Search

Abstract Minimal hepatic encephalopathy (MHE) is diagnosed using PHES battery, but other tests are more sensitive, and a simple tool for early MHE detection is required. Assessment of saccadic eye movements is useful for early detection of cognitive alterations in different pathologies. We characterized the alterations in saccadic eye movements in MHE patients, its relationship with cognitive alterations and its utility for MHE diagnosis. One-hundred and eighteen cirrhotic patients (86 without and 32 with MHE) and 35 controls performed PHES and Stroop test and an eye movements test battery by OSCANN system: visual saccades, antisaccades, memory-guided saccades, fixation test and smooth pursuit. We analyzed 177 parameters of eye movements, assessed their diagnostic capacity for MHE, and correlated with cognitive alterations. MHE patients showed alterations in 56 of the 177 variables of eye movements compared to NMHE patients. MHE patients showed longer latencies and worse performance in most eye movements tests, which correlated with mental processing speed and attention impairments. The best correlations found were for antisaccades and memory-guided saccades, and some parameters in these tests could be useful for discriminating MHE and NMHE patients. Eye movements analysis could be a new, rapid, reliable, objective, and reproducible tool for early diagnose MHE.

Abstract Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) which affects their quality of life and life span. It has been proposed that a shift in peripheral inflammation triggers the appearance of MHE. However, the mechanisms involved in this immune system shift remain unknown. In this work we studied the broad molecular changes involved in the induction of MHE with the goal of identifying (1) altered genes and pathways in peripheral blood cells associated to the appearance of MHE, (2) serum metabolites and cytokines with modified levels in MHE patients and (3) MHE-regulated immune response processes related to changes in specific serum molecules. We adopted a multi-omic approach to profile the transcriptome, metabolome and a panel of cytokines of blood samples taken from cirrhotic patients with or without MHE. Transcriptomic analysis supports the hypothesis of alternations in the Th1/Th2 and Th17 lymphocytes cell populations as major drivers of MHE. Cluster analysis of serum molecules resulted in six groups of chemically similar compounds, suggesting that functional modules operate during the induction of MHE. Finally, the multi-omic integrative analysis suggested a relationship between cytokines CCL20, CX3CL1, CXCL13, IL-15, IL-22 and IL-6 with alteration in chemotaxis, as well as a link between long-chain unsaturated phospholipids and the increased fatty acid transport and prostaglandin production. We found altered immune pathways that may collectively contribute to the mild cognitive impairment phenotype in MHE. Our approach is able to combine extracellular and intracellular information, opening new insights to the understanding of the disease.

Abstract Peripheral inflammation acts synergistically with hyperammonemia in inducing neurological alterations in cirrhotic patients with minimal hepatic encephalopathy (MHE). We hypothesized that appearance of MHE would be associated to some specific qualitative change in peripheral inflammation. The aim of this work was to characterize the changes in peripheral inflammation associated to appearance of MHE. We analyzed it by immunophenotyping and cytokine profile analysis, in cirrhotic patients without or with MHE and controls. The main alterations associated specifically with MHE are: 1) increased activation of all subtypes of CD4+ T-lymphocytes, with the increased expression of CD69; 2) increased amount of CD4+CD28− T lymphocytes, associated with increased levels of CX3CL1 and of IL-15; 3) increased differentiation of CD4+ T lymphocytes to Th follicular and Th22; 4) increased activation of B lymphocytes and serum IgG. This study has identified some specific alterations of the immune system associated with appearance of the neurological alterations in MHE patients.