Minimal Hepatic Encephalopathy Group Research Articles

Diffusion-Weighted Imaging in Minimal Hepatic Encephalopathy Using Mono-, Bi-, and Stretched Exponential Models

Background: Currently, there is no gold standard for diagnosing minimal hepatic encephalopathy (MHE). Diffusion-weighted imaging (DWI) can non-invasively evaluate changes in brain volume and damage to brain function. Objectives: The current study aims to evaluate changes in cerebral blood flow and brain function as predictors of MHE using DWI. Patients and Methods: Participants from October 2016 to October 2021 were scanned using a 3.0T superconductive MR machine (Discovery MR750, GE Medical Systems). Intravoxel incoherent motion DWI (IVIM-DWI) images of 30 patients with MHE and 30 controls were analyzed in a retrospective case-control study. The parameters of mono-, bi-, and stretched exponential models of the regions of interest, delineated from cerebral perfusion pseudo-color maps, were measured. The significance of the differences in parameter values between the groups was assessed using an independent t-test. Furthermore, the receiver operating characteristic curve was used to analyze the predictive efficiency of each parameter for MHE. Results: Compared to the control group, the distributed diffusion coefficient (DDC) of the bilateral frontal lobe, temporal lobe, occipital lobe, parietal lobe, cingulate gyrus, and thalamus in the MHE group was statistically different (P < 0.05). The pseudo-diffusion coefficient (D*) and DDC demonstrated good diagnostic efficacy for MHE. D* had the highest area under the curve (AUC) in the bilateral parietal lobe, bilateral cingulate gyrus, and left occipital lobe. In contrast, DDC had the highest AUC in the right occipital and bilateral temporal lobes. Conclusion: Intravoxel incoherent motion DWI is an imaging method that can detect MHE. In addition, D* and DDC are better diagnostic parameters for screening MHE. Intravoxel incoherent motion DWI will be helpful in uncovering deeper intrinsic pathophysiological mechanisms and improving predictive efficiency.

Functional connectivity disruption of insular subregions in the cirrhotic patients with minimal hepatic encephalopathy.

We investigated abnormal functional connectivity (FC) patterns of insular subregions in patients with minimal hepatic encephalopathy (MHE) and examined their relationships with cognitive dysfunction using resting-state functional magnetic resonance imaging (fMRI). We collected resting-state fMRI data in 54 patients with cirrhosis [20 with MHE and 34 without MHE (NHE)] and 25 healthy controls. After defining six subregions of insula, we mapped whole-brain FC of the insular subregions and identified FC differences through three groups. FC of the insular subregions was correlated against clinical parameters (including venous blood ammonia level, Child-Pugh score, and cognitive score). The discrimination performance between the MHE and NHE groups was evaluated by performing a classification analysis using the FC index. Across three groups, the observed FC differences involved four insular subregions, including the left-ventral anterior insula, left-dorsal anterior insula, right-dorsal anterior insula, and left-posterior insula (P < 0.05 with false discovery rate correction). Moreover, the FC of these four insular subregions progressively attenuated from NHE to MHE. In addition, hypoconnectivity of insular subregions was correlated with the poor neuropsychological performance and the evaluated blood ammonia levels in patients (P < 0.05 with Bonferroni correction). The FC of insular subregions yielded moderate discriminative value between the MHE and NHE groups (AUC = 0.696-0.809). FC disruption of insular subregions is related to worse cognitive performance in MHE. This study extended our understanding about the neurophysiology of MHE and may assist for its diagnosis.

The interaction of ammonia and manganese in abnormal metabolism of minimal hepatic encephalopathy: A comparison metabolomics study.

This study was to investigate the effects of ammonia and manganese in the metabolism of minimal hepatic encephalopathy (MHE). A total of 32 Sprague-Dawley rats were divided into four subgroups: chronic hyperammonemia (CHA), chronic hypermanganese (CHM), MHE and control group (CON). 1H-NMR-based metabolomics was used to detect the metabolic changes. Sparse projection to latent structures discriminant analysis was used for identifying and comparing the key metabolites. Significant elevated blood ammonia were shown in the CHA, CHM, and MHE rats. Significant elevated brain manganese (Mn) were shown in the CHM, and MHE rats, but not in the CHA rats. The concentrations of γ-amino butyric acid (GABA), lactate, alanine, glutamate, glutamine, threonine, and phosphocholine were significantly increased, and that of myo-inositol, taurine, leucine, isoleucine, arginine, and citrulline were significantly decreased in the MHE rats. Of all these 13 key metabolites, 10 of them were affected by ammonia (including lactate, alanine, glutamate, glutamine, myo-inositol, taurine, leucine, isoleucine, arginine, and citrulline) and 5 of them were affected by manganese (including GABA, lactate, myo-inositol, taurine, and leucine). Enrichment analysis indicated that abnormal metabolism of glutamine and TCA circle in MHE might be affected by the ammonia, and abnormal metabolism of GABA might be affected by the Mn, and abnormal metabolism of glycolysis and branched chain amino acids metabolism might be affected by both ammonia and Mn. Both ammonia and Mn play roles in the abnormal metabolism of MHE. Chronic hypermanganese could lead to elevated blood ammonia. However, chronic hyperammonemia could not lead to brain Mn deposition.

White matter microstructural disruption in minimal hepatic encephalopathy: a neurite orientation dispersion and density imaging (NODDI) study.

To evaluate the ability of neurite orientation dispersion and density imaging (NODDI) for detecting white matter (WM) microstructural abnormalities in minimal hepatic encephalopathy (MHE). Diffusion-weighted images, enabling the estimation of NODDI and diffusion tensor imaging (DTI) parameters, were acquired from 20 healthy controls (HC), 22 cirrhotic patients without MHE (NHE), and 15 cirrhotic patients with MHE. Tract-based spatial statistics were used to determine differences in DTI (including fractional anisotropy [FA] and mean/axial/radial diffusivity [MD/AD/RD]) and NODDI parameters (including neurite density index [NDI], orientation dispersion index [ODI], and isotropic volume fraction [ISO]). Voxel-wise analyses of correlations between diffusion parameters and neurocognitive performance determined by Psychometric Hepatic Encephalopathy Score (PHES) were completed. MHE patients had extensive NDI reduction and rare ODI reduction, primarily involving the genu and body of corpus callosum and the bilateral frontal lobe, corona radiata, external capsule, anterior limb of internal capsule, temporal lobe, posterior thalamic radiation, and brainstem. The extent of NDI and ODI reduction expanded from NHE to MHE. In both MHE and NHE groups, the extent of NDI change was quite larger than that of FA change. No significant intergroup difference in ISO/MD/AD/RD was observed. Tissue specificity afforded by NODDI revealed the underpinning of FA reduction in MHE. The NDI in left frontal lobe was significantly correlated with PHES. MHE is characterized by diffuse WM microstructural impairment (especially neurite density reduction). NODDI can improve the detection of WM microstructural impairments in MHE and provides more precise information about MHE-related pathology than DTI.

Metabolite profiling analysis of hepatitis B virus-induced liver cirrhosis patients with minimal hepatic encephalopathy using gas chromatography-time-of-flight mass spectrometry and ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry.

This study used gas chromatography-time-of-flight mass spectrometry (GC-TOFMS) and ultra-performance liquid chromatography-quadrupole TOFMS (UPLC-QTOFMS) metabonomic analytical techniques in combination with bioinformatics and pattern recognition analysis methods to analyze the serum metabolite profiling of hepatitis B virus (HBV)-induced liver cirrhosis patients with minimal hepatic encephalopathy (MHE), to find the specific biomarkers of MHE, to reveal the pathogenesis of MHE, and to determine a promising approach for early diagnosis of MHE. Serum samples of 100 normal controls (NC group), 29 HBV-induced liver cirrhosis patients with MHE (MHE group), and 24 HBV-induced liver cirrhosis patients without MHE [comprising 12 cases of compensated cirrhosis (CS group) and 12 cases of decompensated cirrhosis (DS group)] were collected and employed into GC-TOFMS and UPLC-QTOFMS platforms for serum metabolite detection; the outcome data were then analyzed using principal component analysis and orthogonal partial least squares-discriminant analysis (OPLS-DA). There were no significant differential metabolites between the NC group and the CS group. A series of key differential metabolites were detected. According to the variable influence in projection values and P-values, 60 small-molecule metabolites were considered to be dysregulated in the MHE group (compared to the NC group); 27 of these 60 dysregulated differential metabolites were considered to be the potential biomarkers (see Table 4, marked in bold); 66 small-molecule metabolites were considered to be dysregulated in the DS group (compared to the NC group); 34 of these 66 dysregulated differential metabolites were considered to be the potential biomarkers (see Table 5, marked in bold). According to the fold-change values, 9 of these 27 metabolites, namely valine, oxalic acid, erythro-sphingosine, 4,7,10,13,16,19-docosahexaenoic acid, isoleucine, allo-isoleucine, thyroxine, rac-octanoyl carnitine, and tocopherol (vitamin E), were downregulated in the MHE group (compared to the NC group); the other 18, namely adenine, glycochenodeoxycholic acid, fucose, allothreonine, glycohyocholic acid, glycoursodeoxycholic acid, tyrosine, taurocheno-deoxycholate, phenylalanine, 2-hydroxy-3-methyl-butanoic acid, hydroxyacetic acid, taurocholate, sorbitol, rhamnose, tauroursodeoxycholate, tolbutamide, pyroglutamic acid, and malic acid, were upregulated; 6 of these 34 metabolites were downregulated in the DS group (compared to the NC group), and the other 28 were upregulated, as shown in Table 5. (a) GC-TOFMS and UPLC-QTOFMS metabonomic analytical platforms can detect a range of metabolites in the serum; this might be of great help to study the pathogenesis of MHE and may provide a new approach for the early diagnosis of MHE. (b) Metabonomics analysis in combination with pattern recognition analysis might have great potential to distinguish the HBV-induced liver cirrhosis patients who have MHE from the normal healthy population and HBV-induced liver cirrhosis patients without MHE.

The role of butyrylcholinesterase in the regulation of cognitive dysfunction in minimal hepatic encephalopathy: A potential blood marker of disease evolution.

Patients with cirrhosis commonly experience minimal hepatic encephalopathy (MHE), and alterations in neurotransmitters have been thought to be related to cognitive function. However, the relationship between alterations in peripheral and central butyrylcholinesterase (BuChE) with MHE disease progression remains unknown. As such, this study was designed to investigate potential changes in peripheral and central BuChE activity and their effects on cognitive function in the context of MHE. We enrolled 43 patients with cirrhosis secondary to hepatitis B, 20 without MHE and 23 with MHE, and 25 with healthy controls (HC). All the selected subjects underwent resting-state functional MRI, and the original images were processed to obtain the regional homogeneity (ReHo) brain maps. Thereafter, the correlation of BuChE activity with ReHo, number connection test of type A (NCT-A), and digital symbol test (DST) scores with MHE patients were analyzed using Person correlation analysis. Meanwhile, we purchased 12 Sprague-Dawley (SD) rats and divided them into an experimental group (n = 6) and a control group (n = 6). The rats in the experimental group were intraperitoneally injected with thioacetamide (TAA) to prepare MHE model rats. After modeling, we used the Morris water maze (MWM) and elevated plus maze (EPM) to assess the cognition function and exploratory behavior of all rats. The activity of serum, hippocampus, and frontal lobe tissue BuChE was detected by ELISA. BuChE activity gradually decreased among the HC, patients with cirrhosis, and MHE groups (all P < 0.01). We observed a linear correlation between serum BuChE and NCT-A and DST scores in MHE patients (all P < 0.01). We noted that BuChE activity can negatively correlate with ReHo values in the left middle temporal gyrus and left inferior temporal gyrus, and positively correlate with ReHo values in the right inferior frontal gyrus, and also found that the peripheral BuChE activity of MHE rats was significantly lower than their control counterparts, and the BuChE activity in frontal lobe extracts was significantly higher than the control rats (all P < 0.05). The altered activity of BuChE may contribute to cognitive impairment in MHE patients, which may be a potential biomarker of disease evolution in the context of MHE.

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.

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.

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.

Oral magnesium sulphate administration in rats with minimal hepatic encephalopathy: NMR-based metabolic characterization of the brain

To investigate the metabolic changes in rats with minimal hepatic encephalopathy (MHE) treated with oral magnesium sulphate administration. A total of 30 Sprague-Dawley rats were divided into a control group and MHE group (further divided into an MHE group and an MHE-Mg group treated with oral administration of 124 mg/kg/day magnesium sulphate). Morris water maze (MWM), Y maze and narrow beam walking (NBW) were used to evaluate cognitive and motor functions. Brain manganese and magnesium content were measured. The metabolic changes in rats with MHE were investigated using hydrogen-nuclear magnetic resonance. Metabolomic signatures were identified with enrichment and pathway analysis. A significantly decreased number of entries into the MWM within the range of interest, longer latency and total time during NBW, and higher brain manganese content were found in rats with MHE. After magnesium sulphate treatment, the rats with MHE had better behavioural performance and lower brain manganese content. The 25 and 26 metabolomic signatures were identified in the cortex and striatum of rats with MHE. The pathway analysis revealed alanine, aspartate and glutamate metabolism as the major abnormal metabolic pathways associated with these metabolomic signatures. Alanine, aspartate and glutamate metabolism are major abnormal metabolic pathways in rats with MHE, which could be restored by magnesium sulphate treatment.

The Role of Helicobacter Pylori Eradication on the Pathogenesis of Minimal Hepatic Encephalopathy in Egyptian Patients with Liver Cirrhosis

Abstract Background Hepatic Encephalopathy (HE) is defined as alteration of mental state in the absence of other causes of encephalopathy due to liver failure and/or abnormal shunting of blood from portal to systemic circulation often accompanied by elevated blood ammonia. Objectives The aim of this study was to determine the relation between the Helicobacter pylori infectionand minimal hepatic encephalopathy (MHE) in cirrhotic patients and to assess the outcome after treatment of H. pylori. Patients and Methods This study was can•ied out at Egyptian Railway Medical Centre at the in-patients section at Gastroenterology and Hepatology Medicine Department with chronic liver disease who agreed to participate in the study. After performing the psychometric tests the patients were allocated in one of the two groups according to test results: Group I: consisted of 30 consecutive patients who have chronic liver disease and presented with evidence of Minimal hepatic encephalopathy (MHE), as recognized by positive psychometric tests, Group Il: included 30 consecutive patients who presented with chronic liver disease and did not have Minimal hepatic encephalopathy, as confirmed by negative psychometric test. Results In this study a significant reduction was found in blood ammonia levels in MHE and non- MHE after triple-drug anti-H. pylori treatment (p &amp;lt; 0.001). This reduction was more marked in patients with MHE group compared to non-MHE group with % improvement in ammonia level 26.1 ± 8.36 umol/L and 17.79 ± 7.308 for MHE and non-MHE respectively. This finding indicates that H. pylori may contribute to the development of hyperammonemia in patients with liver disease and MHE. The role of H. pylori in the pathogenesis of hyperammonemia has been shown in previous studies which showed a reduction in blood ammonia levels after eradication of H.pylori infection. Conclusion Helicobacter Pylori infection was more prevalent in patients with MHE than without MHE. Serum arnrnonia levels were significantly higher in MHE patients than without MHE and even higher in H.pylori positive patients than without H.pylori infection. Helicobacter Pylori eradication treatment significantly improves ammonia levels, results of psychometric tests and improves manifestations of MHE.

Whole brain atlas-based diffusion kurtosis imaging parameters for evaluation of minimal hepatic encephalopathy.

Minimal hepatic encephalopathy (MHE) has no recognizable clinical symptoms, but patients have cognitive and psychomotor deficits. Hyperammonemia along with neuroinflammation lead to microstructural changes in cerebral parenchyma. Changes at conventional imaging are detected usually at the overt clinical stage, but microstructural alterations by advanced magnetic resonance imaging techniques can be detected at an early stage. Whole brain diffusion kurtosis imaging (DKI) data acquired at 3T was analyzed to investigate microstructural parenchymal changes in 15 patients with MHE and compared with 15 age- and sex-matched controls. DKI parametric maps, namely kurtosis fractional anisotropy (kFA), mean kurtosis (MK), axial kurtosis (AK) and radial kurtosis (RK), were evaluated at 64 white matter (WM) and gray matter (GM) regions of interest (ROIs) in the whole brain and correlated with the psychometric hepatic encephalopathy score (PHES). The MHE group showed a decrease in kFA and AK across the whole brain, whereas MK and RK decreased in WM ROIs but increased in several cortical and deep GM ROIs. These alterations were consistent with brain regions involved in cognitive function. Significant moderate to strong correlations (-0.52 to -0.66; 0.56) between RK, MK and kFA kurtosis metrics and PHES were observed. DKI parameters show extensive microstructural brain abnormalities in MHE with minor correlation between the severity of tissue damage and psychometric scores.

Evaluation of different diagnostic modalities of minimal hepatic encephalopathy in cirrhotic patients: case-control study.

IntroductionMinimal hepatic encephalopathy (MHE) represents one of the most overlooked complications of liver cirrhosis.Aim of the studyTo compare the utility and efficacy of different MHE diagnostic modalities.Material and methodsThis case-control study was conducted on hepatitis C virus (HCV)-related compensated cirrhotic patients. The Psychometric Hepatic Encephalopathy Score (PHES) was used to assign patients to MHE and controls. All patients were subjected to plasma ammonia, serum 3-nitrotyrosine (3-NT), critical flicker frequency (CFF), and the modified inhibitory control test (ICT).ResultsCFF was significantly lower in the control group (38.5, 40 Hz, p = 0.003). The unweighted lures on ICT were 8.7, 4.9 in MHE and controls (p < 0.001). Moreover, ammonia was higher in the MHE group (89, 61.5 µmol/l, p < 0.001). 3-NT was also higher in the MHE group (31.5, 13.7 nmol/l, p < 0.001) respectively. CFF at cutoff < 39 Hz had sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 57.5%, 77.5%, 71.9% and 64.6%, respectively; in modified ICT, at cutoff > 5 unweighted lures the values were 87.5%, 80%, 81.4% and 86.5%, respectively; in ammonia, at cutoff ≥ 76.45 µmol/l the values were 65%, 72.5%, 70.3% and 67.4%, respectively; for 3-NT at cutoff ≥ 14.15 nmol/l the values were 85%, 82.5%, 82.9% and 84.6%, respectively. The accuracy for MHE diagnosis was 67.5%, 83.3%, 68.8%, 83.8% relying on CFF, 3-NT, ammonia, and ICT respectively. On multivariate analysis, CFF < 39 Hz (OR = 10.2, p = 0.04), modified ICT > 5 unweighted lures (OR = 43.2, p = 0.002), and serum 3-NT levels ≥ 14.15 nmol/l (OR = 50.4, p < 0.001) were independent predictors of MHE.Conclusions3-NT and ICT are advantageous to reveal MHE in compensated liver cirrhosis, while CFF can be only used as adjuncts, with humble merits of ammonia.

Interaction of Manganese and Ammonia in the Brain of Hepatic Encephalopathy Rats

Background: Both ammonia and manganese (Mn) play a key role in the pathogenesis of hepatic encephalopathy (HE) and cause similar morphological and functional changes in astrocytes. Objectives: To investigate the interaction between brain Mn and ammonia in HE rats. Methods: Three rat models of minimal HE (MHE), chronic manganism (CHM), and chronic hyperammonemia (CHA) were constructed. A total of 48 Sprague-Dawley rats were divided into one control group (n = 6), MHE groups (n = 18, among which six rats were used to evaluate the MHE model), CHM groups (n = 12), and CHA groups (n = 12). The CHM, CHA, and the rest of MHE rats were randomly divided further into two subgroups, according to the MgSO4 treatment (oral administration of 496 mg/kg/day for seven weeks): MHE-7W and MHE + Mg-7W; CHM-7W and CHM + Mg-7W; and CHA-7W and CHA + Mg-7W, respectively. Rats’ blood ammonia, brain Mn, glutamine synthetase (GS), and glutamine (GLN) levels were measured and compared among groups. Results: Significantly higher brain Mn content in MHE-7W and CHM-7W rats, higher blood ammonia levels, brain GS activity, and GLN content were observed in MHE-7W, CHM-7W, and CHA-7W rats than in control rats. After MgSO4 treatment for seven weeks, significantly lower brain Mn content, blood ammonia levels, and GLN content were observed in MHE, CHM, and CHA rats. Conclusions: Our study showed that brain Mn accumulation could increase brain ammonia levels, while the accumulation of brain ammonia had no effect on the content of brain Mn.

Aberrant brain structural network and altered topological organization in minimal hepatic encephalopathy.

We aimed to investigate the multilevel impairments of brain structural network in patients with minimal hepatic encephalopathy (MHE). Twenty-two patients with MHE and 22 well-matched healthy controls (HC) underwent structural magnetic resonance imaging (MRI) brain scans and neuropsychological evaluations. Individual brain structural networks were constructed using diffusion tensor imaging. Comparing with HC, we investigated the possible impairments of brain structural network in MHE, by applying graph-theory approaches to analyze the topological organization at global, modular, and local levels. The correlations between altered brain structural network and neuropsychological tests scores and venous ammonia levels were also examined in MHE patients. In the MHE group, small-worldness showed significant decrease and normalized characteristic path length showed increase at the global level. In the modular section, six modules were identified. The inter-modular connective strengths showed significant increase between modules 2 and 4 and between modules 4 and 5. The results of node analysis showed similar hub distributions in the MHE and HC groups except for the right postcentral gyrus, which was only found in the MHE group. No significant differences were found in connective strength of edges between MHE and HC groups using network-based statistics. The altered brain structural networks with reduced network integration and module segregation were demonstrated in patients with MHE. The dysconnectivity of brain structural network could provide an explanation for the brain dysfunctions of MHE.

Animal Naming Test - a simple and accurate test for diagnosis of minimal hepatic encephalopathy and prediction of overt hepatic encephalopathy.

Aim of the studyMinimal hepatic encephalopathy (MHE) is the mildest form in the spectrum of hepatic encepha-lopathy (HE). We compared the usefulness of the Psychometric Hepatic Encephalopathy Score (PHES) and Animal Naming Test (ANT) for the diagnosis of MHE and the prediction of the development of overt episodes of HE.Material and methods103 consecutive patients with liver cirrhosis without overt HE were subjected to PHES and ANT evaluation. The receiver-operating characteristic curve was used to determine the optimum cut-off of the ANT value for the diagnosis of MHE.ResultsThirty-seven (35.9%) patients had MHE as assessed by altered PHES. ANT (< 14) was positive in 36 (34.95%) patients with MHE with a sensitivity of 89.19% and specificity of 95.7%, positive predictive value (PPV) of 91.67%, negative predictive value (NPV) of 94.03% and diagnostic accuracy of 93.20%. The area under the curve for diagnosis of MHE was 0.978 (95% CI: 0.954-1.0). MHE patients had significantly lower ANT as compared to non-MHE patients and controls (10.81 ±0.324 vs. 15.27 ±0.147 vs. 15.78 ±0.192, respectively, p = 0.01). ANT correlated with PHES (r = 0.752, p = 0.001) and also with Child-Pugh (r = –0.408, p = 0.001) and MELD (r = –0.318, p = 0.001) scores. During follow-up, 14 patients in the MHE group and 4 in the non-MHE group developed overt episodes of HE (p = 0.001).ConclusionsANT is simple and accurate for the diagnosis of MHE and prediction of overt episodes of HE in patients with cirrhosis and correlates well with the Child-Pugh and MELD scores.

P: 28 Decreased Mean Kurtosis in the Putamen Is a Diagnostic Feature of Minimal Hepatic Encephalopathy in Patients With Cirrhosis

BACKGROUND: To prevent development of overt hepatic encephalopathy, early intervention for minimal hepatic encephalopathy (MHE) based on accurate diagnosis is essential. This study evaluated to investigate whether magnetic resonance diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) could detect brain microstructure abnormalities in MHE. The aim was to confirm whether brain microstructure abnormalities detected by magnetic resonance imaging were used as diagnosis of MHE. METHODS: Thirty-two subjects were prospectively examined with a 3-T MR scanner. Tract-based spatial statistics and region of interest analyses of diffusion imaging were performed to compare mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) values between patients with/without minimal hepatic encephalopathy. Diagnostic performance for detection of MHE was assessed with the receiver operating characteristic analysis. RESULTS: Ten subjects were diagnosed as MHE by neuropsychological testing. After exclusion of unsuitable subjects, we analyzed 9 subjects with MHE and 14 subjects without MHE. There were no significant differences in the sex, age, and etiology of liver cirrhosis (alcohol/HCV/NAFLD; 4/3/2 vs 7/3/4, P = 0.87) in the MHE group and non-MHE group. In TBSS, compared with FA and MD, MK detected the broadest area with significant changes in the white matter of patients with MHE (MK, 54.8%; FA, 34.3%; MD, 4.0%, respectively). Regarding ROI analysis in the basal ganglia, FA values of the caudate nucleus (CN), putamen (Put), and globus pallidus (GP) were significantly lower in the MHE group (0.15, 0.19, and 0.29, respectively) when compared with the non-MHE group (0.16, 0.21, and 0.32, respectively) (P = 0.012, 0.002, and 0.0001, respectively). In contrast, MD values in the basal ganglia showed no apparent differences between the groups. Subsequently, we performed ROC analysis on the sites where significant differences were found in the ROI analysis. Among the metrics, MK values of the Put achieved AUROC of 0.90, and sensitivity, specificity, positive predictive value, and negative predictive value of more than 80% (0.89, 0.86, 0.80, and 0.92, respectively) between the MHE and non-MHE groups. In conclusion, mean kurtosis on the putamen was a useful finding to distinguish patients with MHE among subjects with liver cirrhosis. CONCLUSIONS: DKI detects changes in the cerebral white matter and basal ganglia regions of the patients with MHE more sensitively than DTI. MK values in the putamen can be a useful marker for diagnosing MHE from cirrhotic patients without MHE.

P: 63 Animal Naming Test Is Highly Accurate and Reliable for Diagnosis of Minimal Hepatic Encephalopathy in Outpatients With Cirrhosis

BACKGROUND: Background and Aims: Minimal hepatic encephalopathy (MHE) is the mildest form in the spectrum of hepatic encephalopathy that impairs health-related quality of life. PHES remains the gold standard for the diagnosis of this condition. Animal naming test (ANT) is reliable and sensitive tool for diagnosis of MHE and can also predict overt episodes of HE. We compared usefulness of PHES and ANT for the diagnosis of MHE and for the prediction of the development of overt episodes of HE. METHODS: Between July 2017 to June 2018, one hundred and three consecutive patients with liver cirrhosis without overt HE were subjected to PHES and ANT evaluation. MHE was diagnosed when the PHES was ≤−5. Receiver-operating characteristic (ROC) curve was used to determine the optimum cut-off of ANT value for the diagnosis of MHE. The best sensitivity and specificity was found at &lt;14. Patients were followed-up every 3-6 months till October 2018. RESULTS: Thirty-seven (35.9%) patients had MHE as assessed by altered PHES. ANT (&lt;14) was present in 36 (34.95%) patients with MHE with sensitivity of 89.19% and specificity of 95.7%, PPV of 91.67%, NPV of 94.03% and diagnostic accuracy of 93.20%. The area under the curve for diagnosis of MHE was 0.978 (95% CI 0.954–1.0). MHE patients had significantly lower ANT as compared to non MHE patients and controls (10.81 ± 0.324 vs 15.27 ± 0.147 vs 15.78 ± 0.192, respectively, P = 0.01). MHE patients had lower hand grip strength compared to non-MHE patients and the control group (Males: 26 vs 30 vs 38, Females 25 vs 28 vs 28, P &gt; 0.05). PHES significantly correlated with Child-Pugh (r = −0.421, P = 0.001) and model for end-stage liver disease (MELD) (r = −0.345, P = 0.001) scores. ANT correlated with PHES (r = 0.752, P = 0.001) and also with Child-Pugh (r = −0.408, P = 0.001) and MELD (r = −0.318, P = 0.001) scores. During follow-up, 14 patients in MHE group and 4 in non-MHE group developed overt episodes of HE (P = 0.001). Out of 37 patients with abnormal PHES 14 patients developed overt HE on follow up and out of 36 patients with abnormal ANT 14 patients developed overt HE on follow up. 33 patients had both PHES and ANT abnormal. 4 patients had PHES abnormal and ANT normal. 3 patients had PHES normal and ANT abnormal. CONCLUSIONS: ANT is a highly accurate and reliable test for the diagnosis of MHE and prediction of overt episodes of HE in outpatients of cirrhosis as compared to PHES and correlates well with the Child-Pugh and MELD scores.

Altered Topological Properties of Gray Matter Structural Covariance Networks in Minimal Hepatic Encephalopathy.

Background and Aims: Liver cirrhosis commonly induces brain structural impairments that are associated with neurological complications (e.g., minimal hepatic encephalopathy (MHE)), but the topological characteristics of the brain structural network are still less well understood in cirrhotic patients with MHE. This study aimed to conduct the first investigation on the topological alterations of brain structural covariance networks in MHE.Methods: This study included 22 healthy controls (HCs) and 22 cirrhotic patients with MHE. We calculated the gray matter volume of 90 brain regions using an automated anatomical labeling (AAL) template, followed by construction of gray matter structural covariance networks by thresholding interregional structural correlation matrices as well as graph theoretical analysis.Results: MHE patients showed abnormal small-world properties of the brain structural covariance network, i.e., decreased clustering coefficient and characteristic path length and lower small-worldness parameters, which indicated a tendency toward more random architecture. In addition, MHE patients lost hubs in the prefrontal and parietal regions, although they had new hubs in the temporal and occipital regions. Compared to HC, MHE patients had decreased regional degree/betweenness involving several regions, primarily the prefrontal and parietal lobes, motor region, insula and thalamus. In addition, the MHE group also showed increased degree/betweenness in the occipital lobe and hippocampus.Conclusion: These results suggest that MHE leads to altered coordination patterns of gray matter morphology and provide structural evidence supporting the idea that MHE is a neurological complication related to disrupted neural networks.

Abnormal Regional Homogeneity and Functional Connectivity of Baseline Brain Activity in Hepatitis B Virus-Related Cirrhosis With and Without Minimal Hepatic Encephalopathy.

Background and Aims: Abnormalities in neural activity have been reported in cirrhosis with minimal hepatic encephalopathy (MHE). However, little is known about the neurophysiological mechanisms in this disorder. We aimed to investigate the altered patterns of regional synchronization and functional connections in hepatitis B virus-related cirrhosis (HBV-RC) patients with and without MHE using both regional homogeneity (ReHo) and region of interest (ROI)-based functional connectivity (FC) computational methods.Methods: Data of magnetic resonance imaging scans were collected from 30 HBV-RC patients with MHE, 32 HBV-RC patients without MHE (NMHE) and 64 well-matched controls. Several regions showing differences in ReHo after one-way analysis of variance (ANOVA) were defined as ROIs for FC analysis. Next, post hoc t-tests were applied to calculate the group differences in ReHo and FC (false discovery rate (FDR) correction, p < 0.05). Correlations between clinical variables and the altered ReHo and FC were then assessed in patient groups.Results: Across three groups, significant ReHo differences were found in nine ROI regions mainly within the visual network (VN), dorsal attention network (DAN), somatomotor network (SMN), fronto parietal control (FPC) network and thalamus. Compared with healthy controls (HC), the MHE group exhibited abnormal FC mainly between the right calcarine (CAL.R) and middle frontal gyrus (MFG.L)/right thalamus. The MHE patients showed increased FC between the MFG.L and CAL.R compared to NMHE patients. Disease duration of MHE patients was positively correlated with increased mean ReHo values in the right fusiform gyrus (FFG); psychometric hepatic encephalopathy score (PHES) test scores were negatively correlated with increased FC between MFG.L and CAL.R and positively correlated with reduced FC between the CAL.R and THA.R. For NMHE patients, the mean ReHo values in the right frontal pole were positively correlated with disease duration and positively correlated with the PHES scores.Conclusion: Our results exhibited that the functional brain modifications in patients with and without MHE are characterized by compound alterations in local coherence and functional connections in the VN, SMN, DAN, FPC networks and thalamus by using a combination of ReHo and ROI-based FC analysis. These functional imaging changes are correlated with disease duration/PHES. This study helped us gain a better understanding of the features of brain network modifications in cirrhosis.