Focal cortical damage parallels cognitive impairment in minimal hepatic encephalopathy.

Little attention has been paid to cortical integrity in patients with minimal hepatic encephalopathy (MHE), although cognitive functions affected in early stages of liver disease are mainly allocated in different neocortical structures. Here we used cortical surface-based analysis techniques to investigate if patterns of cortical thinning accompany the mildest form of HE. To aim this goal, cortical thickness obtained from high-resolution 3T magnetic resonance imaging (MRI) was measured in patients with no MHE (NMHE), MHE, and healthy controls. Further correlation analyses were performed to examine whether scores in the critical flicker frequency (CFF) test, and blood ammonia levels accounted for the loss of cortical integrity in different stages of liver disease. Finally, we assessed group differences in volume of different subcortical regions and their potential relationships with CFF scores/blood ammonia levels. Results showed a focal thinning of the superior temporal cortex and precuneus in MHE patients when compared with NMHE and controls. Relationships between blood ammonia levels and cortical thickness of the calcarine sulcus accounted for impaired visual judgment in patients with MHE when compared to NMHE. Regression analyses between cortical thickness and CFF predicted differences between controls and the two groups of HE patients, but failed to discriminate between patients with NMHE and MHE. Taking together, these findings provide the first report of cortical thinning in MHE patients, and they yield novel insights into the neurobiological basis of cognitive impairment associated with early stages of liver diseases.

Patients with minimal hepatic encephalopathy show impaired mismatch negativity correlating with reduced performance in attention tests.

UNLABELLED: Attention deficit is an early event in the cognitive impairment of patients with minimal hepatic encephalopathy (MHE). The underlying mechanisms remain unclear. Mismatch negativity (MMN) is an auditory event-related potential that reflects an attentional trigger. Patients with schizophrenia show impaired attention and cognitive function, which are reflected in altered MMN. We hypothesized that patients with MHE, similarly to those with schizophrenia, should show MMN alterations related with attention deficits. The aims of this work were to assess whether (1) MMN is altered in cirrhotic patients with MHE, compared to those without MHE, (2) MMN changes in parallel with performance in attention tests and/or MHE in a longitudinal study, and (3) MMN predicts performance in attention tests and/or in the Psychometric Hepatic Encephalopathy Score (PHES). We performed MMN analysis as well as attention and coordination tests in 34 control subjects and in 37 patients with liver cirrhosis without MHE and 23 with MHE. Patients with MHE show reduced performance in selective and sustained attention tests and in visuomotor and bimanual coordination tests. The MMN wave area was reduced in patients with MHE, but not in those without MHE. In the longitudinal study, MMN area improved in parallel with performance in attention tests and PHES in 4 patients and worsened in parallel in another 4. Logistic regression analyses showed that MMN area predicts performance in attention tests and in PHES, but not in other tests or critical flicker frequency. Receiver operating characteristic curve analyses showed that MMN area predicts attention deficits in the number connection tests A and B, Stroop tasks, and MHE, with sensitivities of 75%-90% and specificities of 76%-83%. CONCLUSION: MMN area is useful to diagnose attention deficits and MHE in patients with liver cirrhosis.

Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy.

To assess the contribution of hyperammonemia and inflammation to induction of mild cognitive impairment (or MHE). We analyzed the presence of mild cognitive impairment (CI) by using the PHES battery of psychometric tests and measured the levels of ammonia and of the inflammatory cytokines IL-6 and IL-18 in blood of patients with different types of liver or dermatological diseases resulting in different grades of hyperammonemia and/or inflammation. The study included patients with 1) liver cirrhosis, showing hyperammonemia and inflammation; 2) non-alcoholic fatty liver disease (NAFLD) showing inflammation but not hyperammonemia; 3) non-alcoholic steatohepatitis (NASH) showing inflammation and very mild hyperammonemia; 4) psoriasis, showing inflammation but not hyperammonemia; 5) keloids, showing both inflammation and hyperammonemia and 6) controls without inflammation or hyperammonemia. The data reported show that in patients with liver diseases, cognitive impairment may appear before progression to cirrhosis if hyperammonemia and inflammation are high enough. Five out of 11 patients with NASH, without liver cirrhosis, showed cognitive impairment associated with hyperammonemia and inflammation. Patients with keloids showed cognitive impairment associated with hyperammonemia and inflammation, in the absence of liver disease. Hyperammonemia or inflammation alone did not induce CI but the combination of certain levels of hyperammonemia and inflammation is enough to induce CI, even without liver disease.

3-nitro-tyrosine as a peripheral biomarker of minimal hepatic encephalopathy in patients with liver cirrhosis.

OBJECTIVES: Between 30 and 50% of the cirrhotic patients who do not show symptoms of clinical hepatic encephalopathy (HE) present minimal hepatic encephalopathy (MHE), with mild cognitive impairment. MHE impairs the quality of life, increases the risk of suffering accidents, predicts the appearance of clinical HE, and is associated with shortened lifespan. Early detection of MHE would be very useful. The "gold standard" for MHE diagnosis is the psychometric hepatic encephalopathy score (PHES). However, it is time consuming and needs adjusting for age and educational level. It would be very useful to have some blood biomarker reflecting the presence of MHE in cirrhotic patients. The aim of this work was to identify serum molecules useful as biomarkers for MHE. METHODS: We measured in 63 controls, 43 cirrhotic patients without MHE, and 44 patients with MHE, from Hospital Clinico de Valencia, serum levels of different amino acids, cyclic guanosine monophosphate (cGMP), nitrites+nitrates, and 3-nitrotyrosine. We analyzed for each parameter its diagnostic accuracy as an indicator of MHE, as assessed using the PHES. RESULTS: These studies supported that 3-nitro-tyrosine is a good marker for MHE. To validate its utility as a biomarker for MHE, we analyzed in a second cohort of 44 cirrhotic patients without MHE and 18 patients with MHE, from Hospital Arnau de Vilanova, serum levels of 3-nitro-tyrosine, methionine, and citrulline. Citrulline (173±17%), methionine (173±16%), and 3-nitro-tyrosine (857±92%) were increased in sera from patients with MHE when compared with those without MHE. The receiver operating characteristic (ROC) curve analysis of 3-nitro-tyrosine for the diagnosis of MHE in the first cohort showed an area under the curve (AUC) value of 0.96 (95% confidence interval 0.93-0.99). At the cutoff of 14 nM, the specificity was 93%, sensitivity 89%, and positive and negative predictive values were both 91%. When the same cutoff was applied to the second cohort, the specificity was 83% and sensitivity was 94%. The positive and negative predictive values were 70 and 97%, respectively. CONCLUSIONS: This pilot study, to be validated in a larger cohort, shows that determination of 3-nitro-tyrosine in serum, which is easy and not time consuming, is useful to identify patients with MHE, with good sensitivity, specificity, and positive and negative predictive values.

Serum metabolic signature of minimal hepatic encephalopathy by (1)H-nuclear magnetic resonance.

Minimal hepatic encephalopathy (MHE) reduces quality of life of cirrhotic patients, predicts overt hepatic encephalopathy, and is associated with poor prognosis. We hypothesized that MHE arises once metabolic alterations derived from the liver reach a particular threshold. Our aim was to assess whether metabolic profiling of serum samples by high-field (1)H-nuclear magnetic resonance spectroscopy ((1)H NMR) and subsequent multivariate analyses would be useful to characterize metabolic perturbations associated with MHE and to identify potential metabolic biomarkers. Metabolic serum profiles from controls (n = 69) and cirrhotic patients without MHE (n = 62) and with MHE (n = 39) were acquired using high field NMR. Supervised modeling of the data provided perfect discrimination between healthy controls and cirrhotic patients and allowed the generation of a predictive model displaying strong discrimination between patients with and without MHE (R(2)Y = 0.68, Q(2)Y = 0.63). MHE patients displayed increased serum concentrations of glucose, lactate, methionine, TMAO, and glycerol, as well as decreased levels of choline, branch amino acids, alanine, glycine, acetoacetate, NAC, and lipid moieties. Serum metabonomics by (1)H NMR offers a useful approach for characterizing underlying metabolic differences between patients with and without MHE. This procedure shows great potential as a diagnostic tool of MHE as it objectively reflects measurable biochemical differences between the patient groups and may facilitate monitoring of both disease progression and effects of therapeutic treatments.