Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE), with mild cognitive impairment, psychomotor slowing, attention deficits and motor incoordination that reduce quality of life and increase accidents, hospitalizations and sanitary costs and reduce life span. MHE progress to overt HE that may lead to coma and death. Around 40% of cirrhotic patients suffer MHE (2,000,000 in the European Union). MHE is a serious clinical, social and economic problem. We have recently shown that mild cognitive impairment also appears in a relevant percentage (15-20%) of patients with non-alcoholic fatty liver disease (NAFLD), before reaching cirrhosis.
The mechanisms responsible for cognitive and motor alterations in MHE are not well known and there are no specific treatments for MHE. Identifying these mechanisms would help to design and test new therapeutic treatments to improve or restore cognitive and motor function. Early treatment of MHE would allow improving life quality and span, prevent progression of HE and reduce costs. Chronic hyperammonemia and peripheral inflammation induce neuroinflammation, which alters neurotransmission, leading to cognitive and motor impairment. Results from our team indicate that there is an interaction between neuroinflammation, glutamatergic and GABAergic neurotransmission and cyclic GMP in the induction of cognitive and motor deficits in MHE. The mechanisms underlying these interactions remain unclear.

This project involves studies both in animal models of hyperammonemia, steatohepatitis and MHE and in patients with NAFLD or cirrhosis. The general aims are:

Identify the mechanisms leading to cognitive and motor impairment in MHE.

Assess the contribution of hyperammonemia and peripheral inflammation to the mechanisms of previous point.

Identify which processes are involved in the transmission to brain of peripheral alterations

Identify targets to reverse cognitive and motor impairment

Design and assess in rats with hyperammonemia and MHE new treatments to reverse cognitive and motor alterations.

To better characterize the neurological, cerebral, immunological, metabolic, in microbiota and in exosomes alterations associated with appearance of cognitive and motor impairment in patients with MHE or NAFLD

Study the underlying mechanisms and use this knowledge to identify and evaluate new earlier and more sensitive diagnostic procedures for cognitive impairment associated to chronic liver diseases.

Identify gender differences in the above objectives

Groups participating in Prometeo

Alicia Salvador

Universitat de Valencia

Laboratory of Social Cognitive Neuroscience. Departamento de Psicobiología

Gaspar Pérez


Lactic Acid Bacteria and Probiotics Laboratory. Department of Biotechnology. Instituto de Agroquímica y Tecnología de Alimentos

Desamparados Escudero

Hospital Clinico Universitario de Valencia - Universidad de Valencia

Servicio de Digestivo, Hospital Clinico Universitario de Valencia 

Carmina Montoliu


Laboratorio de Deterioro Neurológico. INCLIVA. Universitat de Valencia

Marta Llansola

Centro de Investigación Príncipe Felipe

Laboratorio de Neurobiologia

Vicente Felipo

Centro de Investigación Príncipe Felipe

Laboratorio de Neurobiologia