Minimal Hepatic Encephalopathy Research Articles

A double-blind randomized placebo-controlled trial of albumin in outpatients with hepatic encephalopathy: HEAL study

Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life (QoL), can persist. A double-blind, placebo-controlled randomized clinical trial was performed to determine the impact of albumin vs. saline on MHE and QoL in individuals with prior HE already on standard of care. Outpatients with cirrhosis and prior HE, MHE and hypoalbuminemia already on treatment for HE were included. Patients on regular IV albumin infusions were excluded. Participants were randomized 1:1 to receive either weekly infusions of 25% IV albumin 1.5g/kg or saline over 5 weeks. MHE was defined using either psychometric hepatic encephalopathy score (PHES), Stroop or critical clicker frequency. MHE, QoL (based on sickness impact profile [SIP] total, physical, psychosocial domain) and serum markers (inflammation, endothelial dysfunction, and ischemia-modified albumin) were compared between baseline, the final infusion visit (end-of-drug [EOD]) and 1-week post final infusion (end-of-study [EOS]). Forty-eight (24/group) participants were randomized and balanced (including by HE medication use) at baseline. Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and ischemia-modified albumin decreased only in the albumin group at EOD and EOS vs. baseline. PHES and Stroop MHE reversal and improvement were greater in the albumin group at EOD and persisted at EOS. SIP total and psychosocial, but not physical, domain improved only in the albumin group at EOD and EOS vs. baseline. A significant reduction in IL-1β and endothelial dysfunction markers was also observed in the albumin group. In a double-blind, placebo-controlled trial of outpatients with cirrhosis, prior HE and current MHE, albumin infusions were associated with improved cognitive function and psychosocial QoL, likely due to amelioration of endothelial dysfunction. www. gov NCT03585257. Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life, can persist. We found that intravenous albumin infusions were associated with improved cognitive function and psychosocial quality of life, likely owing to amelioration of endothelial dysfunction, compared to placebo in outpatients with prior HE and current MHE. In patients who continue to demonstrate cognitive dysfunction and impaired quality of life despite standard of care therapy for HE, albumin infusions could be considered if these results are validated.

Altered dynamic spontaneous neural activity in minimal hepatic encephalopathy.

Background and aims:Abnormal regional neural activity has been identified by the analysis of the static amplitude of low-frequency fluctuation (ALFF) in the setting of minimal hepatic encephalopathy (MHE). Brain activity is highly dynamic. This work sought to evaluate the temporal variability of ALFF to reveal MHE-related alterations in the dynamics of spontaneous neural activity.MethodsA total of 29 healthy controls and 49 patients with cirrhosis [including 20 patients with MHE and 29 patients without MHE (NHE)] who underwent resting-state functional magnetic resonance imaging and Psychometric Hepatic Encephalopathy Score (PHES) examination were enrolled in this investigation. Utilizing a sliding-window approach, we calculated the dynamic ALFF (dALFF) variability to reflect the temporal dynamics of regional neural activity. An analysis of the correlation between dALFF variability and PHES was performed, and receiver operating characteristic (ROC) curve analysis to determine the potential of the dALFF variability index in identifying MHE was completed.ResultsThe dALFF variability in the bilateral precuneus/posterior cingulate gyrus and left middle frontal gyrus progressively decreased from NHE to MHE group. In cirrhotic patients, the value of dALFF variability in the bilateral precuneus/posterior cingulate gyrus was positively correlated with their neurocognitive performance (r = 0.383 and P = 0.007). The index of dALFF variability in the bilateral precuneus/posterior cingulate gyrus could be used to distinguish NHE and MHE patients, with moderate power (area under the ROC curve = 0.712 and P = 0.012).ConclusionOur findings highlight the existence of aberrant dynamic brain function in MHE, which could underlie the neural basis of cognitive impairments and could be associated with the development of the disease. Analyzing dALFF could facilitate new biomarker identification for MHE.

Hepatic Encephalopathy and Treatment Modalities: A Review Article.

Hepatic encephalopathy (HE) is a condition that is commonly seen in individuals suffering from liver cirrhosis. After excluding brain illness, HE is described as a range of neuropsychiatric disorders in individuals with liver impairment. It is characterized by personality changes, intellectual impairment, and a depressed level of consciousness. Toxins that are typically eliminated from the body by the liver build up in the blood and eventually reach the brain, causing HE. Many signs and symptoms of HE may often be treated if caught early and treated properly. It is important to remember that not everyone who is affected may experience every symptom mentioned below. Affected individuals should speak with their doctor and medical staff about their specific disease, associated symptoms, and general prognosis. Many people only have minor symptoms, known as minimal HE. The exact pathophysiology of HE is still being debated, with the primary theories focusing on neurotoxins, reduced neurotransmission caused by alterations in brain energy metabolism, systemic inflammatory response, and blood-brain barrier (BBB) disturbances in liver failure, as well as metabolic irregularities.

The Assessment of Driving Fitness Using an On-Road Evaluation in Patients With Cirrhosis.

The association between cirrhosis and driving performance is of particular clinical relevance because of the life-threatening safety issues both for the driver with cirrhosis and the general public. Study aims were to assess (i) driving competency through the use of an in-office computerized battery and on-road driving assessment (DriveABLE) and (ii) the association between minimal hepatic encephalopathy (MHE), in-office paper-pencil tools, and additional measures (e.g., frailty, depression, cognitive testing) with unsafe driving. Patients were prospectively recruited from 2 tertiary care liver clinics. In-office tests and in-office and on-road assessments of driving competence were completed. The χ 2 test and 1-way analysis of variance were used to analyze differences among those with and without MHE. Logistic regression was used to evaluate predictors of an indeterminate/fail result on the in-office computerized driving assessment battery (DriveABLE Cognitive Assessment Tool [DCAT]). Eighty patients participated with a mean age of 57 years, 70% male, 75% Child-Pugh B/C, and 36% with a history of overt hepatic encephalopathy. Thirty percent met MHE criteria on both the psychometric hepatic encephalopathy score and the Stroop app tests. Only 2 patients (3%) were categorized as "unfit to drive" in the on-road driving test, one with MHE and the other without. Fifty-eight percent of the patients were scored as indeterminate/fail on the DCAT. This corresponded to a higher mean number of on-road driving errors (5.3 [SD 2.1] vs 4.2 [SD 1.6] in those who passed the DCAT, P = 0.01). Older age (odds ratio 1.3; confidence interval 1.1, 1.5; P = 0.001) and MHE by Stroop/psychometric hepatic encephalopathy score (odds ratio 11.0; confidence interval 2.3, 51.8; P = 0.002) were independently predictive of worse performance on the DCAT. Worse performance in in-office testing was associated with worse scores on a computerized driving assessment battery and more on-road driving errors, but in-office tools were insufficient to predict on-road driving failures. A diagnosis of MHE should not be used alone to restrict driving in patients with cirrhosis. At-risk patients require on-road driving tests under the supervision of driving regulatory agencies. Future studies should continue to refine and evaluate in-office or at-home testing to predict driving performance.

Decreased brain noradrenaline in minimal hepatic encephalopathy is associated with cognitive impairment in rats

Background and aimsMinimal hepatic encephalopathy (MHE) is a common neuropsychiatric complication in patients with cirrhosis. Alterations in monoamine neurotransmitters have been associated with the pathogenesis of MHE. We investigated the levels of hippocampal noradrenergic neurotransmitter in a rat model of thioacetamide-induced chronic liver failure-related MHE, and their role in cognitive impairment. Materials18 male Sprague-Dawley (SD) rats were equally divided in MHE and control groups. A rat model of MHE was established by intraperitoneal injection of thioacetamide (TAA) for 12 weeks. Cognitive function was assessed using the Morris water maze (MWM) test and locomotor activity and exploratory behavior assessed with open field test. The concentration of hippocampal noradrenaline (NE) was detected by ELISA, and the magnetic susceptibility value in the hippocampus was detected by quantitative susceptibility mapping. Hippocampal iron content was quantified by Prussian blue staining. ResultsMHE rats performed significantly poorer than their control counterparts in the MWM test, as seen by decreased number of platform crossings and time in the target quadrant, and increased path length to reach the target zone (P < 0.05 for all parameters). In the open field test, the MHE group exhibited lower locomotor activity and exploratory behavior than the control group (P < 0.05 for all parameters). We detected pronounced iron staining in the hippocampus of MHE rats, whereas no iron-stained particles were found in control rats. We observed an imbalance of inflammatory (increased pro- and decreased anti-) cytokines in the hippocampus of MHE rats. Further analysis of the data showed that the level of hippocampal noradrenaline in MHE rats was significantly lower than that of control rats (P < 0.05). We observed a correlation between the level of inflammatory cytokine and noradrenaline land susceptibility value in the rat hippocampus of the MHE group. ConclusionOur results suggest that MHE associated with TAA-induced chronic liver failure is associated with alterations in noradrenergic neurotransmission. We propose that iron imbalance in the brain might lead to reduction in the levels of noradrenaline, and cognitive impairment.

Altered gut microbiota is associated with sleep disturbances in patients with minimal hepatic encephalopathy caused by hepatitis B-related liver cirrhosis

ABSTRACT Background Sleep disturbances are prevalent in patients with minimal hepatic encephalopathy (MHE). This study aimed to evaluate the association between sleep disturbances and altered gut microbiota in patients with MHE caused by hepatitis B-related liver cirrhosis. Research design and methods Ninety-eight and 45 patients with MHE were included in exploration and validation cohorts, respectively. Sleep disturbances were assessed using the Chinese version of the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Microbiota in fecal samples were analyzed via amplicon sequencing of bacterial 16S ribosomal RNA genes. Results The gut microbiomes of MHE patients with sleep disturbances were characterized by lower bacterial diversity and distinct bacterial composition. Relative abundances of Streptococcus salivarius and Veillonella were independent predictors of sleep disturbances in MHE patients and well-distinguished MHE patients with and without sleep disturbances in both the exploration and validation cohorts. Moreover, the relative abundances of S. salivarius were positively correlated with plasma ammonia levels, and functional modules associated with protein digestion and absorption and lipopolysaccharide biosynthesis were enriched in the microbiomes of MHE patients with sleep disturbances. Conclusions Both S. salivarius and Veillonella were associated with sleep disturbances in patients with MHE caused by hepatitis B-related liver cirrhosis.

A meta-analysis of the association between Helicobacter pylori infection and risk of hepatic encephalopathy.

Although the association between Helicobacter pylori (H. pylori) infection and hepatic encephalopathy (HE) has been confirmed through some research, the results of these relevant studies still remain controversial. We conducted an updated meta-analysis based on published studies to address this issue. A systematic search was conducted, reviewing all studies about the association between H. pylori infection and HE, through November 2021. The outcome measures were presented as odds ratios (ORs) with 95% confidence intervals (CIs). In total, 13 studies provided data from 2784 subjects. H. pylori infection increased the risk of HE by 32% (OR=2.32, 95% CI: 1.78-3.04). The effect became greater after hepatic encephalopathy was divided into overt HE and minimal hepatic encephalopathy (MHE) (HE OR=2.66, 95% CI: 2.01-3.51, MHE OR=1.74, 95% CI: 1.10-2.76). After H. pylori eradication, the risk of HE was reduced by 64%. H. pylori infection is significantly associated with HE, and the infection rate of H. pylori also increases with the severity of HE. Eradication of H. pylori has a protective effect on HE. Therefore, it is necessary to eradicate H. pylori in HE treatments.

Risk factors for hepatic encephalopathy and mortality in cirrhosis: The role of cognitive impairment, muscle alterations and shunts.

Muscle alterations, portosystemic shunts (SPSS) and minimal hepatic encephalopathy (MHE) are related to hepatic encephalopathy (HE), however no studies have investigated the relative role of all these risk factors detected in the same patients. The aim of the study was to assess the prognostic impact of muscle alterations, MHE and SPSS on hepatic encephalopathy and transplant free survival. 114 cirrhotics were submitted to Psychometric Hepatic Encephalopathy Score (PHES) and Animal Naming Test (ANT) to detect MHE. CT scan was used to analyze the skeletal muscle index (SMI), muscle attenuation and SPSS. The incidence of the first episode of HE and survival were estimated. Previous HE was present in 47 patients (41%). The variables independently associated to previous HE were: sarcopenia, MHE and SPSS. 44 patients (39%) developed overt HE during 14±11 months; MHE and SPSS were the only variables significantly asociated to overt HE. During the same follow-up, 42 patients died (37%); MELD and sarcopenia were the only variables significantly asociated to transplant free survival. MHE, sarcopenia and SPSS are clinically relevant and should be sought for in cirrhotics. In particular, MHE and SPSS are the only risk factors significantly associated to the development of HE while MELD and sarcopenia are independently associated to overall mortality.

Speech patterns and enunciation for encephalopathy determination-A prospective study of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a complication of cirrhosis that benefits from early diagnosis and treatment. We aimed to characterize speech patterns of individuals with HE to investigate its potential to diagnose and monitor HE. This was a single‐center prospective cohort study that included participants with cirrhosis with HE (minimal HE [MHE] and overt HE [OHE]), cirrhosis without HE, and participants without liver disease. Audio recordings of reading, sentence repetition, and picture description tasks were obtained from these groups. Two certified speech‐language pathologists assessed speech rate (words per minute) and articulatory precision. An overall severity metric was derived from these measures. Cross‐sectional analyses were performed using nonparametric Wilcoxon statistics to evaluate group differences. Change over time in speech measures was analyzed descriptively for individuals with HE. The study included 43 total participants. Speech results differed by task, but the overall pattern showed slower speech rate and less precise articulation in participants with OHE compared to other groups. When speech rate and precision ratings were combined into a single speech severity metric, the impairment of participants with OHE was more severe than all other groups, and MHE had greater speech impairment than non‐liver disease controls. As OHE improved clinically, participants showed notable improvement in speech rate. Participants with OHE demonstrated impaired speech rate, precision, and speech severity compared with non‐liver disease and non‐HE cirrhosis. Participants with MHE had less pronounced impairments. Speech parameters improved as HE clinically improved. Conclusion: These data identify speech patterns that could improve HE diagnosis, grading, and remote monitoring.

Extracellular Vesicles From Hyperammonemic Rats Induce Neuroinflammation in Cerebellum of Normal Rats: Role of Increased TNFα Content.

Hyperammonemia plays a main role in the neurological impairment in cirrhotic patients with hepatic encephalopathy. Rats with chronic hyperammonemia reproduce the motor incoordination of patients with minimal hepatic encephalopathy, which is due to enhanced GABAergic neurotransmission in cerebellum as a consequence of neuroinflammation. Extracellular vesicles (EVs) could play a key role in the transmission of peripheral alterations to the brain to induce neuroinflammation and neurological impairment in hyperammonemia and hepatic encephalopathy. EVs from plasma of hyperammonemic rats (HA-EVs) injected to normal rats induce neuroinflammation and motor incoordination, but the underlying mechanisms remain unclear. The aim of this work was to advance in the understanding of these mechanisms. To do this we used an ex vivo system. Cerebellar slices from normal rats were treated ex vivo with HA-EVs. The aims were: 1) assess if HA-EVs induce microglia and astrocytes activation and neuroinflammation in cerebellar slices of normal rats, 2) assess if this is associated with activation of the TNFR1-NF-kB-glutaminase-GAT3 pathway, 3) assess if the TNFR1-CCL2-BDNF-TrkB pathway is activated by HA-EVs and 4) assess if the increased TNFα levels in HA-EVs are responsible for the above effects and if they are prevented by blocking the action of TNFα. Our results show that ex vivo treatment of cerebellar slices from control rats with extracellular vesicles from hyperammonemic rats induce glial activation, neuroinflammation and enhance GABAergic neurotransmission, reproducing the effects induced by hyperammonemia in vivo. Moreover, we identify in detail key underlying mechanisms. HA-EVs induce the activation of both the TNFR1-CCL2-BDNF-TrkB-KCC2 pathway and the TNFR1-NF-kB-glutaminase-GAT3 pathway. Activation of these pathways enhances GABAergic neurotransmission in cerebellum, which is responsible for the induction of motor incoordination by HA-EVs. The data also show that the increased levels of TNFα in HA-EVs are responsible for the above effects and that the activation of both pathways is prevented by blocking the action of TNFα. This opens new therapeutic options to improve motor incoordination in hyperammonemia and also in cirrhotic patients with hepatic encephalopathy and likely in other pathologies in which altered cargo of extracellular vesicles contribute to the propagation of the pathology.

Exploration of the Severity of Hepatic Encephalopathy Deterioration Process Through Dynamics of the EEG Band Power time series.

Cirrhosis is a liver disease that could impair the functionality of the neural system, limiting cognitive processes and reduce mobility, possibly because alterations on dynamics of neural communications. In this study the dynamics of band power fluctuations on ß and γ bands were studied on three groups: control, patients with cirrhosis and patients diagnosed with minimal hepatic encephalopathy. EEG signals were recorded on an oddball paradigm and analyzed to obtain the latency and amplitude of the P300 wave and Detrended Fluctuation Analysis (DFA) exponent values over ß and γ band power time series for each channel. As expected, the latency of the P300 wave was significantly different for control subjects ( ). Amplitudes were not as different, but they tend to decrease for cirrhosis and minimal hepatic encephalopathy groups. DFA exponent values also tends to describe a more regular process and seems to be related with presence of symptoms of hepatic encephalopathy. These subtle changes could be produced by the mechanisms of a mild neurological impairment and be used, if it is confirmed, as an index to evaluate such deterioration.

Evaluation of Interleukin-6 for stepwise diagnosis of minimal hepatic encephalopathy in patients with liver cirrhosis

Evaluation of Interleukin-6 for stepwise diagnosis of minimal hepatic encephalopathy in patients with liver cirrhosis

CyberLiver Animal Recognition Test (CL-ART): a novel remote monitoring tool to assess minimal hepatic encephalopathy

CyberLiver Animal Recognition Test (CL-ART): a novel remote monitoring tool to assess minimal hepatic encephalopathy

Psychomotor speed from minimal hepatic encephalopathy testing is associated with physical frailty in patients with end-stage liver disease

Psychomotor speed from minimal hepatic encephalopathy testing is associated with physical frailty in patients with end-stage liver disease

Aberrant stability of brain functional architecture in cirrhotic patients with minimal hepatic encephalopathy.

To investigate the stability changes of brain functional architecture and the relationship between stability change and cognitive impairment in cirrhotic patients. Fifty-one cirrhotic patients (21 with minimal hepatic encephalopathy (MHE) and 30 without MHE (NHE)) and 29 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging and neurocognitive assessment using the Psychometric Hepatic Encephalopathy Score (PHES). Voxel-wise functional connectivity density (FCD) was calculated as the sum of connectivity strength between one voxel and others within the entire brain. The sliding window correlation approach was subsequently utilized to calculate the FCD dynamics over time. Functional stability (FS) is measured as the concordance of dynamic FCD. From HCs to the NHE and MHE groups, a stepwise reduction of FS was found in the right supramarginal gyrus (RSMG), right middle cingulate cortex, left superior frontal gyrus, and bilateral posterior cingulate cortex (BPCC), whereas a progressive increment of FS was observed in the left middle occipital gyrus (LMOG) and right temporal pole (RTP). The mean FS values in RSMG/LMOG/RTP (r = 0.470 and P = 0.001; r = -0.458 and P = 0.001; and r = -0.384 and P = 0.005, respectively) showed a correlation with PHES in cirrhotic patients. The FS index in RSMG/LMOG/BPCC/RTP showed moderate discrimination potential between the NHE and MHE groups. Changes in FS may be linked to neuropathological bias of cognitive impairment in cirrhotic patients and could serve as potential biomarkers for MHE diagnosis and monitoring the progression of hepatic encephalopathy.

EncephalApp Stroop Test for covert hepatic encephalopathy screening in Tunisian cirrhotic patients

Background: Covert hepatic encephalopathy (CHE) is underdiagnosed and is difficult to detect. The EncephalApp Stroop test is validated for its screening. The aim of the study was to define Tunisian norms for the test based on healthy controls norms and to estimate the prevalence of CHE in cirrhotic Tunisian patients. Methods: A prospective, multicenter, cross‐sectional study was conducted. Ambulatory or hospitalized cirrhotic patients aged 40 years and over were recruited at 11 centers. Healthy subjects aged 40 years and over were recruited at 8 centers. We used a translated Arabic version of the streamlined EncephalApp Stroop test. The task has two components: “Off” and “On” state depending on the discordance or concordance of the stimuli. Results: 142 patients were included. The mean age was 57.26 years [40–86]. 40 (28.17%) of cirrhotic patients who were included were diagnosed as having a minimal hepatic encephalopathy or CHE. Among the ineligible patients, 22 had overt hepatic encephalopathy. If we consider these patients, the overall prevalence rate of CHE was around 24.39% in cirrhotic patients. It was more frequent in women (34.21% vs 25.96%), and in patients whose level of school education is between 6 and 13 years. Its prevalence does not appear to be affected by gender, MELD score, etiology of cirrhosis and age group of patients, as these variables were independent with respective p according to the chi-square test 0.413; 0.736; 0.663 and 0.1. The stroop times (On / Off and On + Off) correlated significantly with each other, are associated significantly and positively with age (respective Pearson coefficients: 0.578; 0.567 and 0.6). The more the age increases, the more the stroop response times increases (p &gt; 10-3). Conclusions: EncephalApp Stroop test was an efficient screening tool for CHE in Tunisian cirrhotic patients.

Analysis of Gut Microbiome Structure Based on GMPR+Spectrum

The gut microbiome is related to many major human diseases, and it is of great significance to study the structure of the gut microbiome under different conditions. Multivariate statistics or pattern recognition methods were often used to identify different structural patterns in gut microbiome data. However, these methods have some limitations. Minimal hepatic encephalopathy (MHE) datasets were taken as an example. Due to the physical lack or insufficient sampling of the gut microbiome in the sequencing process, the microbiome data contains many zeros. Therefore, the geometric mean of pairwise ratios (GMPR) was used to normalize gut microbiome data, then Spectrum was used to analyze the structure of the gut microbiome, and lastly, the structure of core microflora was compared with Network analysis. GMPR calculates the Intraclass correlation coefficient (ICC), whose reproducibility was significantly better than other normalization methods. In addition, running-time, Normalized Mutual Information (NMI), Davies-Boulding Index (DBI), and Calinski-Harabasz index (CH) of GMPR+Spectrum were far superior to other clustering algorithms such as M3C, iClusterPlus. GMPR+Spectrum can not only perform better but also effectively identify the structural differences of intestinal microbiota in different patients and excavate the unique critical bacteria such as Akkermansia, and Lactobacillus in MHE patients, which may provide a new reference for the study of the gut microbiome in disease.

Randomized Clinical Trial: Effects of β-Hydroxy-β-Methylbutyrate (HMB)-Enriched vs. HMB-Free Oral Nutritional Supplementation in Malnourished Cirrhotic Patients.

β-Hydroxy-β-methylbutyrate (HMB) supplementation increases muscle and strength mass in some muscle-wasting disorders. Malnutrition and sarcopenia are often present in liver cirrhosis. We aimed to investigate the effects of oral HMB supplementation on changes in body composition and liver status in patients with cirrhosis and malnutrition. In a randomized, controlled, double-blind trial, 43 individuals were randomized to receive twice a day and for 12 weeks an oral nutritional supplement (ONS) enriched with 1.5 g of calcium HMB per bottle or another supplement with similar composition devoid of HMB. Inclusion criteria were liver cirrhosis with at least one previous decompensation and clinical malnutrition. Liver function, plasma biochemistry analyses, and physical condition assessment were carried out at baseline, then after six and 12 weeks of supplementation. A total of 34 patients completed the clinical trial. An improvement in liver function and an increase in fat mass index were observed in both groups. None of the two ONS changed the fat-free mass. However, we observed an upward trend in handgrip strength and a downward trend in minimal hepatic encephalopathy in the HMB group. At the end of the trial and regardless of the supplement administered, fat mass content increased with no change in fat-free mass, while liver function scores and nutritional analytic markers also improved.

Rifaximin Improves Spatial Learning and Memory Impairment in Rats with Liver Damage-Associated Neuroinflammation.

Patients with non-alcoholic fatty liver disease (NAFLD) may show mild cognitive impairment. Neuroinflammation in the hippocampus mediates cognitive impairment in rat models of minimal hepatic encephalopathy (MHE). Treatment with rifaximin reverses cognitive impairment in a large proportion of cirrhotic patients with MHE. However, the underlying mechanisms remain unclear. The aims of this work were to assess if rats with mild liver damage, as a model of NAFLD, show neuroinflammation in the hippocampus and impaired cognitive function, if treatment with rifaximin reverses it, and to study the underlying mechanisms. Mild liver damage was induced with carbon-tetrachloride. Infiltration of immune cells, glial activation, and cytokine expression, as well as glutamate receptors expression in the hippocampus and cognitive function were assessed. We assessed the effects of daily treatment with rifaximin on the alterations showed by these rats. Rats with mild liver damage showed hippocampal neuroinflammation, reduced membrane expression of glutamate N-methyl-D-aspartate (NMDA) receptor subunits, and impaired spatial memory. Increased C-C Motif Chemokine Ligand 2 (CCL2), infiltration of monocytes, microglia activation, and increased tumor necrosis factor α (TNFα) were reversed by rifaximin, that normalized NMDA receptor expression and improved spatial memory. Thus, rifaximin reduces neuroinflammation and improves cognitive function in rats with mild liver damage, being a promising therapy for patients with NAFLD showing mild cognitive impairment.

Abnormal brain oxygen homeostasis in an animal model of liver disease

Background & AimsIncreased plasma ammonia concentration and consequent disruption of brain energy metabolism could underpin the pathogenesis of hepatic encephalopathy (HE). Brain energy homeostasis relies on effective maintenance of brain oxygenation, and dysregulation impairs neuronal function leading to cognitive impairment. We hypothesised that HE is associated with reduced brain oxygenation and we explored the potential role of ammonia as an underlying pathophysiological factor.MethodsIn a rat model of chronic liver disease with minimal HE (mHE; bile duct ligation [BDL]), brain tissue oxygen measurement, and proton magnetic resonance spectroscopy were used to investigate how hyperammonaemia impacts oxygenation and metabolic substrate availability in the central nervous system. Ornithine phenylacetate (OP, OCR-002; Ocera Therapeutics, CA, USA) was used as an experimental treatment to reduce plasma ammonia concentration.ResultsIn BDL animals, glucose, lactate, and tissue oxygen concentration in the cerebral cortex were significantly lower than those in sham-operated controls. OP treatment corrected the hyperammonaemia and restored brain tissue oxygen. Although BDL animals were hypotensive, cortical tissue oxygen concentration was significantly improved by treatments that increased arterial blood pressure. Cerebrovascular reactivity to exogenously applied CO2 was found to be normal in BDL animals.ConclusionsThese data suggest that hyperammonaemia significantly decreases cortical oxygenation, potentially compromising brain energy metabolism. These findings have potential clinical implications for the treatment of patients with mHE.Lay summaryBrain dysfunction is a serious complication of cirrhosis and affects approximately 30% of these patients; however, its treatment continues to be an unmet clinical need. This study shows that oxygen concentration in the brain of an animal model of cirrhosis is markedly reduced. Low arterial blood pressure and increased ammonia (a neurotoxin that accumulates in patients with liver failure) are shown to be the main underlying causes. Experimental correction of these abnormalities restored oxygen concentration in the brain, suggesting potential therapeutic avenues to explore.