW. The HISS story overview: a novel hepatic neurohumoral regulation of peripheral insulin sensitivity in health and diabetes. Can J Physiol Pharmacol. 1999; 77: 553-562. 50. Patarrão RS, Lautt WW, Afonso RA, Ribeiro RT, Fernandes AB, Boavida JM, Macedo MP. Postprandial but not fasting insulin resistance is an early identifier of dysmetabolism in overweight subjects. Can J Physiol Pharmacol. 2012; 90(7): 923-931. 51. Wang HH, Chowdhury KK, Lautt WW. A synergistic, balanced antioxidant cocktail, protects aging rats from insulin resistance and absence of meal-induced insulin sensitization (AMIS) syndrome. Molecules 2015;20(1):669-682. 52. Tiscornia OM, Negri GA, Otero G, Lopez Mingorance F, Waisman H, Tiscornia-Wasserman P. Pancreatic polypeptide: a review of its involvement in neuro-endocrine reflexes, islet acinar interactions and ethanol-evoked physiopathologic pancreatic gland changes. Acta Gastroenterol Latinoam. 2015, 45: 155-164. 53. Tiscornia OM, Dreiling DA. Does the pancreatic gland regenerate? Gastroenterology 1966; 51: 267-271. 54. Tiscornia OM, Dreiling DA. ¿Regenera la glándula pancreática? GEN. 1966; 20: 657-664. 55. Tiscornia OM, Dreiling DA. Recovery of pancreatic exocrine secretory capacity following prolonged ductal obstruction. Bicarbonate and amylase response to hormonal stimulation. Ann Surg.1966; 164: 267-270. 56. Schlegel RD, Tiscornia OM, Vedia y Mitre E, Lembcye AR, Coqui R, Mecagno D, Cravino T, Waisman H. ¿Existe la regeneración pancreática? A. Ge. La. 2000; 30: 107-113.
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Sorafenib for recurrent hepatocellular carcinoma after liver transplantation: a South American experience Federico Piñero,1 Sebastián Marciano,2 Margarita Anders,3 Federico Orozco Ganem,3 Alina Zerega,4 Josemaría Menéndez,5 Manuel Mendizábal,1 Matías Tisi Baña,6 Octavio Gil,4 Solange Gerona,5 Eduardo de Santibañes,2 Ricardo Mastai,3 Adrián Gadano,2 Marcelo Silva1 Hepatology and Liver Transplant Unit. Hospital Universitario Austral. Pilar. Buenos Aires, Argentina. Liver Transplant Program. Hospital Italiano de Buenos Aires. Ciudad Autónoma de Buenos Aires, Argentina. 3 Liver Transplant Unit. Hospital Alemán, Ciudad Autónoma de Buenos Aires, Argentina. 4 Liver Transplant Unit. Sanatorio Allende. Provincia de Córdoba, Argentina. 5 Liver Transplant Program. Hospital Militar-Hospital de Clínicas. Uruguay. 6 Internal Medicine, Biostatistics. Hospital Universitario Austral. Ciudad Autónoma de Buenos Aires, Argentina. 1 2
Acta Gastroenterol Latinoam 2016;46:300-309 Recibido: 12/01/2016 / Aprobado: 14/03/2016 / Publicado en www.actagastro.org el 01/01/2017
Summary
Recurrent hepatocellular carcinoma (HCC) after liver transplantation (LT) has been related with dismal prognosis. The aim of this study was to describe the treatments performed after HCC recurrence in 2 Latin-American countries, and to identify significant factors related to post progression survival. Methods. From 803 adult transplanted patients in 5 LT centers from Argentina and Uruguay (2005-2011), patients with HCC recurrence were included. “Early recurrence” was considered when it occurred during the first year after transplantation. Patients were analyzed according to the treatment introduced after recurrence diagnosis. The post progression survival was compared. Results. Recurrence presented in 20 out of 135 patients (14.8%), 11 (55%) had early recurrences. After recurrence, 14 patients had good performance status and 18 were Child Pugh A. Ten patients received best supportive care (BSC), 10 patients sorafenib, 1 patient local
radiotherapy and 1 patient loco regional surgery. Patients with sorafenib had prolonged post progression survival compared to BSC (5.0 months vs 3.0 months; p = 0.04). On multivariate Cox regression analysis, early recurrence was the only factor related to worst survival, hazard ratio = 3.8 (p = 0.01). A survival benefit with sorafenib in patients with late recurrence when compared to early recurrence was observed (16.0 vs 3.0 months, respectively; p = 0.027). Conclusion. although efficacy of Sorafenib for recurrent HCC should be evaluated in a much-needed randomized controlled trial, a time-selection criterion for this treatment should also be assessed. Key words. Liver, transplantation, cancer, therapeutics.
Sorafenib para el tratamiento de la recurrencia de hepatocarcinoma post trasplante hepático: experiencia sudamericana Resumen
Correspondencia: Federico Piñero Hospital Universitario Austral Av Presidente Perón 1500, (B1629HJ) Pilar. Buenos Aires, Argentina Tel.:(+54) 0230 448-2000 Correo electrónico:
[email protected]
300
Acta Gastroenterol Latinoam 2016;46(4):300-309
La recurrencia post trasplante hepático (TH) del hepatocarcinoma (HCC) es un evento de pobre pronóstico. El objetivo de este estudio fue describir los tratamientos implementados luego de la recurrencia del HCC post TH e identificar los factores pronósticos relacionados a la sobrevida post progresión del HCC. Métodos. De 803 pacientes adultos trasplantados de hígado en 5 centros de TH de Argentina y Uruguay
Sorafenib after transplantation
(2005-2011), aquellos pacientes con recurrencia post TH de HCC fueron incluidos. La recurrencia “temprana” fue catalogada a aquella ocurrida dentro de los primeros 12 meses post TH. Se comparó la sobrevida post progresión. Resultados. La recurrencia de HCC post TH ocurrió en 20 de 135 pacientes (14,8%), 11 (55%) con recurrencia temprana. Al diagnóstico, 14 pacientes presentaban muy buen performance status y 18 tenían un score de Child Pugh A. Desde la recurrencia, 10 pacientes recibieron soporte terapéutico paliativo, 10 sorafenib, 1 paciente radioterapia local y otro resección quirúrgica. Los pacientes que recibieron sorafenib presentaron mejor sobrevida post progresión comparado con soporte paliativo (5,0 vs 3,0 meses, respectivamente; p = 0,04). En el análisis multivariado de regresión Cox, la recurrencia temprana fue la única variable independientemente asociada con peor sobrevida, (Hazard ratio = 3,8; p = 0,01). Se observó un beneficio terapéutico del sorafenib en pacientes con recurrencia tardía comparada vs temprana (16,0 vs 3,0 meses, respectivamente; p = 0,027). Conclusión. La eficacia terapéutica del sorafenib post trasplante debe ser evaluada en un estudio aleatorizado y controlado, el tiempo de diagnóstico de la recurrencia podría contemplarse como criterio de selección terapéutico. Palabras claves. Hígado, trasplante, cáncer, tratamiento.
Abbreviations AE: adverse events. AFP: alpha-fetoprotein. BSC: Best Supportive Care. CI: confidence interval. CsA: Cysclosporine A. CT: computerized tomography. ECOG: East Cooperative Oncology Group. HCC: hepatocellular carcinoma. HR: hazard ratio. iHCC: incidentally found hepatocellular carcinoma. IR: interquartile range. LT: liver transplantation. MELD: model for end-stage liver disease. MMF: mophetilmicophenolate. MRI: magnetic resonance imaging. mTOR: mammalian target of rapamycin inhibitors. Mvi: microvascular invasion. NASH: non-alcoholic steato-hepatitis. RFS: recurrence free survival. Tac: tacrolimus. TTD: total tumor diameter. UCSF: University of California San Francisco.
Federico Piñero y col
The Milan criteria have been accepted in order to select the best hepatocellular carcinoma (HCC) liver transplant candidates.1 However, even with its use, recurrence after liver transplantation (LT) may present at rates reported between 10-15% of the cases.2-5 HCC recurrence after LT is a dramatic event with dismal prognosis and leads to death in most cases.2-4 Median overall survival after recurrence has been described ranging from 14 to 24 months.2-4 Aggressive or combined therapeutic approaches such as systemic chemotherapy or radiotherapy did not show a significant survival benefit after recurrence diagnosis.3, 4 Sorafenib, an oral multikinase inhibitor was the first drug to demonstrate a significant survival advantage in patients with advanced HCC in the non-transplant setting, and is now considered the standard of care in this stage of the disease.6, 7 However, there are no randomized control studies supporting the use of this drug after LT, as these patients have been excluded in previous phase II/III trials.7, 8 Recently, different retrospective published series with a small number of patients have shown that sorafenib prolongs survival in patients with HCC recurrence.9-13 On the other hand, some authors have shown that the key prognostic factor of survival after recurrence diagnosis is time from LT to recurrence.14, 15 Recurrence during the first 12 months after LT (“early recurrence”) has been shown to be an independent predictor of worst survival.14 Consequently, the treatment of HCC in the posttransplant setting is therefore still controversial, particularly regarding the timing of the HCC recurrence. The aim of this cohort study was to describe the treatments performed after HCC recurrence, including sorafenib and to identify significant factors related to post progression survival. Patients and methods
A total of 1542 adult (>17 years of age) LT were performed in Argentina and Uruguay between June 1st 2005 and December 31st 2011. During that period, 803 adult LT were consecutively performed at 4 LT Argentinean centers, the Hospital Universitario Austral, Hospital Italiano from Buenos Aires, Hospital Aleman and the Sanatorio Allende from Cordoba; and at the Hospital MilitarClínicas from Uruguay. From both cohorts, a total of 135 adult cirrhotic LT patients with confirmed HCC in the explanted liver were analyzed and those patients with recurrent HCC were finally included in the study. In all centers, prospectively collected data was retrospectively reviewed for recipient characteristics as well as most recent dynamic tumor images and laboratory Acta Gastroenterol Latinoam 2016;46(4):300-309
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data prior to transplant.16 The number and corresponding diameters of each HCC nodule seen on Computerized Tomography (CT) or Magnetic Resonance Imaging (MRI) were registered in all cases. In all centers, the HCC standard transplant selection were the Milan criteria, and transplantation for patients exceeding this criteria was discussed in a case-by-case scenario. All explants from all patients were routinely examined in all centers. The reports of all patients were retrieved from the Pathology files. Microscopic evaluation for each HCC nodule was conducted to characterize tumor characteristics including: number and largest diameter (cm) of HCC nodules, sum of all diameters or total tumor diameter (TTD), presence of microvascular invasion (Mvi), nuclear grade assessed using the modified Edmonson Steiner grading system18 and Up-to 7 criteria.19 These criteria were assessed only in the explanted liver specimen. Post-LT follow-up visit scheduling was similar in all centers and consisted of one CT or MRI, bone scintigraphy and serum alpha-fetoprotein (AFP) assay every 6 months during the first 3 years in all patients. Tumor recurrence was determined based on imaging criteria16 and serum AFP when there was hepatic involvement or biopsy when isolated extrahepatic metastases of unknown origin were present. Recurrence free survival (RFS) was the period of time calculated in months elapsed from LT to recurrence diagnosis. Recurrence was considered “early HCC recurrence” when it occurred during the first 12 months following transplantation, and “late recurrence” when it occurred later according to previously reported data.14 Performance status according to ECOG and liver function according to the Child Pugh strata was assessed in all patients after recurrence diagnosis. Patients were analyzed according to the treatment strategy introduced when HCC recurrence was diagnosed. Treatment after recurrence diagnosis either with surgical or loco regional therapies, sorafenib or BSC was reached in a case-by-case basis and was thoroughly discussed in every LT center. Clinical follow-up schedules were performed on an outpatient basis, and included physical examination, laboratory analysis and adverse events (AE) monitoring. BSC was defined as only palliative treatment without any systemic chemotherapy, radiotherapy or surgical resection. In those patients who received sorafenib, date of initiation, starting dose and duration of the drug as well as related AE were registered. Related AE were assessed according to common terminology criteria.20 Induction therapy with interleukin 2 receptor antagonist, basiliximab, and maintenance immunosuppression 302
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most frequently used was recorded, such as tacrolimus (Tac), cysclosporine A (CsA) or mammalian target of rapamycin inhibitors (mTOR, sirolimus or everolimus) with or without micophenolate sodium/mophetil (MMF). Although there was no a strict policy of switching from CNI to mTOR immunosuppression, mTORs were considered in all patients, either before or after recurrence diagnosis and was clinically discussed in a caseby-case scenario. The primary outcome analysis was the post progression survival, which was the time from recurrence diagnosis to death, and was calculated in months. This study was conducted in conformance with the 2008 Helsinki declaration and was approved by each institution board. All study participants, or their legal guardian provided informed written consent prior to study enrollment. Statistical analysis
Continuous variables were expressed as mean and standard deviation or median and interquartile ranges (IR) according to their distribution, and were compared with Student’s T test or Mann-Whitney U test. Fisher’s exact test (2-tailed) or Chi-Square (X2) test with Yates’ correction was applied to compare categorical data, and were expressed as frequencies and percentages. For the multivariate analysis of death or post progression survival after recurrence diagnosis, Cox regression was applied to the variables that showed risk of death, with a p value of < 0.1 on univariate analysis [Hazard Ratio (HR), Confidence Interval 95% (CI95%)]. Significant values in the multivariate analysis were considered with a p value of < 0.05. Kaplan Meier curves were assessed for the analysis of survival, and the differences between them was analyzed with log-Rank test. In the final model of survival, the premise of proportional hazard assumption is kept in data. Collected data was included in a database and analyzed with R software (version 3.0.1 for Mac). Results
From 135 adult cirrhotic patients with HCC who were consecutively transplanted with a deceased (n = 132) or living donor (n = 3), 20 (14.8%) presented HCC recurrence (Figure 1). Patients with recurrence had the following pre transplant baseline characteristics: age 60 years (range: 57-64), MELD score 14 ± 7.11 patients (64.7%) were within Milan criteria and had a median serum AFP 47.5 ng/ml (IR: 11.5-523.7 ng/ml). Explanted liver pathology findings revealed that the median number of HCC nodules
Sorafenib after transplantation
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was 2.0 (IR: 1.0-4.0), mean total tumor diameter was 6.4 ± 3.6 cm and major nodule diameter 4.8 ± 2.9 cm. Microvascular invasion was present in 55% (n = 11) of these patients, whereas tumors with ≥ III nuclear grade and beyond Up-to 7 criteria were present in 8 (47%) and 11 (55%) patients, respectively (Table 1). Only 3 out of 20 patients recurred before the year 2008, since sorafenib approval. After recurrence, 14 patients had good performance status (ECOG 0-2) and 18 a well-compensated liver function (Child Pugh A). Median RFS was 10.5 months (IR: 5.0-24.5 months) in a median follow-up period of 16.5 months (IR: 7.5-34.2). Early recurrence presented in 11 patients (55%), while 9 patients had late recurrences. HCC diagnosis after LT was performed with imaging criteria plus AFP in 15 patients (75%) and biopsy in 5 patients (25%). Extra hepatic metastases were present in 18 patients (90%) and only 2 patients had isolated liver involvement (10%) when HCC recurrence occurred. The most frequent recurrence organ location was the liver (n = 12), followed by bones (n = 9), lungs (n = 8) and other sites (n = 6: skin n = 1 and lymph nodes n = 5). Median AFP at time of recurrence diagnosis was 321.5 ng/ml (IR: 21.5-4899.7). Median overall survival and post progression survival were 16.5 months (IR: 8.0-34.2) and 4.0 months (IR: 2.0-7.5), respectively. End-stage and progressive HCC was the main cause of death in all patients.
Figure 1. Inclusion and exclusion criteria flow-chart. n = 1542 adult LT in Argentina-Uruguay 1/2005 a 12/2011
n = 803 adult LT (52.1%) 4 LT centers Argentina, 1 LT center Uruguay
n = 135 LT HCC (16.8%)
Variable
Value
Pre transplant variables Age (years) median (range)
60 (57-64)
MELD* SD
14 ± 7
Hepatitis C n (%)
7 (35)
Hepatitis B n (%)
5 (25)
Milan in n (%)*
11 (64.7)
Median serum AFP ng/ml* (range)
47 (11.5-523.7)
Explanted Liver Median number of nodules (range)
2.0 (1.0-4.0)
Major nodule diameter (cm) SD
4.8 ± 2.9
Microvascular invasion n (%)
11 (55)
Tumor grade ≥ III n (%)
8 (47)
Within up-to 7 n (%)
9 (45)
Clinical Features at Recurrence ECOG performance status n (%)
14 (70)
Child Pugh n (%)
18 (90)
Recurrence location at diagnosis n (%) Liver
12 (60)
Lung
8 (40)
Bones
9 (45)
Lymph nodes
5 (25)
Skin
1 (5)
Treatment after recurrence n (%) Best supportive care
10
Locoregional surgery
1
TACE
0
Chemotherapy
0
Radiotherapy
1
Sorafenib
10
NOTE: Normal Values: Alpha-fetoprotein 0.6-4.4 ng/ml, Abbreviations: AFP: alpha-fetoprotein, HCC: hepatocellular carcinoma; MELD: Model for End Stage Liver Disease.
n = 20 HCC recurrence (14.8%)
n = 10 BSC
Table 1. Patients’ and hepatocellular carcinoma characteristics.
n = 10 Sorafenib
BSC: best supportive care; HCC: hepatocellular carcinoma; LT: liver transplantation.
Basiliximab was administrated in 2 patients, and the most frequent initial maintenance immunosuppression regime was Tac (n = 10, 52%) plus MMF (n = 17, 89%) and steroids (n = 18, 85%). Overall, 12 patients received mTOR immunosuppression (60%), before (n = 7, 58%), or after recurrence diagnosis (n = 5, 42%), either alone or in combinaActa Gastroenterol Latinoam 2016;46(4):300-309
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Treatment performed after recurrence diagnosis
Table 1 shows a descriptive analysis of treatments performed after recurrence. Ten patients received BSC and 10 patients were treated with sorafenib, 1 patient was treated with local radiotherapy and 1 patient with loco regional surgery. Table 2. Comparative analysis between patients with best supportive care or sorafenib after hepatocellular carcinoma recurrence. Variable
BSC n=10 (50.0%)
Sorafenib n=10 (50.0%)
p value
Age (years) median (range)
60 (52-66)
61 (34-69)
0.88
Median AFP ng/ml†
183.5 (11.5-968.0)
36.2 (5.5-380.4)
0.37
Microvascular invasion n (%)¶
6 (60.0)
5 (50.0)
0.50
Nuclear grade ≥III n (%)¶
4 (50.0)
4 (44.4)
0.60
Up-to 7 in n (%)¶
4 (40.0)
5 (50.0)
0.50
Child Pugh A n (%)*
9 (90.0)
9 (90.0)
0.76
ECOG status 0-2 n (%)*
6 (60.0)
8 (80.0)
0.31
mTOR n (%)*
5 (50.0)
7 (70.0)
0.32
3804 (29.3-6742.5)
1147 (2.2-5443.0)
0.58
Early recurrence n (%)
6 (60.0)
5 (50.0)
0.50
Liver recurrence alone n (%)
0 (0.0)
2 (20.0)
0.23
10 (100)
8 (80.0)
0.23
Lung n (%)
5 (50.0)
3 (30.0)
0.32
Bone n (%)
6 (60.0)
3 (30.0)
0.18
Other site n (%)
2 (20.0)
4 (40.0)
0.31
Loco regional Treatment n (%)*
0 (0.0)
1 (10.0)
0.50
Median AFP-Recurrence (ng/ml)*
Extra-Hepatic recurrence n (%)
HCC recurrence between 2009 and 2011 (non-historical controls). A similar median RFS between patients with BSC and those treated with sorafenib was observed (9.0 months, (IR: 2.5-20.0) vs 15.0 months (IR: 6.5-27.2 months), respectively; p = 0.65). Although no significant different overall survival was observed (sorafenib 20 months, (IR: 11.0-46.7) vs; BSC 12.5 months (IR: 4.526.0), respectively; p = 0.10), there was a post progression survival benefit in patients treated with sorafenib (5.0 months, (IR: 3.0-16.7) vs 3.0 months, (IR: 0.7-6.0), respectively; p = 0.04) (Figure 2). Median time from recurrence diagnosis to sorafenib starting dose was 9 weeks (IR: 2-64); 7 patients received 800 mg/day starting dose with an overall 3-months median sorafenib treatment duration (IR: 0.5-6.0). The drug was temporarily interrupted because of AE in 9/10 patients (90%). Most common occurring AE were mild, including diarrhea in 3 patients, fatigue in 4 patients, and hand-foot skin reaction in 1 patient. However, it was completely withdrawn in 2 patients because of severe AE (n = 1 cardiovascular event and n = 1 severe diarrhea).
Figure 2. Kaplan Meier Patient Survival Analysis among those patients with best supportive care vs. sorafenib after recurrence diagnosis (Log-Rank -Mantel Cox- test). BSC 1,0
Sorafenif
p = 0.04 (Log-rank test)
0,8 Comulative Survival
tion with CNI or MMF. No significant difference in overall median survival in patients receiving or not mTOR immunosuppression was observed (19.0 vs 14 months; p = 0.9).
HCC recurrence location:
0,6 0,4 0,2 0,0
NOTE: Normal Values: Alpha-fetoprotein 0.6-4.4 ng/ml. †Pre-LT *Post-LT. ¶ Explanted liver Variables. Abbreviations: BSC: best supportive care. ECOG: Eastern Cooperative Oncology Group performance status. mTOR: overall use of mTOR immunosuppression either before or after recurrence.
0
5
10
15
20
25
Time (months) Patients at Risk
Comparing those patients who received BSC and sorafenib, no significant differences were observed including pre and post-LT patient and tumor characteristics, immunosuppression and early or late recurrences (Table 2). Five out of ten patients treated with BSC had 304
Acta Gastroenterol Latinoam 2016;46(4):300-309
BSC
10
5
1
0
0
0
Sorafenib
10
7
4
4
2
2
NOTE: Overall median survival since hepatocellular carcinoma recurrence was significantly higher among those patients receiving Sorafenib than those with best supportive care (BSC) (5.0 vs 3.0 months; p = 0.04).
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Cox regression univariate analysis showed that related factors with death after recurrence were recipient age, HR = 0.9 (CI95%: 0.87-1.01; p = 0.09), early HCC recurrence, HR = 3.7 (CI95%: 1.28-10.73; p = 0.02) and sorafenib, HR = 0.4 (CI95%: 0.14-1.11; p = 0.07). On multivariate analysis, early HCC recurrence remained the only related factor with death, HR = 3.8 (CI95%: 1.22-12.29; p = 0.01) (Table 3).
Table 3. Cox regression analysis of factors related with death after recurrence diagnosis. Univariate Analysis HR (CI 95%)
p value
Age (years)†
0.9 (0.87-1.01)
0.09
Hepatitis B†
0.8 (0.26-2.45)
0.80
Hepatitis C†
1.2 (0.47-3.31)
0.65
Median AFP (ng/ml)†
1.0 (0.99-1.12)
0.12
Variable
Median AFPRecurrence (ng/ml)
1.0 (0.98-1.08)
Multivariate Analysis HR (CI95%)
3.7 (1.28-10.73)
0.02
Liver recurrence alone
2.7 (0.36-21.01)
0.33
Lung
2.2 (0.81-5.89)
0.12
Bone
0.7 (0.30-1.99)
0.60
Sorafenib
0.4 (0.14-1.11)
0.07
mTOR
0.6 (0.22-1.51)
0.26
Late Recurrence
Early Recurrence p = 0.07 (Log-rank test)
1,0 0,8 0,6 0,4 0,2
p value 0,0 0
5
10
15
20
25
30
Time (months)
Patients at Risk
0.49
Early recurrence
Figure 3. Kaplan Meier patient survival analysis among those patients with early versus late hepatocellular carcinoma recurrence after liver transplantation (Log-Rank -Mantel Cox- test).
Comulative Survival
Post progression survival
3.8 (1.2212.29)
0.01
Early R
11
1
1
1
0
Late R
9
4
3
3
2
NOTE: There was a significant difference in median overall patient survival since recurrence diagnosis between patients with early or late hepatocellular carcinoma recurrence: Early 3.0 vs 6.0 months; p = 0.007.
HCC recurrence:
0.4 (0.13-1.08)
0.07
NOTE: †Pre-transplant variables. Abbreviations: mTOR: overall use of mTOR immunosuppression either before or after recurrence.
There were no significant base line differences when patients with early or late HCC recurrence were compared (Table 4). A higher survival was observed in patients presenting late recurrences, including median overall survival (37 months, (IR: 24.5-48.5) vs 11 months, (IR: 5.0-14.0) respectively; p = 0.001), and median post progression survival (6.0 months, (IR:
5.0-17.5) vs 3.0 months, (IR: 1.0-4.0) respectively; p = 0.007) (Figure 3). When we analyzed the effect of sorafenib in combination with HCC recurrence presentation, we observed that sorafenib treatment had only a survival benefit in those patients with late recurrence, when compared to early recurrences (16.0 months, (IR: 5.0-22.5) vs 3.0 months, (IR: 1.0-6.0) respectively; p = 0.027 log-rank test). Moreover, there was a numerically, though not statistically significant survival benefit, in those patients with late recurrences receiving sorafenib compared to those with BSC (14.2 months, (IR: 5.0-22.5) vs 6.0 months (IR: 1.5-7.5 months), respectively; p = 0.12). This survival benefit was not observed in patients with early HCC recurrence treated with sorafenib compared to BSC (3.0 months, (IR: 2.0-9.0) vs 2.0 months (IR: 0.7-4.0), respectively; p = 0.32) (Figure 4). Acta Gastroenterol Latinoam 2016;46(4):300-309
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Figure 4. Kaplan Meier patient survival analysis among those patients with early (A) and late hepatocellular carcinoma recurrence (B) with best supportive care or Sorafenib treatment (Log-Rank -Mantel Cox- test).
A
Patients with Early Recurrence BSC
1,0
Comulative Survival
Median AFP ng/ml†
Late Recurrence n = 9 (45%)
p value
60 (34-66)
61 (55-69)
0.22
339 (14.0-934.0)
339 (14.0-934.0)
0.30
Microvascular invasion n (%)¶
7 (63.6)
7 (63.6)
0.34
0,6
Nuclear grade ≥III n (%)¶
4 (44.4)
4 (44.4)
0.60
Up-to-7 in n (%)¶
6 (54.4)
6 (54.4)
0.31
0,4
mTOR n (%)
6 (54.5)
6 (54.5)
0.46
0,2
Median AFP-Recurrence (ng/ml)
1147 (2.2-10215.0)
1147 (2.210215.0)
0.25
0,0
Recurrence diagnosis (months)
5.8 ± 3.5
5.8 ± 3.5
0.001
Liver recurrence alone n (%)
1 (9.1)
1 (9.1)
0.71
10 (90.9)
8 (88.9)
0.71
Lung n (%)
5 (45.5)
5 (45.5)
0.46
Bone n (%)
5 (45.5)
5 (45.5)
0.65
Other site n (%)
3 (27.3)
3 (27.3)
0.57
Loco regional treatment n (%)
0 (0.0)
0 (0.0)
0.45
Sorafenib n (%)
5 (45.5)
5 (45.5)
0.50
2,5
5,0
7,5
10,0
12,5
Time (months)
Extra-Hepatic recurrence n (%)
Patients at Risk BSC
6
1
0
0
Sorafenib
5
3
1
1
Patients with Early Recurrence BSC
1,0
Sorafenif
p = 0.12 (Log-rank test) 0,8 Comulative Survival
Age (years)† median (range)
Early Recurrence n = 11 (55%)
0,8
0
0,6
Recurrence Organ Location:
NOTE: †Pre-LT. ¶ Explanted liver Variables. Abbreviations: mTOR: overall use of mTOR immunosuppression either before or after recurrence.
0,4 0,2
Discussion
0,0 0
5
10
15
20
25
Time (months) Patients at Risk BSC
4
1
0
0
0
Sorafenib
5
3
3
3
2
NOTE: Sorafenib treatment had only a survival benefit in those patients with late HCC recurrence when compared with patients with early recurrence (16.0 months, (IR: 5.0-22.5) vs 3.0 months (IR: 1.0-6.0); p = 0.027). Moreover, there was a numerically, though not statistically significant survival benefit, among those patients with late HCC recurrence receiving sorafenib compared to those who received BSC (14.2 months, (IR: 5.0-22.5) vs 6.0 months (IR1.57.5), respectively; p = 0.12) (Panel B). This survival benefit was not observed in patients with early HCC recurrence with sorafenib compared to BSC (3.0 months, IR 2.0-9.0 months vs 2.0 months, IR 0.7-4.0 months; p = 0.32) (Panel A).
306
Variable
Sorafenif
p = 0.32 (Log-rank test)
B
Table 4. Comparative analysis between patients with early or late recurrent hepatocellular carcinoma.
Acta Gastroenterol Latinoam 2016;46(4):300-309
This study reports the factors related to post progression survival after HCC recurrence following transplantation. Our first finding shows that patients with early recurrence had overall worst survival when compared to late recurrences. Second, another factor related to survival was sorafenib treatment. The last finding however, must be validated in large and prospective randomized clinical trials. Meanwhile, there is still no consensus on the management of HCC recurrence following LT. Treatment with sorafenib has been assessed in small retrospective cohort studies9-13, 21, 22 Our results may provide additional information for the field of sorafenib treatment after HCC recurrence. The main finding of our research is that although sorafenib had an overall survival benefit,
Sorafenib after transplantation
patients with late recurrence had the best survival benefit with this drug. Reported mean overall survival in patients treated with sorafenib after recurrence ranges from 5 to 19 months with mean treatment duration with this drug from 2 to 10 months.9-13 There is one recently published retrospective study that has shown that sorafenib (n = 15) prolonged survival compared to BSC (n = 24): 21 vs 12 months, p = 0.0009.9 However, since sorafenib was introduced in 2007, the between subgroups comparison has been carried out with historical controls9 and this probably leaded to a selection bias. Other studies did not compare survival between both treatment options.10-13 In our study, sorafenib had a survival benefit since recurrence diagnosis compared to BSC (5.0 vs 3.0 months; p = 0.04). Median treatment duration (3 months) was comparable with previously reported series.9-13 In the non-transplant setting, overall treatment-related AE with sorafenib are close to 80%, most frequently diarrhea, hand-foot skin reaction, systemic hypertension, alopecia and anorexia.6 In post-LT series, acceptable tolerability and non-serious adverse events were reported, whereas the most frequently occurring AE were diarrhea (13-50%), hand-foot skin reaction (27-60%) and fatigue (20%).9-13 However, in other series, serious AE have been reported.21, 22 In our series, AE presented in 90% of the patients, most of the AE were mild and the drug was withdrawn in 2 patients because of severe AE. Although we observed that sorafenib had an overall survival benefit, a critical issue to be considered is time from LT to recurrence diagnosis or RFS. Recurrence free survival has been reported to be 8-37 months following transplantation and early recurrence has been found in 28-55% of the patients.9, 13 As we previously highlighted, it has been shown that earlier recurrence is associated with lower survival.14, 15 In our study, patients with early HCC recurrence had lower overall survival and lower survival since recurrence diagnosis (6.0 vs 3.0 months, respectively; p = 0.007). Moreover, early HCC recurrence was the only independent variable associated with survival since recurrence diagnosis in the multivariate analysis, (HR = 3.8; p = 0.002). In one recently published study, although sorafenib had a survival benefit, early HCC recurrence was seen in 42% of the patients with BSC and only in 7% of sorafenib treated patients.9 This kind of imbalance was not observed in our series, regarding RFS between patients with BSC and sorafenib (9.0 vs 15.0 months; p = 0.65), including proportion of patients with early recurrences. As we noted before, sorafenib survival benefit was seen in patients with late HCC recurrence
Federico Piñero y col
(16.0 vs 3.0 months, respectively; p = 0.027). It seems that a selective criterion for sorafenib treatment could be time from LT to recurrence diagnosis. This earlier HCC recurrence may suggest an aggressive tumor biology or an undiagnosed pre-LT extrahepatic metastasis.14 In this sense, however, no significant differences were observed regarding explanted tumor characteristics, pre and postLT serum AFP and extrahepatic metastases between those patients with early or late HCC recurrence. If sorafenib has no survival benefit in those patients with early, but only in late recurrences might not be explained with a lack of anti-neoplastic effect. Probably, those early recurrences suggest occult metastatic foci, and at that moment of transplantation, a more aggressive cancer. Consequently, sorafenib anti-cancer effect might be ineffective at that transplant moment possibly supported by a higher recipients’ immunosuppression state. Although it was not our primary aim, an additional factor to be considered is immunosuppression. It has been shown that mTOR inhibitors have anti-cancer effects,23 and the combination of mTORs with sorafenib has an hypothetically synergistic approach9, 11, 21, 22 Sixty percent of our patients received mTOR immunosuppression during the post-LT follow-up period, either before or after recurrence. No significant differences, considering mTOR immunosuppression, between patients with BSC or sorafenib were observed. Although in most of the LT centers mTOR immunosuppression was considered either before or after recurrence, a significant survival benefit was not observed in patients who received mTORs. There is still no randomized control trial in which mTOR immunosuppression supports a survival advantage for these patients. There are several strengths to this study. First, this was a multicenter cohort study from 2 different countries. Second, among all the LT centers, a standardized follow-up and procedures between centers was observed. Third, there were not significant base line patient and tumor characteristics including timing of recurrence diagnosis between patients treated with sorafenib or BSC. Limitations to this study include: the fact that, although the results are statistically significant, they are based on a retrospective cohort study including a small number of patients. Although the absence of randomization limit the strength of the results, a strict revision of the data was centrally performed, and complete followup for the outcomes was assessed. Finally, there is a need for additional tumor biomarkers in the explanted liver analysis in order to select patients for individual treatment options. Prospective randomized and larger series Acta Gastroenterol Latinoam 2016;46(4):300-309
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are needed in order to confirm our data, and should include sorafenib therapeutic effect time-dependency alongside a better characterization of the tumor biology using biomarkers. In summary, our data and other recently retrospective published series suggests that sorafenib treatment might have a survival benefit over BSC for recurrent HCC. However, we observed that patients with early HCC recurrence might not benefit with this treatment. Therefore, time from LT to recurrence diagnosis may be a selection criterion of sorafenib treatment candidates. Nevertheless, safety issues related to sorafenib treatment should be considered in this population. Our results might support the use of this time-selective criterion to design a much-needed randomized controlled trial. Acknowledgments. We thank Kathleen Dowd and Martín O’Flaherty for their assistance with editing this paper. Financial support. This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors. Conflict of interest. The authors declare having no conflict of interest to declare related to this research. Data sharing. No additional data are available.
Referencias 1. Mazzaferro V, Bhoori S, Sposito C, Bongini M, Langer M, Miceli R, Mariani L. Milan criteria in liver transplantation for hepatocellular carcinoma: An evidence-based analysis of 15 years of experience. Liver Transpl 2011; 17: S44-S57. 2. Piñero F, Mendizabal M, Casciato P, Galdame O, Quiros R, Bandi J, Mullen E, Andriani O, de Santibañes E, Podestá LG, Gadano A, Silva M. Is recurrence rate of incidental hepatocellular carcinoma after liver transplantation similar to previously known HCC? Towards a predictive recurrence score. Ann Hepatol 2014; 13: 211-218. 3. Roayaie S, Schwartz JD, Sung MW, Emre SH, Miller CM, Gondolesi GE, Krieger N, Schwartz ME. Recurrence of hepatocellular carcinoma after liver transplant: Patterns and prognosis. Liver Transpl 2004; 10: 534-540. 4. Cescon M, Ravaioli M, Grazi GL, Ercolani G, Cucchetti A, Bertuzzo V, Vetrone G, del Gaudio M, Vivarelli M. Prognostic Factors for Tumor Recurrence after a 12-Year, Single-Center Experience of Liver Transplantations in Patients with Hepatocellular Carcinoma. Journal of Transplantation 2010; 2010: 1-8. 5. Kneteman N, Livraghi T, Madoff D, de Santibañez E, Kew M. Tools for monitoring patients with hepatocellular carcinoma on the waiting list and after liver transplantation. Liver Transpl 2011; 17: S117–S127.
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6. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J-F, Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle P, Seitz JF, Borbath I, Häussinger D, Moscovici DV, Bruix J. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378–390. 7. Ann-Lii Cheng, Yoon-Koo Kang, Zhendong Chen, Chao-Jung Tsao, Shukui Qin, Jun Suk Kim, Rongcheng Luo, Jifeng Feng, Shenglong Ye, Tsai-Sheng Yang, Jianming Xu, Yan Sun, Houjie Liang, Jiwei Liu, Jiejun Wang, Won Young Tak, Hongming Pan, Karin Burock, Jessie Zou, Dimitris Voliotis, and Zhongzhen Guan. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncology 2009; 10: 25-34. 8. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008; 48: 1312–1327. 9. Sposito C, Mariani L, Germini A, Reyes MF, Bongini M, Grossi G, Bhoori S, Mazzaferro V. Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: A case-control study. Journal of Hepatology 2013; 59: 59-66. 10. Vitale A, Boccagni P, Kertusha X, Zanus G, D'Amico F, Lodo E, Pastorelli D, Ramirez R, Lombardi G, Senzolo M, Burra P, Cillo U. Sorafenib for the Treatment of Recurrent Hepatocellular Carcinoma After Liver Transplantation? TPS 2012; 44: 1989-1991. 11. Gómez-Martín C, Bustamante J, Castroagudin JF, Salcedo M, Garralda E, Testillano M, Herrero I, Matilla A, Sangro B. Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation. Liver Transpl 2011; 18: 45-52. 12. Weinmann A, Niederle IM, Koch S, Hoppe-Lotichius M, Heise M, Düber C, Schuchmann M, otto G, Galle P, Wörns M. Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation. Digestive and Liver Disease 2012; 44: 432–437. 13. Wei-feng Tan, Zhi-quan Qiu, Yong Yu, Rong-zheng Ran, Bing Yi, Wan-yee Lau, Chen Liu, Ying-he Qiu, Fei-ling Feng, Jing-han Wang, Pei-ning Yan, Bai-he Zhang, Meng-chao Wu, Xiang-ji Luo, and Xiao-qing Jiang. Sorafenib extends the survival time of patients with multiple recurrences of hepatocellular carcinoma after liver transplantation. Nature Publishing Group 2010; 31: 1643-1648. 14. Toso C, Cader S, Mentha-Dugerdil A, Meeberg G, Majno P, Morard I, Giostra E, Berney T, Kneteman N. Factors predicting survival after post-transplant hepatocellular carcinoma recurrence. J Hepatobiliary Pancreat Sci 2012; 20: 342-347. 15. Woo Young Shin, Kyung-Suk Suh, Hae Won Lee, Joohyun Kim, Taehoon Kim, Nam-Joon Yi, and Kuhn Uk Lee. Prognostic factors affecting survival after recurrence in adult living donor liver transplantation for hepatocellular carcinoma. Liver Transpl 2010;16: 678-684. 16. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42:1208-1236. 17. Yao FY. Liver Transplantation for Hepatocellular Carcinoma: Beyond the Milan Criteria. American Journal of Transplantation 2008; 8: 1982-1989. 18. Villanueva A, Hoshida Y, Battiston C, Tovar V, Sia D, Alsinet C, Cornella H, Liberzon A, Kobayashi M, Kumada H, Thung SN, Bruix J, Newell P, April C, Fan JB, Roayaie S, Mazzaferro V, Schwartz ME, Llovet JM.Combining Clinical, Pathology, and Gene Expression Data to Predict Recurrence of Hepatocellular Carcinoma. Gastroenterology 2011; 140: 1501-1512.
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19. Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, Camerini T, Roayaie S, Schwatrz M, Grazi GL. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncology 2009; 10: 35-43. 20. Trotti A, Colevas A, Setser A, Rusch V, Jaques D, Budach V, Langer C. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Seminars in Radiation Oncology 2003; 13: 176-181. 21. Staufer K, Fischer L, Seegers B, Vettorazzi E, Nashan B, and Sterneck M. High toxicity of sorafenib for recurrent hepatocellular carcinoma after liver transplantation. Transplant Int 2012; 25: 1158-1164.
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22. Zavaglia C, Airoldi A, Mancuso A, Vangeli M, Viganò R, Cordone G, Gentiluomo M, Belli LS. Adverse events affect sorafenib efficacy in patients with recurrent hepatocellular carcinoma after liver transplantation. Eur J Gastroenterol Hepatol 2013; 25: 180-186. 23. Bhat M, Sonenberg N, Gores GJ. The mTOR pathway in hepatic malignancies. Hepatology 2013; 58: 810-818.
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High resolution manometry evaluation of a series of patients with previous caustic stricture of the esophagus Priscila R Armijo,1 Fernando PP Vicentine,1 Fernando AM Herbellar,1 Marco G Patti2 1 2
Department of Surgery, Escola Paulista de Medicina, Federal University of Sao Paulo. Sao Paulo, Brazil. Department of Surgery, University of Chicago, Il. Chicago, EE.UU.
Acta Gastroenterol Latinoam 2016;46:310-313 Recibido: 14/01/2016 / Aprobado: 12/10/2016 / Publicado en www.actagastro.org el 01/01/2017
Summary
Dysphagia after caustic ingestion may persist even after wellsucceeded dilatation procedures and an open lumen suggesting other etiology for this symptom, such as dysmotility. Aims. This study aims to evaluate motility in a series of patients with previous esophageal stenosis after caustic ingestion at the light of high resolution manometry (HRM). Material and methods. Ten adult patients 5 women, mean age 54 (range: 28-83) years with previous esophageal caustic stenosis were recruited. The mean time from caustic ingestion to the esophageal test was 22 (range 6-45) months. All patients underwent successful endoscopic dilatation of the strictures and all of them were able to eat an unrestricted diet. Two (20%) patients complaint of mild dysphagia and 1 (10%) complaint of heartburn. All patients underwent a HRM. Results. Lower esophageal sphincter (LES) was defective in 8 (80%) patients with normal relaxation. Absence of peristalsis was present in 8 (80%) patients. Conclusion. Motility impairment was present in all patients with previous caustic ingestion that may explain dysphagia even when a mechanical obstruction is not detected by radiologic or endoscopic methods. Key words. Caustic stenosis, motility, high resolution manometry, dysphagia, peristalsis, lower esophageal sphincter.
Correspondencia: Fernando AM Herbella Department of Surgery, Escola Paulista de Medicina Rua Diogo de Faria 1087 cj 301, 04037-003. Sao Paulo, SP, Brazil Tel.: +55-11-99922824 Correo electrónico:
[email protected]
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Evaluación con manometría de alta resolución de una cohorte de pacientes con antecedentes de estenosis esofágica por la ingesta de cáusticos Resumen
La disfagia como consecuencia de la ingesta de cáusticos puede persistir incluso después de procedimientos exitosos de dilatación y con lumen abierto, lo que sugiere que otra etiología sea la responsable del síntoma como es la alteración de la motilidad del esófago. Objetivo. Evaluar la motilidad en una cohorte de pacientes con antecedentes de estenosis esofágica resultante de la ingesta de cáusticos mediante el uso de manometría de alta resolución (MAR). Material y métodos. Diez pacientes adultos, 5 mujeres, edad mediana: 54 años (rango: 28-83) con antecedentes de estenosis caústica esofágica fueron reclutados. El tiempo entre la ingesta de los cáusticos y la MAR fue de 22 meses (rango: 6-45). Todos los pacientes fueron sometidos a una dilatación endoscópica exitosa de las zonas con estenosis y eran capaces de comer una dieta sin restricciones. Dos pacientes (20%) presentaron disfagia leve y 1 de ellos (10%) presentó pirosis. Todos los pacientes fueron sometidos a MAR. Resultados. El esfínter esofágico inferior (EEI) fue defectuoso en 8 pacientes (80%) con relajación normal. El aperistaltismo estuvo presente en 8 pacientes (80%). Conclusión. Las alteraciones en la motilidad estuvieron presentes en todos los pacientes con antecedentes de ingesta de cáusticos, lo que podría explicar la disfagia, incluso cuando una obstrucción mecánica no es detectada por métodos radiológicos o endoscópicos. Palabras claves. Estenosis cáustica, motilidad, manometría de alta resolución, disfagia, peristaltismo, esfínter esofágico inferior.
Motility in caustic stricture of the esophagus
Caustic ingestion is a relevant public health problem in several countries. In the United States, from 5.000 to 15.000 caustic ingestions are estimated to occur per year.1 Esophageal stricture is a severe consequence of the corrosive ingestion leading frequently to repeated endoscopic dilations. However, dysphagia may persist even after well-succeeded dilatation procedures and an open lumen suggesting other etiology for this symptom.1, 2 Few previous studies focused on the esophageal motility by conventional manometry in patients after caustic ingestion.3, 4 High resolution manometry (HRM), however, seems to be a more adequate method for evaluation of these patients due to superior accuracy for the detection of incomplete lower esophageal sphincter (LES) relaxation and segmental peristalses defects.5, 6 This study aims to evaluate the motility in patients with esophageal stenosis after caustic ingestion at the light of HRM. Material and methods
Population Ten voluntary adult patients, median age: 54 years (range: 28-83), 50% females with esophageal caustic stenosis were recruited. Patients who refused to participate or with previous foregut operations were excluded from the study. The median time from caustic ingestion to the esophageal test was 22 months (range: 6-45). All patients underwent successful endoscopic dilatation (no stenosis detected at the radiologic evaluation) of the strictures and all of them were able to eat an unrestricted diet. Two (20%) patients complaint of mild dysphagia and 1 (10%) complaint of heartburn. Manometry All patients underwent a HRM following previously described protocol.7 Medications that interferes with esophageal and gastric motility were discontinued 3 days before the study. HRM data of all volunteers were acquired using a solid-state HRM assembly with 36 sensors spaced at 1 cm intervals (Medtronics, Los Angeles, CA). All studies were performed with patients in sitting position, after a minimum fasting period of eight hours. Position, pressure (defined as the mid-respiratory pressure), relaxation, and length of the lower esophageal sphincter (LES) were recorded. Esophageal body function was assessed by giving 10 wet swallows of 5 ml water boluses at 30-sec intervals when amplitude, duration and propagation of the peristaltic waves were assessed at 3 and 7 cm above the LES. Plots were manually reviewed for segmental defects of peristalsis. Upper esophageal sphincter (UES) pressure was also measured.
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The normal values considered in this study were: LES length > 2.7cm, LES basal pressure 13-43 mmHg, LES residual pressure 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria. Liver Transpl 2014; 20: 945-951. 131. Piñero F, Marciano S, Anders M, Orozco F, Zerega A, Cabrera CR, Baña MT, Gil O, Andriani O, de Santibañes E, McCormack L, Gadano A, Silva M. Screening for liver cancer during transplant waiting list. Eur J Gastroenterol Hepatol 2015; 27: 355-360. 132. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999; 30: 1434-1440. 133. Yao FY, Bass NM, Nikolai B, Davern TJ, Kerlan R, Wu V, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: analysis of survival according to the intention-to-treat principle and dropout from the waiting list. Liver Transpl 2002; 8: 873-883. 134. Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B, Perrier A; OLT for HCC Consensus Group. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012; 13: e11-e22. 135. Millonig G, Graziadei IW, Freund MC, Jaschke W, Stadlmann S, Ladurner R, Margreiter R, Vogel W. Response to preoperative chemoembolization correlates with outcome after liver transplantation in patients with hepatocellular carcinoma. Liver Transpl 2007; 13: 272-279. 136. Alba E, Valls C, Dominguez J, Martínez L, Escalante E, Lladó L, Serrano T. Transcatheter arterial chemoembolization in patients with hepatocellular carcinoma on the waiting list for orthotopic liver transplantation. Am J Roentgenol 2008; 190: 1341-1348. 137. Mazzaferro V, Battiston C, Perrone S, Pulvirenti A, Regalia E, Romito R, Sarli D, Schiavo M, Garbagnati F, Marchianò A, Spreafico C, Camerini T, Mariani L, Miceli R, Andreola S. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann Surg 2004; 240: 900-909.
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138. Graziadei IW, Sandmueller H, Waldenberger P, Koenigsrainer A, Nachbaur K, Jaschke W, Margreiter R, Vogel W. Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome. Liver Transpl 2003; 9: 557-563. 139. Yao FY, KerIan RK, Hirose R, Davern TJ 3rd, Bass NM, Feng S, Peters M, Terrault N, Freise CE, Ascher NL, Roberts JP. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology 2008; 48: 819-827. 140. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30: 52-60. 141. Majno P, Sarasin F, Mentha G, Hadengue A. Primary liver resection and salvage transplantation or primary liver transplantation in patients with single, small hepatocellular carcinoma and preserved liver function: An outcome-oriented decision analysis. Hepatology 2000; 31: 899-906. 142. Sposito C, Mariani L, Germini A, Flores Reyes M, Bongini M, Grossi G, Bhoori S, Mazzaferro V. Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study. J Hepatol 2013; 59: 59-66. 143. Raoul JL, Sangro B, Forner A, Mazzaferro V, Piscaglia F, Bolondi L, Lencioni R. Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization. Cancer Treat Rev 2011; 37: 212-220. 144. Burrel M, Reig M, Forner A, Barrufet M, de Lope CR, Tremosini S, Ayuso C, Llovet JM, Real MI, Bruix J. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design. J Hepatol 2012; 56: 1330-1335. 145. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35: 1164-1171. 146. Llovet JM, Real MI, Montañá X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Solà R, Rodés J, Bruix J; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359: 1734-1739. 147. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37: 429-442. 148. Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, Ayuso C, Castells L, Montañá X, Llovet JM, Bruix J. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 2007; 46: 474-481. 149. Lammer J, Malagari K, Vogl T Pilleul F, Denys A, Watkinson A, Pitton M, Sergent G, Pfammater T, Terraz S, Benhamou Y, Avajon Y, Gruenberger T, Pomoni M, Langerberger H, Schuchmann M, Dumortier J, Chevallier P, Lencioni R; PRECISION V Investigators. Prospective randomized study of doxorubicineluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 2010; 33: 41-52.
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150. Vogl TJ, Lammer J, Lencioni R, Malagari K, Watkinson A, Pilleul F, Denys A, Lee C. Liver, gastrointestinal and cardiac toxicity in intermediate hepatocellular carcinoma treated with PRECISION TACE with drug-eluting beads: results from the PRECISION V randomized trial. AJR Am J Roentgenol 2011; 197: W562-W570. 151. Malagari K, Pomoni M, Moschouris H, Bouma E, Koskinas J, Stefaniotou A, Marinis A, Kelekis A, Alexopoulou E, Chatziioannou A, Chatzimichael K, Dourakis S, Kelekis N, Rizos S, Kelekis D. Chemoembolization with doxorubicin-eluting beads for unresectable hepatocellular carcinoma: five-year survival analysis. Cardiovasc Intervent Radiol 2012; 35: 1119-1128. 152. Sangro B, Salem R. Transarterial chemoembolization and radioembolization. Semin Liver Dis 2014; 34: 435-443. 153. Lau WY, Ho S, Leung TWT, Chan M, Ho R, Johnson PJ, Li AK. Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres. Int J Radiat Oncol Biol Phys 1998; 40: 583-592. 154. Lewandowski RJ, Kulik L, Riaz A, Senthilnathan S, Mulcahy MF, Ryu RK, Ibrahim SM, Sato KT, Baker T, Miller FH, Omary R, Abecassis M, Salem R. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Amer J Transplant 2009; 9: 1920-1928. 155. Sangro B, Bilbao JI, Boan J, Martínez Cuesta A, Benito A, Rodriguez J, Panizo A, Gil B, Inarrairaegui M, Herrero I, Quiroga J, Prieto J. Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2006; 66: 792-800. 156. Sangro B, Carpanese L, Cianni R, Golfieri R, Gasparini D, Ezziddin S, Paprottka PM, Fiore F, Van Buskirk M, Bilbao JI, Ettorre GM, Salvatori R, Giampalma E, Geatti O, Wilhelm K, Hoffman RT, Izzo F, Inarrairaegui M, Maini CL, Urigo C, Cappelli A, Vit A, Ahmadzadehfar H, Jakobs TF, Lastoria S; European Network on Radioembolization with Yttrium-90 Resin Microspheres (ENRY). Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona Clinic Liver Cancer stages: a European evaluation. Hepatology 2011; 54: 868-878. 157. Salem R, Lewandowski RJ, Kulik L, Wang E, Riaz A, Ryu RK, Sato KT, Gupta R, Nikolaidis P, Miller FH, Yaghmai V, Ibrahim SM, Senthilnathan S, Baker T, Gates VL, Atassi B, Newman S, Memon K, Chen R, Vogelzang RL, Nemcek AA, Resnick SA, Chrisman HB, Carr J, Omary RA, Abecassis M, Benson AB 3rd, Mulcahy MF. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology 2011; 140: 497-507. 158. https://clinicaltrials.gov/ct2/show/NCT01381211?term=radioe mbolization+hcc&rank=3. 159. https://clinicaltrials.gov/ct2/show/NCT02004210?term=radioe mbolization+hcc&rank=5. 160. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-390.
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♦REUNIÓN DE EXPERTOS Human gut microbiota - A lifetime history: from birth to adulthood (Riviera Maya, Mexico - June 26th, 2015) Luis Bustos Fernández,1 Henry Cohen,2 Francisco Guarner,3 Aldo Maruy,4 Keira Leon,5 Jaime Ramírez-Mayans,6 Vera Sdepanian,7 Yvan Vandenplas8 Centro Médico Bustos Fernández. Ciudad Autónoma de Buenos Aires, Argentina. Uruguay Medical School. Montevideo, Uruguay. 3 Hospital Vall d'Hebron. Barcelona, Spain. 4 Cayetano Heredia Hospital. Lima, Perú. 5 Hospital General del Este “Dr Domingo Luciani”, IVSS. Caracas, Venezuela. 6 Instituto Nacional de Pediatría. México City, México. 7 Sao Paulo Federal University. Sao Pablo, Brazil. 8 Free University of Brussels. Brussels, Belgium. 1 2
Acta Gastroenterol Latinoam 2016;46:375-382 Recibido: 12/08/2016 / Aprobado: 31/08/2016 / Publicado en www.actagastro.org el 01/01/2017
Summary
The objective of the Meeting was to raise recognition and expand knowledge of the gut microbiota among gastroenterologists, pediatricians and general practitioners in Latin American countries. Recognized international experts shared new findings on a number of topics including microbiota in health and disease, and probiotics in obtaining physiological effects and clinical benefits. This meeting report aims to provide a general overview of the topics discussed and the reader is referred to the cited references to gain further insight into the meeting’s content. Key words. Gut microbiota, gut-brain axis, probiotics, saccharomyces boulardii CNCM I-745.
Microbiota intestinal humana - Una historia de vida: del nacimiento a la edad adulta (Riviera Maya, México - Junio 26, 2015) Resumen
El objetivo de la reunión fue ampliar el conocimiento de la microbiota intestinal entre los gastroenterólogos, pediatras y médicos generales en los países de América Latina. Reconocidos expertos internacionales compartieron los nuevos conocimientos sobre una serie de temas, incluyendo la microbiota en la salud y la enfermedad, asi como efectos fisiológicos y beneficios clínicos de los probióticos. Este informe de la reunión tiene como objetivo proporcionar una visión general de los temas tratados y remitir al lector las referencias citadas para obtener una mayor comprensión del contenido de la misma. Palabras claves. Microbiota intestinal, eje cerebro-intestinal, probióticos, saccharomyces boulardii CNCM I-745. Role of the gut microbiota in human health
Correspondencia: Luis Bustos Fernández Echeverría 2771 CABA 1428 Argentina Correo electrónico:
[email protected]
Of the 100 trillion cells inside each one of us, 90% are not ours but aliens: bacteria, fungi, and other microbes.1, 2 The human gastrointestinal tract harbors one of the most complex and abundant ecosystems colonized by more than 100 trillion microorganisms. The gut microbiota of young adults have higher proportions of firmicutes, whereas the elderly have a higher proportion of Acta Gastroenterol Latinoam 2016;46(4):375-382
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Human gut microbiota during life spam
bacteroidetes.3, 5, 6 Two plenary sessions were respectively dedicated to review: (i) structural and functional aspects of the human gut microbiota, and (ii) changes in the microbial composition along the life cycle. The key note address was given by Professor Francisco Guarner. Professor Guarner discussed the structure and functions of the human gut microbiota.3 Bacterial or fungal symbionts have evolutionary adapted to provide the required organic compounds (essential amino acids and vitamins) and the ability to obtain energy from different sources.7, 8 The gut microbiota influences host metabolism,8 physiology9-12 and immune system development.13 The overall structure of predominant genera in the human gut can be assigned into three robust clusters, which are known as ‘enterotypes’.5, 14-16 Each of the three enterotypes is identifiable by the levels of one of three genera: bacteroides (enterotype 1), prevotella (enterotype 2) and ruminococcus (enterotype 3). Diet and antibiotics have an important impact on the structure and function of the intestinal microbiota.17 The bacteroides enterotype is associated with diets enriched in protein and fat. In contrast, the prevotella enterotype is linked to diets with predominance of fibres, carbohydrates and sugars. Use of antibiotics induces a decrease in microbial diversity (loss of richness in the ecosystem) and overgrowth of resistant species. Immense populations of viruses live in the human gut.18 They are mostly unique to each individual, and define the structure of gut bacterial communities by predation: every day, 7.5% of gut bacteria are killed by predators. Perturbations of the gut microbial ecosystem during infancy combined with genetic susceptibility may have a long-lasting impact on the immune system leading to disease or predisposition to disease later in life.19 Professor Luis Bustos Fernández followed on with a report on human gut microbiota onset and shaping through life stages. Up to date, the majority of studies have focused on the adult population, where the gut microbiota shows great stability and resistance to change. However, it appears unstable throughout childhood and in later stages of life.20 At birth, the child is colonized by bacteria originating mostly from the mother and from the outside environment.21 The neonatal gut microbiome, beginning in utero, is affected by the nutritional status (breastfed versus formula fed) and gestational age (term versus preterm).21 Similarly, during the latter stages of life, the gut microbiota undergoes other pathological changes, which contribute to its further destabilization (high proportion of bacteroidetes, reduction in species diversity, in resistance to environment fluctuations and in beneficial microorganisms, greater 376
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susceptibility to infections, e.g. C difficile). Therefore, it is during these extreme stages of life where different strategies for modulating the gut microbiota may have a strong impact on health. The gut-brain axis
Gut and brain originated from the same tissue, the neural crest, and are in constant, bi-directional communication through the vagus nerve, the hypothalamic-pituitaryadrenal axis and the immune system.22-26 The microbiota was recently found to play a role in such “gut-brain axis”, thus coining the term “microbiota-gut-brain axis”.22-26 Doctors Luis Bustos Fernández and Jaime RamírezMayans reviewed recent evidence in favor of a microbiota-gut-brain axis.22-26 Thus, differences in behavior and stress responses were reported between germ-free and conventional mice.10, 27, 28 The behavioral phenotype can be transferred between mice by microbiota transplantation.25 Selected probiotics can modify brain activity and behavior in animals and humans.25, 29 Antibiotic or diet perturbations of the gut's flora (dysbiosis) can modify brain chemistry and behavior.30, 31 Doctors Bustos Fernández and Ramírez-Mayans concluded that, acute and chronic stress may alter gut microenvironment and give rise to a dysbiotic microbiota leading to anxious/depressive states. The exact pathways and mediators have not been completely elucidated (bacteria likely modulate behavior through an action on the enteric nervous system neurotransmitters). In the future, microbiota modulation using probiotics and/or symbiotics might play an increasingly important role in treating diseases such as IBS with anxiety and depression comorbidity. Microbiota and related disorders
In Latin America, the prevalence of type 2 diabetes mellitus in urban areas ranges from 7% to 8%, versus only 1% to 2% in rural areas.32, 33 Recent studies have pointed out that, loss of biodiversity in the human gut microbiota is associated with far reaching consequences on host health.34 Several disease states have been associated with changes in the composition of fecal and intestinal mucosal communities.34 Professor Francisco Guarner presented data showing that a perturbed gut microbial colonization might be involved in some chronic non-communicable diseases of increasing incidence in modern society. Individuals with a low bacterial richness (23% of the population) are characterized by more marked overall adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype when compared with high bacte-
Human gut microbiota during life spam
rial richness individuals.34 Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.36 Reduced microbial gene diversity was found in IBD.16 Low microbial gene diversity and depletion of Akkermansia mucini-phila was found associated with a relapsing course of ulcerative colitis.37 Low gene richness and the enterotype bacteroides were found in Crohn’s disease.38 Recent studies suggest a role for the microbiota in autism spectrum disorders.39 Diet, probiotics and gut microbiota transplantation are the principal tools in clinical practice for improving host-microbial symbiosis, and warrant further investigation for their ability to restore microbial richness in various disease states. Professor Aldo Maruy followed on with a report on microbiota, obesity and type 2 diabetes mellitus (T2DM). Mice bred in a “germ-free” environment show 40% less body fat than those with a normal microbiota, despite eating less than 30% of what germ-free mice do.40 A 60% increase in body fat and insulin resistance is observed when transplanting caecal content from a normal to a germ-free mouse, despite a decrease in food intake.40 Obese mice show a 50% reduction in bacteroidetes with a proportional increase in firmicutes.41 This ratio changes in lean rats.41 Similar changes were found in humans42 and T2DM patients.43 Gut microbiota in obese individuals and T2DM patients is altered and seems to be more efficient in extracting energy from food. It appears that dietary fat is an important factor which affects gut microbiota composition as well as the gut barrier function and the plasma levels of LPS.44, 45 This metabolic endotoxemia would contribute to the development of systemic low grade inflammation, insulin resistance and T2DM.44-46 Modulating gut microbiota through the use of prebiotics, probiotics, antibiotics and fecal transplant might be beneficial by improving glucose metabolism and insulin resistance in the host.36, 47-49 Probiotic strains and products
In 1907, Élie Metchnikoff (Nobel Prize for Physiology in Medicine) suggested that: "the dependence of the intestinal microbes on the food makes it possible to adopt measures to modify the flora in our bodies and to replace the harmful microbes by useful microbes”50 and recommended that people should consume fermented milk containing lactobacilli to prolong their lives, as accelerated aging is due to autointoxication caused by the toxins produced by the gut microflora.51 There are thousands of different probiotics on the market, with very important differences between bacterial and yeast probiotics.52, 53 A plenary session was dedicated to discuss such differences.
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Professor Yvan Vandenplas presented data regarding differences between probiotic strains and products. Some bacterial probiotic strains are part of healthy eating.54 Probiotic strains have even been isolated from breast milk.55, 56 However, most of the strains in (fermented) food are only poorly resistant to gastric acid and other digestive secretions. Survival of strains in commercialized products can be very different. Strains of the same gender may also behave different in commercialized products because of differences in industrial preparation. Some are natural preparations (fermented milk products like yogurt), others are industrial preparations of fermented milk, others are food supplements commercialized in “health care shops” (encapsulated “medication-like” preparations), but all of these differ from approved medications. Medicinal products can only be advertised if they possess scientific proof of benefit.52 Guidelines for the evaluation of probiotics in food leading to the substantiation of health claims have been edited by the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO).57 Although most probiotics are bacteria (bifidobacteria, lactobacilli), one strain of yeast, Saccharomyces boulardii (S boulardii), has been found to be an effective probiotic in doubleblind clinical studies.58 Conversely, Conway et al59 failed to demonstrate that yoghurt has any effect on antibioticassociated diarrhea.60-64 While many bacterial probiotic strains are poorly resistant to antibiotics, yeast probiotics are resistant to all antibiotics, but then very sensitive to antifungals. These differences may be relevant in the rare cases of sepsis or fungemia. The intrinsic resistance to antibiotics of some bacterial probiotic strains has been shown to be transferable to the gastro-intestinal flora of the host and to pathogens. S boulardii was discovered by Henry Boulard in the early 1920s and was first registered as a drug in 1961.65 S cerevisiae and S boulardii CNCM I-745 are members of the same species with different metabolic and genetic properties.66 One important difference in favor of S boulardii CNCM I-745 is an increased expression of important genes for increased growth rate and better survival in acid pH.67 A meta-analysis of data from five randomized-controlled trials showed efficacy of S boulardii in preventing antibiotic-associated diarrhea in children and adults (mainly respiratory tract infections).68 Finally, S boulardii has a well investigated mode of action,69 the quality of 15 probiotic products containing S boulardii was verified70 and the ESPGHAN Working Group for Probiotics and Prebiotics recommended S boulardii for acute gastroenteritis.71 Acta Gastroenterol Latinoam 2016;46(4):375-382
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Professor Yvan Vandenplas concluded that probiotics do differ, and only products that have been clinically tested should be used in medical indications. The (theoretical but existing) possibility of transfer of intrinsic resistance is a valid reason to not use strains that have not been tested for this potential risk. Saccharomyces boulardii CNCM I-745
This session was a series of 3 interactive workshops dedicated to S boulardii CNCM I-745. Clinical evidence in children Probiotics have been extensively studied over the past several years in treating sporadic infectious diarrhea in pediatric populations. The vast majority of the published trials show a statistically significant benefit of a few, wellidentified probiotic strains, including S boulardii.72 Probiotics were also found to reduce the risk of antibiotic associated diarrhea (AAD) in children and for every 7-10 patients one less would develop AAD.73 Professor Vandenplas reviewed clinical evidence of S boulardii CNCM I-745 in pediatrics. Recently, research has focused on newborn and preterm infants, despite of the fact that S boulardii is not registered or indicated in this age group. A review and meta-analysis showed that S boulardii is safe and has clear beneficial effects in children who have acute diarrhea.74 Pooling data from 22 trials showed that S boulardii significantly reduced the duration of diarrhea, stool frequency on day 2 and day 3, the risk for diarrhea on day 3 and day 4 after intervention compared with control.74 A randomized trial in children with acute infectious diarrhea confirmed such results and showed that the mean length of hospital stay was shorter with more than 36 h of difference in the S boulardii group (4.60 ± 1.72 vs 6.12 ± 1.71 days, p