Research Group on Neurological Impairment
Metabolism and Organic Damage Area
Chronic liver disease progresses in different phases, including alcoholic or nonalcoholic liver disease and nonalcoholic steatohepatitis (NASH) that can lead to fibrosis and cirrhosis.The incidence of non-alcoholic steatohepatitis (NASH) has increased considerably in recent decades due to the lifestyle of the western population and is beginning to be a leading cause of liver cirrhosis. It is etiologically related mainly to obesity, diabetes, hyperlipidemia, and insulin resistance with features of the metabolic syndrome.40% of patients with cirrhosis have minimal hepatic encephalopathy (MHE), with mild cognitive impairment and motor disorders that reduce their quality of life and survival. EHM progresses to clinical EH and can lead to coma and death.
Early detection and treatment and prevention of cognitive and functional impairment would improve the quality of life, survival and vitality of patients with chronic liver diseases and would reduce hospitalizations and the demand for resources on the health system, improving its sustainability.
In patients with cirrhosis, high levels of ammonia in the blood together with high levels of peripheral inflammation act synergistically to produce EHM, inducing neuroinflammation, which alters neurotransmission, leading to cognitive and motor impairment.
A better characterization of the metabolic, immunological, cerebral and neurological alterations will make it possible to identify and evaluate new, earlier and more sensitive diagnostic procedures for EHM.
The mechanisms that lead to these alterations are not well known and there are no specific treatments to reverse them. A better study of the mechanisms involved will make it possible to design and test new, more effective treatments.
Our research aims to better characterize the alterations in EHM and the mechanisms that produce them, evaluating new diagnostic and therapeutic procedures.
• Understand the biology of immunological changes associated with the appearance of EHM in cirrhotic patients
• To advance in the knowledge of the molecular mechanisms that lead to neurological alterations in EHM
• Identify new therapeutic targets
• Improve the treatment of cognitive and functional impairment in cirrhotic patients with EHM and symptoms
• Improve the early diagnosis of EHM, which will allow the treatment of patients who are not currently treated
Coordinator
Dra. Carmina Montoliu Félix
cmontoliu@incliva.es; carmina.montoliu@uv.es
RESEARCHERS
Established, R3
Amparo Escudero García
José Ballester Fayos
José Luis León Guijarro
Roberto Aliaga Méndez
First Stage, R1
Adrià López Gramaje
Franc Casanova Ferrer
STAFF
Collaborating Researchers
Mika Aiko Gesler
Nurse
Mª Jesús Campa Santiago
Technicians
Laura Ávila Fernández
Administrative assistant
Publications
Improved cognition after rifaximin treatment is associated with changes in intra- and inter-brain network functional connectivity. Casanova-Ferrer F, Gallego J, Fiorillo A, Urios A, Rios M, Leon J, Ballester M, Escudero-Garcia D, Kosenko E, Belloch V, Montoliu C. Journal of Translational Medicine. 2024 Jan 12;22(1):49. doi: 10.1186/s12967-023-04844-7. PMID: 38217008Liver disorders and celiac disease. Monton Rodriguez C, Sanchez Serrano J, Poyatos Garcia P, Abril Garcia C, Gomez Medina C, Capilla-Lozano M, Lluch Garcia P, Pascual Moreno I. Revista Espanola de Enfermedades Digestivas. 2024 Jan;116(1):41-42. doi: 10.17235/reed.2023.9516/2023. PMID: 37204091
Automatic video-oculography system for detection of minimal hepatic encephalopathy using machine learning tools. Calvo Cordoba A, Garcia Cena C, Montoliu C. Sensors. 2023 Sep 25;23(19):8073. doi: 10.3390/s23198073. PMID: 37836903Biological treatment interruption in Inflammatory Bowel Disease: motivation and predictive factors. González MRD, Ballester MP, Romero-González E, Sánchez-Pardo AM, Marti-Aguado D, Tosca J, Suria C, Ausejo RA, Moreno IP, Silvestre MDP, Pérez MM, Bosca-Watts MM. Gastroenterologia y Hepatologia. 2023 Nov;46(9):671-681. doi: 10.1016/j.gastrohep.2022.10.021. PMID: 36375696
Corrigendum to Development and validation of the AMMON-OHE model to predict risk of overt hepatic encephalopathy occurrence in outpatients with cirrhosis [J Hepatol 79(4) (2023 Oct) 967-976]. Ballester MP, Tranah TH, Balcar L, Fiorillo A, Ampuero J, Kerbert AJC, Thomsen KL, Escudero MD, Mandorfer M, Reiberger T, Shawcross DL, Romero-Gómez M, Montoliu C, Carbonell-Asins JA, Jalan R. Journal of Hepatology. 2023 Dec;79(6):1571. doi: 10.1016/j.jhep.2023.10.013. PMID: 37919110
Development and validation of an image biomarker to identify metabolic dysfunction associated steatohepatitis: MR-MASH score. Marti-Aguado D, Arnouk J, Liang J, Lara-Romero C, Behari J, Furlan A, Jimenez-Pastor A, Ten-Esteve A, Alfaro-Cervello C, Bauza M, Gallen-Peris A, Gimeno-Torres M, Merino-Murgui V, Perez-Girbes A, Benlloch S, Perez-Rojas J, Puglia V, Ferrández-Izquierdo A, Aguilera V, Giesteira B, França M, Monton C, Escudero-García D, Alberich-Bayarri A, Serra M, Bataller R, Romero-Gomez M, Marti-Bonmati L. Liver International. 2023 Oct 30. doi: 10.1111/liv.15766. PMID: 37904633
Development and validation of the AMMON-OHE model to predict risk of overt hepatic encephalopathy occurrence in outpatients with cirrhosis. Ballester M, Tranah T, Balcar L, Fiorillo A, Ampuero J, Kerbert A, Thomsen K, Escudero M, Mandorfer M, Reiberger T, Shawcross D, Romero-Gomez M, Montoliu C, Carbonell-Asins J, Jalan R. Journal of Hepatology. 2023 Oct;79(4):967-976. doi: 10.1016/j.jhep.2023.05.022. PMID: 37277075
Adherence to endoscopic surveillance for advanced lesions and colorectal cancer in inflammatory bowel disease: an AEG and GETECCU collaborative cohort study. Pilar Ballester M, Mesonero F, Florez-Diez P, Gomez C, Fuentes-Valenzuela E, Martin N, Senosiain C, Vela M, Fernandez-Clotet A, Perez P, Rubin de Celix C, Calvino-Suarez C, Hermida B, Munoz R, Gonzalez-Vivo M, Brunet E, Jimenez N, Botella B, Yebra J, Suarez-Ferrer C, Bouhmidi A, Lopez-Serrano A, Ponferrada A, Duenas C, Minguez M. Alimentary Pharmacology & Therapeutics. 2022 Jun;55(11):1402-1413. doi: 10.1111/apt.16832. PMID: 35224758Autoimmune hepatitis triggered by COVID-19. Monton Rodriguez C, Navarro Cortes P, Lluch Garcia P, Minguez Perez M. Revista Espanola de Enfermedades Digestivas. 2022 Jan;114(1):64-65. doi: 10.17235/reed.2021.8045/2021. PMID: 34015933
Automated whole-liver MRI segmentation to assess steatosis and iron quantification in chronic liver disease. Marti-Aguado D, Jimenez-Pastor A, Alberich-Bayarri A, Rodriguez-Ortega A, Alfaro-Cervello C, Mestre-Alagarda C, Bauza M, Gallen-Peris A, Valero-Perez E, Ballester MP, Gimeno-Torres M, Perez-Girbes A, Benlloch S, Perez-Rojas J, Puglia V, Ferrandez A, Aguilera V, Escudero-Garcia D, Serra MA, Marti-Bonmati L. Radiology. 2022 Feb;302(2):345-354. doi: 10.1148/radiol.2021211027. PMID: 34783592
Hyperammonemia alters the function of AMPA and NMDA receptors in hippocampus: extracellular cGMP reverses some of these alterations. Sancho-Alonso M, Taoro-Gonzalez L, Cabrera-Pastor A, Felipo V, Teruel-Marti V. Neurochemical Research. 2022 Jul;47(7):2016-2031. doi: 10.1007/s11064-022-03588-y. PMID: 35386048
Is NMDA-receptor-mediated oxidative stress in mitochondria of peripheral tissues the essential factor in the pathogenesis of hepatic encephalopathy?. Kosenko E, Tikhonova L, Alilova G, Montoliu C. Journal of Clinical Medicine. 2022 Feb 4;11(3):827. doi: 10.3390/jcm11030827. PMID: 35160278
A new score unveils a high prevalence of mild cognitive impairment in patients with nonalcoholic fatty liver disease. Gimenez-Garzo C, Fiorillo A, Ballester-Ferre M, Gallego J, Casanova-Ferrer F, Urios A, Benlloch S, Marti-Aguado D, San-Miguel T, Tosca J, Rios M, Monton C, Durban L, Escudero-Garcia D, Aparicio L, Felipo V, Montoliu C. Journal of Clinical Medicine. 2021 Jun 25;10(13):2806. doi: 10.3390/jcm10132806. PMID: 34202269Botulinum toxin injection plus topical diltiazem for chronic anal fissure: a randomized double-blind clinical trial and long-term outcome. Herreros B, Espi A, Monton Rodriguez C, Garcia-Granero E, Sanchiz V, Ferriols FL, Almela P, Hernandez V, Mora F, Minguez M. Diseases of the Colon and Rectum. 2021 Dec 1;64(12):1521-1530. doi: 10.1097/DCR.0000000000001983. PMID: 34747917
Caustic ingestion: development and validation of a prognostic score. Tosca J, Villagrasa R, Sanahuja A, Sanchez A, Trejo G, Herreros B, Pascual I, Mas P, Pena A, Minguez M. Endoscopy. 2021 Aug;53(8):784-791. doi: 10.1055/a-1297-0333. PMID: 33096569
Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: a longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects. Ampuero J, Aller R, Gallego-Duran R, Crespo J, Abad J, Gonzalez-Rodriguez A, Gomez-Camarero J, Caballeria J, Lo Iacono O, Ibanez L, Garcia-Samaniego J, Martin-Mateos R, Frances R, Fernandez-Rodriguez C, Diago M, Soriano G, Andrade RJ, Latorre R, Jorquera F, Morillas RM, Escudero D, Estevez P, Hernandez-Guerra M, Augustin S, Pareja-Megia MJ, Banales JM, Aspichueta P, Benlloch S, Rosales JM, Salmeron J, Turnes J, Romero-Gomez M. Liver International. 2021 Sep;41(9):2076-2086. doi: 10.1111/liv.14898. PMID: 33896100
Digital pathology: accurate technique for quantitative assessment of histological features in metabolic-associated fatty liver disease. Marti-Aguado D, Rodriguez-Ortega A, Mestre-Alagarda C, Bauza M, Valero-Perez E, Alfaro-Cervello C, Benlloch S, Perez-Rojas J, Ferrandez A, Alemany-Monraval P, Escudero-Garcia D, Monton C, Aguilera V, Alberich-Bayarri A, Serra M, Marti-Bonmati L. Alimentary Pharmacology & Therapeutics. 2021 Jan;53(1):160-171. doi: 10.1111/apt.16100. PMID: 32981113
Projects
Title: Estudio de las vesículas extracelulares en plasma de pacientes con obesidad mórbida antes y tras cirugía bariátrica. Subvenciones concedidas a grupos de investigación emergentes
Funding body: Conselleria de Educación
Principal Investigator: Andrea Cabrera Pastor
Duration: 2022 – 2023
Total budget: 20.000 €
Title: Role of extracellular vesicles, metabolome and altered intercellular communication in the induction of minimal hepatic encephalopathy: mechanisms, therapeutic and diagnostic implications
Funding body: Instituto de Salud Carlos III – Cofinanciado FEDER
Principal Investigator: Andrea Cabrera Pastor
Duration: 2021 – 2024
Total budget: 40.000 €
Title: LIGAM1: Efecto de la activación de TLR por medio de sus ligandos sobre la polarización de macrófagos hacia M1 y su función citocida frente a las células madre de glioblastoma
Funding body: Universidad de Valencia – INCLIVA
Principal Investigator: Javier Megías Vericat, Andrea Cabrera Pastor
Duration: 2021 – 2022
Total budget: 4.608 €
Title: Caracterización de las alteraciones neurológicas y cerebrales en pacientes con encefalopatía hepática mínima. Contribucu¡ión de la Inflamación. Implicaciones diagnósticas y terapéuticas
Funding body: Instituto de Salud Carlos III – Cofinanciado FEDER
Principal Investigator: Carmina Montoliu Félix
Duration: 2019 – 2021
Total budget: 171.820 €
Title: Papel de los exosomas en el inicio y progresión de la neuroinflamación, alteraciones en la neurotransmisión y deterioro cognitivo y motor en encefalopatía hepática mínima. Posible utilidad como biomarcadores tempranos
Funding body: Conselleria de Educación
Principal Investigator: Andrea Cabrera Pastor
Duration: 2019 – 2020
Total budget: 16.000 €
Title: Mecanismos moleculares y cerebrales de las alteraciones cognitivas y motoras en hiperamonemia y encefalopatía hepática. lmplicaciones terapéuticas y diagnósticas
Funding body: Conselleria de Educación, Cultura y Deporte
Principal Investigator: Vicente Felipo Orts
Duration: 2018 – 2021
Total budget: 289.194,57
+ Info
Doctoral candidate: Fiorillo, Alesandra
Director(s): Montoliu Felix, Carmina; San Miguel Díaz, Teresa
Date of the defense: 01/11/2023
University: University de ValenciaTitle: Caracterización de las alteraciones en el inmunofenotipo asociadas a la aparición de la encefalopatía hepática mínima en pacientes cirróticos. Implicación de las vesículas extracelulares
Doctoral candidate: Gallego Roig, Juan José
Director(s): Montoliu Felix, Carmina; Megías Vericat, Javier
Date of the defense: 01/11/2023
University: University de ValenciaTitle: Characterization and evaluation of alterations in sensitivity and autonomic function in patients with minimal hepatic encephalopathy
Doctoral candidate: Rega Caballero, Dalia
Director(s): Montoliu Felix, Carmina; Uriós Lluch, Amparo; Cases Bergón, Paula
Date of the defense: 05/12/2022
University: Universitat Politècnica de València
Title: Papel de las vesículas extracelulares en el deterioro cognitivo y motor en hiperamonemia y encefalopatía hepática. Mecanismos moleculares e implicaciones terapéuticas
Doctoral candidate: Izquierdo Altarejos, Paula
Director(s): Felipo Orts, Vicente; Cabrera Pastor, Andrea
Date of the defense: 20/05/2022
University: Universitat de València
Title: Mecanismos moleculares por los que la hiperamonemia crónica induce neuroinflamación y alteraciones en la neurotransmisión en cerebelo de ratas hiperamonémicas
Doctoral candidate: Arenas Ortiz, Yaiza María
Director(s): Cabrera Pastor, Andrea; Balzano, Tiziano; Felipo Orts, Vicente
Date of the defense: 12/04/2022
University: Universitat de València
Title: Impacto de la inmunosuppresión y otros factores de riesgo en el desarrollo de infecciones en pacientes con enfermedad inflamatoria intestinal: estudio caso-control
Doctoral candidate: García Gimeno, Natalia
Director(s): Mínguez Pérez, Miguel; Tosca Cuquerella, Joan; Mora Miguel, Francisco
Date of the defense: 05/11/2021
University: Universitat de València
Title: Estudio epidemiológico retrospectivo de 10 años de los enfermos con virus C diagnosticados en el servicio de Medicina Digestiva del Hospital Clínico Universitario de Valencia
Doctoral candidate: Puchades Lanza, Laura
Director(s): Serra Desfilis, Miguel Ángel; Escudero García, Desamparados
Date of the defense: 28/06/2021
University: Universitat de València
Title: Caracterización del deterioro neurológico y la respuesta al tratamiento con rifaximina en pacientes con encefalopatía hepática mínima
Doctoral candidate: Ballester Ferré, Maria Pilar
Director(s): Montoliu Félix, Carmina; Escudero García, Desamparados; Serra Desfílis Miguel Ángel
Date of the defense: 08/01/2021
University: Universitat de València