Minimal Hepatic Encephalopathy Research Articles

Sleep disturbance in patients with cirrhosis and transjugular intrahepatic portosystemic shunt

BackgroundSleep disturbance (SD) is a common occurrence in individuals with cirrhosis and significantly impacts their quality of life. Datas regarding post transjugular intrahepatic portosystemic shunt (TIPS) SD are scarce. This study aimed to explore the incidence and outcomes of post-TIPS SD.MethodsFrom August 2018 to November 2019, 73 patients who underwent TIPS were prospectively recruited for the study. Sleep quality was evaluated via the Pittsburgh Sleep Quality Index (PSQI), and the presence of hepatic encephalopathy was evaluated according to the West Haven criteria before and after the TIPS procedure.ResultsNineteen patients (26%) experienced new-onset SD after TIPS, with a median latency of 67 (40–98) days from the procedure. The median time from TIPS creation to occurrence was 67 (40–98) days. Minimal hepatic encephalopathy (MHE) post-TIPS emerged as an independent predictor of SD, with an odds ratio of 3 (95% CI: 1.04–8.78, P = 0.046). Notably, five of the six (83%) patients with SD experienced improvement after being administered eszopiclone. Ten of the thirteen (77%) patients with SD improved spontaneously without treatment. Furthermore, the prevalence of MHE was significantly greater among patients with SD than among those without SD (58% vs. 31%, P = 0.04).ConclusionsSD is prevalent in patients who undergo TIPS. MHE is an independent risk factor for the development of SD post-TIPS. Eszopiclone may be a safe and effective treatment option for patients with SD after TIPS. The study was registered with ClinicalTrials.gov under the identifier NCT03685994, with a registration date of September 23, 2018.

Extracellular Vesicles from Mesenchymal Stem Cells Reverse Neuroinflammation and Restore Motor Coordination in Hyperammonemic Rats.

Cirrhotic patients may show minimal hepatic encephalopathy (MHE), with mild cognitive impairment and motor deficits. Hyperammonemia and inflammation are the main contributors to the cognitive and motor alterations of MHE. Hyperammonemic rats reproduce these alterations. There are no specific treatments for the neurological alterations of MHE. Extracellular vesicles from mesenchymal stem cells (MSC-EVs) are promising to treat inflammatory and immune diseases. We aimed to assess whether treatment of hyperammonemic rats with MSC-EVs reduced neuroinflammation in cerebellum and restored motor coordination and to study the mechanisms involved. The effects of MSC-EVs were studied in vivo by intravenous injection to hyperammonemic rats and ex vivo in cerebellar slices. Motor coordination was analyzed using the beam walking test. Effects on neuroinflammation were assessed by immunohistochemistry, immunofluorescence and Western blot. Injection of MSC-EVs reduced microglia and astrocytes activation in cerebellum and restored motor coordination in hyperammonemic rats. Ex vivo experiments show that MSC-EVs normalize pro-inflammatory factors, including TNFα, NF-kB activation and the activation of two key pathways leading to motor incoordination (TNFR1-NF-kB-glutaminase-GAT3 and TNFR1-CCL2-BDNF-TrkB-KCC2). TGFβ in the EVs was necessary for these beneficial effects. MSC-EVs treatment reverse neuroinflammation in the cerebellum of hyperammonemic rats and the underlying mechanisms leading to motor incoordination. Therapy with MSC-EVs may be useful to improve motor function in patients with MHE.

Alteration of dynamical degree centrality in brain functional network and its association with metabolic disorder in minimal hepatic encephalopathy.

To investigate dynamical degree centrality (dDC) alteration and its association with metabolic disturbance and cognitive impairment in minimal hepatic encephalopathy (MHE). Fifty-eight cirrhotic patients (22 with MHE, 36 without MHE [NHE]) and 25 healthy controls underwent resting-state functional magnetic resonance imaging, 1H-magnetic resonance spectroscopy, and neurocognitive examination based on the Psychometric Hepatic Encephalopathy Score (PHES). We obtained metabolite ratios in the bilateral posterior cingulate cortex and precuneus, including glutamate and glutamine (Glx)/total creatine (tCr), myo-inositol (mI)/tCr, total choline/tCr, and N-acetyl aspartate/tCr. For each voxel, degree centrality was calculated as the sum of its functional connectivity with other voxels in the brain; and sliding-window correlation was used to calculate dDC per voxel. We observed a stepwise increase in Glx/tCr and a decrease in mI/tCr from NHE to MHE. The intergroup dDC differences were observed in the bilateral posterior cingulate cortex and precuneus (region of interest [ROI1]), bilateral superior-medial frontal gyrus and anterior cingulate cortex (ROI2), and left caudate head. The dDC in ROI2 (r = 0.450, P < 0.001) and mI/tCr (r = 0.297, P = 0.024) was correlated with PHES. Significant correlations were found between dDC in ROI1 and Glx/tCr (r = - 0.413, P = 0.001) and mI/tCr (r = 0.554, P < 0.001). The dDC in ROI2, Glx/tCr, and mI/tCr showed potential for distinguishing NHE from MHE (areas under the curve = 0.859, 0.655, and 0.672, respectively). Our findings suggested dynamic brain network disorganization in MHE, which was associated with metabolic derangement and neurocognitive impairment.

Structural and functional neural correlates of sensorimotor deficits in progression of hepatic encephalopathy

Hepatic encephalopathy (HE) is a neurological condition that occurs as a complication of liver dysfunction that involves sensorimotor symptoms in addition to cognitive and behavioral changes, particularly in cases of severe liver disease or cirrhosis. Previous studies have reported spatially distributed structural and functional abnormalities related to HE, but the exact relationship between the structural and functional alterations with respect to disease progression remains unclear. In this study, we performed surface-based cortical thickness comparisons and functional connectivity (FC) analyses between three cross-sectional groups: healthy controls (HC, N=51), patients with minimal hepatic encephalopathy (MHE, N=50), patients with overt hepatic encephalopathy (OHE, N=51). In addition to the distributed cortical thinning that is extensively thought to be associated with cognitive decline in HE, we found significant cortical thickening in the left parahippocampal gyrus cortex in the OHE group (p<0.001, p=0.009) as compared to the HC and MHE group respectively, which is further corroborated by the significant correlation between the cortical thickness and digit symbol test (DST) scores. Furthermore, the decreased FC between the right postcentral gyrus and several sensory regions (bilateral somatosensory and visual cortices) was found to be significant in MHE patients as compared to the HC group. Our results revealed cross-sectional structural and functional variations concerning disease progression across different subsystems (e.g., visual, motor and sensory), providing evidence that can potentially explain the mechanisms underlying the sensorimotor and cognitive deficits related to HE.

S1788 Prior Overt Hepatic Encephalopathy and Diagnosis of Minimal HE Significantly Adds to Risk Prediction for MELD3.0 in Patients With Cirrhosis

S1788 Prior Overt Hepatic Encephalopathy and Diagnosis of Minimal HE Significantly Adds to Risk Prediction for MELD3.0 in Patients With Cirrhosis

Validation of EncephalApp Stroop Test for Diagnosing Minimal Hepatic Encephalopathy in the Romanian Population.

Minimal hepatic encephalopathy (MHE) represents the mildest form of hepatic encephalopathy. MHE has been associated with impairment of quality of life and job performance, and is a major cause of premature retiring in cirrhotic patients. However, MHE is usually overlooked by most physicians, due to its asymptomatic nature. We aim to present our experience with the EncephalApp Stroop Test for diagnosing MHE in cirrhotic patients. We also want to establish if Stroop test performance correlates with age, educational level, liver disease severity (as assessed by the MELD and Child-Pugh scores), duration of disease, previous episodes of overt hepatic encephalopathy, and other relevant clinical or laboratory parameters. A cross-sectional observational single-center study, in which 100 adult patients diagnosed with liver cirrhosis were evaluated for the presence of MHE by using the EncephalApp Stroop Test. In parallel, 45 healthy adult controls without liver cirrhosis were recruited and tested under the same conditions as the patients. There were no age-related differences between the two groups (p=0.6). Stroop test performance of the controls (143.1 ± 20.8 seconds) was significantly better than that of the patients (171.9 ± 33.3 seconds) (p<0.0001). Stroop test results correlated with the MELD (R=0.28, p=0.005) and Child-Pugh scores (R=0.2, p=0.04). There was a positive correlation between Stroop test results and age in patients (R=0.45, p<0.0001) and controls (R=0.75, p<0.0001). Stroop test performance was not influenced by the duration of liver disease (p=0.4) or prior episodes of overt hepatic encephalopathy (p=0.25). Gender and level of education did not have an impact on Stroop test results. Alcoholic liver disease, diabetes mellitus, hyperglycemia, anemia and hyponatremia were associated with poorer performances. EncephalApp Stroop Test proved to be a quick and simple method for diagnosing minimal hepatic encephalopathy in the hospital setting. Test performance was influenced primarily by age, but also by liver disease severity, anemia, hyponatremia and hyperglycemia.

A nomogram prediction model for individualized prediction of the risk of covert (minimal) hepatic encephalopathy occurrence in patients with liver cirrhosis

Objective: To construct an individualized nomogram prediction model for predicting the risk of the occurrence of covert hepatic encephalopathy (CHE) in patients with liver cirrhosis. Methods: 325 cases of liver cirrhosis admitted from January 2020 to December 2022 were selected as the study subjects. Patients were divided into training (n=213) and validation (n=112) sets using a cluster randomization method. The risk factors for CHE occurrence in patients with cirrhosis in the training set were analyzed by univariate and multivariate logistic regression. A prediction model related to the nomogram was established. Results: Independent risk factors for the occurrence of CHE in patients with cirrhosis were a history of hepatic encephalopathy, co-infection, gastrointestinal bleeding, severe ascites, prothrombin time ≥16 seconds, high total bilirubin, and high blood ammonia levels (P<0.05). Nomogram model validation results: The model had a net benefit for the training and validation sets, with C-indices of 0.830 (95%CI: 0.802-0.858) and 0.807 (95%CI: 0.877-0.837), respectively, within the range of 0-96%. The calibration curves of both sets were evenly close to the ideal curves. The AUCs for the ROC curves in both sets were 0.827 (95%CI: 0.796-0.858) and 0.811 (95%CI: 0.787-0.836), respectively. Conclusion: Patients with cirrhosis have many risk factors for CHE occurrence. The nomogram model constructed based on these risk factors possesses a good predictive value for assessing CHE occurrence in cirrhotic patients.

HEAR-MHE study: Automated speech analysis identifies minimal hepatic encephalopathy and may predict future overt hepatic encephalopathy.

Hepatic encephalopathy (HE) is a major cause of poor quality of life in patients with cirrhosis. A simple diagnostic test to identify minimal HE (MHE) and predict future overt HE (OHE) is lacking. We aimed to evaluate if analysis of speech patterns using a modern speech platform: 1) correlates with validated HE tests, 2) correlates with MHE, and 3) predicts future OHE. In a two-center prospective cohort study of 200 outpatients with cirrhosis and 50 controls, patients underwent baseline speech recording and validated HE diagnostic testing with psychometric HE score (PHES). Patients were followed for 6 months to identify episodes of OHE. 752 speech variables were extracted using an automated speech analysis platform, reflecting the acoustic, lexical, and semantic aspects of speech. Patients with cirrhosis were median 63 years old (IQR 54, 68), 49.5% (99) were female. Over 100 speech variables were significantly associated with PHES (p <0.05 with FDR adjustment). A three-variable speech model (two acoustic, one speech tempo variable) was similar to animal naming test in predicting MHE (AUC 0.76 vs. 0.69; p=0.11). Adding age and MELD-Na improved accuracy of the speech model (AUC: 0.82). A combined clinical-speech model ("HEAR-MHE model") predicted time to OHE with a concordance of 0.74 (p=0.06). Automated speech analysis highly correlated with validated HE tests, associated with MHE, and may predict future OHE. Future research is needed to validate this tool and to understand how it can be implemented in clinical practice.

Role of peripheral inflammation in minimal hepatic encephalopathy.

Many patients with liver cirrhosis show minimal hepatic encephalopathy (MHE) with mild cognitive impairment (MCI) and motor alterations that reduce their quality of life. Some patients with steatotic liver disease also suffer MCI. To design treatments to improve MHE/MCI it is necessary to understand the mechanisms by which liver disease induce them. This review summarizes studies showing that appearance of MHE/MCI is associated with a shift in the immunophenotype leading to an "autoimmune-like" form with increased pro-inflammatory monocytes, enhanced CD4 T and B lymphocytes activation and increased plasma levels of pro-inflammatory cytokines, including IL-17, IL-21, TNFα, IL-15 and CCL20. The contribution of peripheral inflammation to trigger MHE is supported by studies in animal models and by the fact that rifaximin treatment reverses MHE in around 60% of patients in parallel with reversal of the changes in peripheral inflammation. MHE does not improve in patients in which peripheral inflammation is not improved by rifaximin. The process by which peripheral inflammation induces MHE involves induction of neuroinflammation in brain, with activation of microglia and astrocytes and increased pro-inflammatory TNFα and IL-1β, which is observed in patients who died with steatotic liver disease (SLD) or liver cirrhosis and in animal models of MHE. Neuroinflammation alters glutamatergic and GABAergic neurotransmission, leading to cognitive and motor impairment. Transmission of peripheral alterations into the brain is mediated by infiltration in brain of extracellular vesicles from plasma and of cells from the peripheral immune system. Acting on any step of the process peripheral inflammation - neuroinflammation - altered neurotransmission may improve MHE.

Fall Risk, Postural Control, Muscle Strength and Cognitive Function in Patients with Liver Cirrhosis

Aim: Falls and fall-related injuries are common in liver cirrhosis. Studies mostly focus on minimal hepatic encephalopathy manifested by cognitive dysfunction as a predisposing factor for increased fall risk and postural instability in this population. Our aim was to investigate fall risk, postural control, muscle strength and cognitive function in patients with liver cirrhosis. Materials and Methods: Twenty-four patients and 24 healthy controls were enrolled in the study. Postural control was assessed using a posturographic system. Fall risk was assessed with Falls Efficacy Scale (FES) and Timed Up and Go Test (TUGT). Lower extremity muscle strength was assessed using a dynamometer. Cognitive function was evaluated with Stroop test. Results: Postural sway velocity (PSV) on foam surface eyes open (FSEO), FES score and TUGT duration were higher in patient group (p

Stroop test, Quickstroop, and the 1-min animal naming test for minimal hepatic encephalopathy diagnosis: A multicenter study in Mexico

Introduction and ObjectivesAlthough the Psychometric Hepatic Encephalopathy Score (PHES) remains the gold standard in diagnosing minimal hepatic encephalopathy (MHE), its complexity limits its application in clinical practice. While more convenient tests, such as the Stroop test, Quickstroop, and the 1-min animal naming test (ANT-1), have emerged, they haven't been validated in our setting. Our objective was to validate these tests in our population. Patients and MethodsThis multicenter, observational, descriptive, and cross-sectional study was conducted in three hospitals in northeastern Mexico. MHE was defined as a PHES <-4. We included patients with cirrhosis aged >15 years without a history of overt hepatic encephalopathy. Data regarding sex, age, education, Child-Pugh/MELD-Na scores, etiology of cirrhosis, diabetes, hypertension, obesity, ascites, and clinically significant portal hypertension was collected. Fisher's exact test, Mann-Whitney U test, and receiver operating characteristic (ROC) curves were used for statistical analysis. ResultsOf the 121 patients included, 35.5 % were diagnosed with MHE. The presence of MHE was significantly associated with education level, years of study, and scores in the Stroop test, Quickstroop, and ANT-1. The AUROC curves were 77.9 %, 74.6 %, and 72.7 % for the Stroop test, Quickstroop, and ANT-1, respectively. The resulting cut-off points were 218.398 (sensitivity: 74 %; specificity: 74 %), 40.535 (sensitivity: 77 %; specificity: 68 %), and <16 animals (sensitivity: 58 %; specificity: 79 %), respectively. ConclusionsThese tests are valid diagnostic tools for detecting MHE in our population. Their simpler use and applicability could increase the early diagnosis of MHE and prompt primary prophylaxis initiation for overt hepatic encephalopathy.

Portosystemic Hepatic Encephalopathy Scores (PHES) differ between Danish and German healthy populations despite their geographical and cultural similarities

Minimal hepatic encephalopathy (MHE) is common in liver cirrhosis and is identified by psychometric tests. The portosystemic hepatic encephalopathy score (PHES) is the most widely used and serves as an inter-study comparator. PHES has not been standardised for use in the Danish population, where German normal values have been applied until now based on the notion that the populations are comparable. This study aimed to evaluate if German PHES normal values can be applied in the Danish population and establish Danish normal values if needed. 200 Danish and 217 German healthy persons underwent Number Connection Test A and B (NCT), Line Tracing Test (LTT), Digit Symbol Test (DST), and Serial Dotting Test (SDT), and based on performance, PHES was calculated. German and Danish PHES performance declined with age in all subtests but more rapidly in Danes. Both German and Danish norms were impacted by gender and education, but to a different extent in the single tests of the test battery. Accordingly, there was a need for specific Danish normal values, which are presented here. Applying the new Danish normal values instead of the German in patients with cirrhosis yielded a lower percentage of out-of-norm performances (58% vs. 66%) and, hence, a lower prevalence of MHE. Danes and Germans perform differently on PHES, and therefore, normal German values cannot be used in Danish patients. Danish normal values are presented here and yield a lower number of ‘out of norm’ performances.

Detection of minimal hepatic encephalopathy in patients with cirrhosis based on the Stroop-CN model (NCRCID-CHESS 2106): aprospective multicenter study.

Minimal hepatic encephalopathy (MHE) has a substantial impact on the clinical outcomes and quality of life (QOL) of patients with cirrhosis. However, timely diagnosis and intervention are challenging due to sophisticated diagnostic methods. In this study, 673 healthy controls and 905 patients with cirrhosis were screened, and 660 healthy controls and 757 patients with cirrhosis, divided into the test (292 patients) and validation (465 patients) cohort, were analyzed after screening. A diagnostic model of the Stroop test (Stroop-CN) was constructed by multivariate linear regression based on the results of healthy controls. The prevalence of MHE and the comparison results with psychometric hepatic encephalopathy score through the Stroop-CN model were stable in the test and validation cohorts. Moreover, the prevalence of MHE remained significantly higher in patients with worse disease conditions marked as high Child-Pugh grades and the Model for End-stage Liver Disease and Sodium (MELD-Na) scores in the test and validation cohort. The EuroQol 5-D questionnaire revealed that patients with MHE had a worse QOL than those without MHE both in the test and validation cohort. In conclusion, an easy and practical Stroop-CN model for MHE diagnosis based on the EncephalApp is established. It is found that a considerable number of Chinese patients with cirrhosis experience MHE, which significantly impacts their QOL.

Elevated serum neurofilament light chain levels are associated with hepatic encephalopathy in patients with cirrhosis.

Increasing evidences implicate vital role of neuronal damage in the development of hepatic encephalopathy (HE). Neurofilament light chain (NfL) is the main frame component of neurons and is closely related to axonal radial growth and neuronal structural stability. We hypothesized that NfL as a biomarker of axonal injury may contribute to early diagnosis of HE. This study recruited 101 patients with liver cirrhosis, 10 healthy individuals, and 7 patients with Parkinson's disease. Minimal hepatic encephalopathy (MHE) was diagnosed using psychometric hepatic encephalopathy score. Serum NfL levels were measured by the electrochemiluminescence immunoassay. Serum NfL levels in cirrhotic patients with MHE were significantly higher than cirrhotic patients without MHE, and increased accordingly with the aggravation of HE. Serum NfL levels were associated with psychometric hepatic encephalopathy score, Child-Pugh score, model for end-stage liver disease score, and days of hospitalization. Additionally, serum NfL was an independent predictor of MHE (odds ratio of 1.020 (95% CI 1.005-1.034); P = 0.007). The discriminative abilities of serum NfL were high for identifying MHE (AUC of 0.8134 (95% CI 0.7130-0.9219); P ˂ 0.001) and OHE (AUC of 0.8852 (95% CI 0.8117-0.9587); P ˂ 0.001). Elevated serum NfL levels correlated with the presence of MHE and associated with the severity of HE, are expected to be a biomarker in patients with cirrhosis. Our study suggested that neuronal damage may play a critical role in the development of HE.

Brain-Derived Neurotrophic Factor as a Potential Diagnostic Marker in Minimal Hepatic Encephalopathy

Abstract Background Based on the etiology, liver cirrhosis is sub-classified into viral hepatitis (hepatitis B, C, and D), due to toxins (alcohol and drugs), autoimmune hepatitis, Cholestatic (primary biliary cholangitis, and primary sclerosing cholangitis), vascular (Budd-Chiari syndrome, sinusoidal obstruction syndrome, and cardiac cirrhosis), and metabolic causes (hemochromatosis, NASH, Wilson disease, alpha-1 antitrypsin deficiency, cryptogenic cirrhosis). Aim of the Work The aim of the current study is to detect Minimal Hepatic Encephalopathy (MHE) among cirrhotic patients of Child C with no or clinically manifest encephalopathy using Brain-Derived Neurotrophic Factor (BDNF) and study the diagnostic value of BDNF serum marker versus Psychometric Hepatic Encephalopathy Score (PHES) in detecting MHE. Patients and Methods 90 patients were enrolled into a clinical cross-sectional study. All patients gave informed written consent. Patients are divided equally into 3 groups, 30 patients each. Patients are either in-patient or out-patients in Ain shams University Hospitals. Group 1 The Examined Group (EG): includes 30 patients diagnosed as hepatitis C, cirrhotic, Child class C with no overt or clinically manifest encephalopathy. Group 2 The Hepatic Encephalopathy Group (HEG): includes 30 patients diagnosed as hepatitis C, cirrhotic, Child class C with overt or clinically manifest encephalopathy. Group 3 The Control Group (CG): includes 30 healthy individuals (volunteers). Results In the present study among the whole sample (n = 90), there was a significant positive correlation between PHES score &amp; BDNF serum level with Hb, platelet count and albumin. While, there was a significant negative correlation between PHES score and BDNF serum level with AST, ALT, total bilirubin, direct bilirubin, INR and Child’s Score. On the other hand, Stawicka et al. 2021, reported that BDNF had a negative correlation with bilirubin (R = –0.35, p = 0.005) and international normalized ratio (INR) (R = –0.37, p = 0.003), and positive with platelets (R = 0.36, p = 0.004), while no associations with age, sex, body mass index (BMI), waist-hip ratio (WHR), creatinine and ammonia. Conclusion MHE constitutes a significant medical problem in a common patient population. Unfortunately, it is often underdiagnosed, likely related to the notion that testing is time consuming requiring highly specialized personnel. Additionally, the term ‘MHE’ may create the impression that this condition has limited impact on patient’s wellbeing; however, it has been shown that MHE has clinical implications on the patient as well as public safety concerns. Diagnosing and treating MHE is difficult owing to the subclinical nature of the disease. The use of Psychometric Hepatic Encephalopathy Score (PHES) and Brain-Derived Neurotrophic Factor could be of great help in early detection of the condition and to give suitable preventive treatment.

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 &lt; 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.

PHES scores have limited impact on the risk of overt HE in patients with minimal HE.

Minimal hepatic encephalopathy, defined by the portosystemic hepatic encephalopathy score (PHES), is associated with a higher risk of subsequent OHE. It remains unclear if there is a stepwise increase in OHE risk with worse PHES results. In this multicenter study, patients with minimal hepatic encephalopathy, as defined by abnormal PHES, were followed for OHE development. In all, 207 patients were included. There was no stepwise increase in OHE risk with worse PHES results. Abnormal PHES is associated with a higher OHE risk, but we found no stepwise increase in OHE risk with worse PHES results below the established cutoff.

Increased levels and activation of the IL-17 receptor in microglia contribute to enhanced neuroinflammation in cerebellum of hyperammonemic rats

BackgroundPatients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with mild cognitive impairment and motor incoordination. Rats with chronic hyperammonemia reproduce these alterations. Motor incoordination in hyperammonemic rats is due to increased GABAergic neurotransmission in cerebellum, induced by neuroinflammation, which enhances TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway activation. The initial events by which hyperammonemia triggers activation of this pathway remain unclear. MHE in cirrhotic patients is triggered by a shift in inflammation with increased IL-17. The aims of this work were: (1) assess if hyperammonemia increases IL-17 content and membrane expression of its receptor in cerebellum of hyperammonemic rats; (2) identify the cell types in which IL-17 receptor is expressed and IL-17 increases in hyperammonemia; (3) assess if blocking IL-17 signaling with anti-IL-17 ex-vivo reverses activation of glia and of the TNFα-TNFR1-S1PR2-CCL2-BDNF-TrkB pathway.ResultsIL-17 levels and membrane expression of the IL-17 receptor are increased in cerebellum of rats with hyperammonemia and MHE, leading to increased activation of IL-17 receptor in microglia, which triggers activation of STAT3 and NF-kB, increasing IL-17 and TNFα levels, respectively. TNFα released from microglia activates TNFR1 in Purkinje neurons, leading to activation of NF-kB and increased IL-17 and TNFα also in these cells. Enhanced TNFR1 activation also enhances activation of the TNFR1-S1PR2-CCL2-BDNF-TrkB pathway which mediates microglia and astrocytes activation.ConclusionsAll these steps are triggered by enhanced activation of IL-17 receptor in microglia and are prevented by ex-vivo treatment with anti-IL-17. IL-17 and IL-17 receptor in microglia would be therapeutic targets to treat neurological impairment in patients with MHE.

Proton pump inhibitor use and risk of hepatic encephalopathy: A multicentre study

Background & AimsData on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting, and data from multicenter studies are scarce. The aim of this study was to dissect the potential association between PPI use and minimal (MHE) and overt HE (OHE). MethodsData from patients with cirrhosis recruited at seven centers across Europe and the US were analyzed. MHE was defined by the Psychometric Hepatic Encephalopathy Score (PHES). PPI use was recorded on the day of testing with PHES. Patients were followed for OHE development and death/liver transplantation (LTx). Results1160 patients with a median MELD of 11 were included (Child-Pugh stages: A 49%/B 39%/C 11%). PPI use was noted in 58% of the patients. Median follow-up time was 18.1 months, during which 230 (20%) developed an OHE episode, and 224 (19%) reached the composite endpoint of death/LTx. In multivariable analyses, PPI use was neither associated with the presence of MHE at baseline nor OHE development during follow-up. These findings were consistent in subgroup analyses of patients with Child-Pugh A or B cirrhosis and after excluding patients with a history of OHE. PPI use was also not associated with a higher risk of OHE, neither in patients with an indication for treatment nor in patients without an indication. ConclusionsPPI use is not associated with a higher risk of HE in patients with liver cirrhosis. On the basis of these findings, a prescription should currently not be prohibited in case of a generally accepted indication. Impact and implicationsData on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting. In this study, PPI use was not associated with a higher risk of minimal HE at baseline or overt HE during follow-up in patients with liver cirrhosis. On the basis of these findings, a prescription of a PPI by a physician should currently not be prohibited in case of a generally accepted indication.

Cравнительная эффективность различных режимов терапии рифаксимином-α у пациентов с минимальной печеночной энцефалопатией и циррозом печени (анализ шестимесячного наблюдения)

Minimal hepatic encephalopathy (MHE) is the earliest and mildest form of hepatic encephalopathy (HE), however, its occurrence is associated with an unfavorable prognosis for cirrhosis in patients in this category. MHE increases the number of falls, injuries, patients getting into road traffic accidents, and accidents, which has serious consequences for the quality of life, and also affects the increase in the frequency of hospitalizations and mortality in patients in this category. Timely correction of cognitive impairment is the key to treating and reversing MHE, as well as improving the quality of life in patients with cirrhosis. Objectives. To study the optimal regimens for the use of rifaximin-α and study its effect on the main clinical and laboratory parameters and quality of life of patients with MHE against the background of cirrhosis during long-term treatment. Material and methods. Inclusion criteria: men and women from 18 to 75 years old; availability of CPU; presence of MHE; signed voluntary informed consent. Non-inclusion criteria: refusal to participate in the study; acute hepatitis; HIV co-infection; severe comorbid pathology; mental illness; Wilson – Konovalov disease. Research methods: clinical examination (analysis of patient complaints, assessment of objective status); laboratory tests (ammonia levels); assessment of the severity of liver disease according to the Child – Pugh scale; assessment of the degree of HE based on the results of psychometric tests (number connection test, animal naming test, brief mental status scale); quality of life questionnaire (SF-36). Results. In the absence of rifaximin-α therapy, there is a deterioration in the quality of life due to a decrease in indicators of the mental component of health, as well as an increase in time in performing the psychometric number connection test. Against the background of continuous and cyclic therapy with rifaximin-α in patients with cirrhosis and MHE during 6 months of observation, the level of capillary blood ammonia decreases. Conclusions. When comparing the effectiveness of continuous and course therapy with rifaximin-α, the results did not show significant differences, which indicates the equivalence of these treatment regimens after 6 months of observations.