Psychometric Hepatic Encephalopathy Score Research Articles

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.

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.

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.

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.

Other causes of neurocognitive impairment than covert hepatic encephalopathy (CHE) are very frequent, either alone or associated with CHE, in cirrhotic patients with cognitive complaints.

Although it is well admitted that cirrhotic patients display various causes of neurocognitive impairment (NI) hampering the diagnosis of covert hepatic encephalopathy (CHE), those are almost never investigated per se. The aims of this study were, in cirrhotic patients displaying cognitive complaints explored by a complete multimodal work-up, to assess: (1) the prevalence of CHE and/or that of other causes of NI and (2) their outcomes, according to the cause of NI. Prospective cohort of cirrhotic patients referred in a dedicated clinic because of cognitive complaints. Work-up included a complete neuropsychological assessment, electroencephalogram (EEG) and brain magnetic resonance imaging with spectroscopy. The diagnosis of CHE was made by an adjudication committee involving the physicians/neuropsychologist. One hundred and twenty-three patients were included (alcohol/MASLD/virus in 63/53/14%, MELD = 11). Sixty-six per cent of them were diagnosed with CHE; among them, 73% exhibited also other causes of NI, mainly cerebrovascular diseases/psychiatric. Among patients without CHE, 48% and 59% displayed pathological Psychometric Hepatic Encephalopathy Score and animal naming test, respectively. Clinical improvement was observed in 77% of the patients re-evaluated after specific management. CHE, but not the other causes of NI, was independently associated with OHE occurrence. Other causes of NI than CHE are frequent in patients with cirrhosis, and not ruled-out by the classical tests dedicated to CHE. Prognosis was influenced by the cause of NI. The management of patients even without CHE led to clinical improvement, underlining the need for a multifaceted approach of cirrhotic patients with cognitive complaints.

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.

Bacterial DNA Translocation Is Associated With Overt Hepatic Encephalopathy and Mortality in Patients With Cirrhosis.

Data on the relationship between bacterial translocation, hepatic encephalopathy (HE), and mortality are scarce. This study aimed to assess the association between bacterial DNA (bactDNA) translocation, inflammatory response, ammonia levels, and severity of HE in patients with cirrhosis, as well as the role of bactDNA translocation in predicting mortality. Cirrhotic patients without bacterial infection were prospectively enrolled between June 2022 and January 2023. Grading of HE was classified by the West Haven Criteria and Psychometric Hepatic Encephalopathy Score ≤ -5. Overall, 294 cirrhotic patients were enrolled, with 92 (31.3%) and 58 (19.7%) having covert and overt HE, respectively. BactDNA translocation was detected in 36.1% of patients (n = 106). Patients with overt HE had more bactDNA translocation and higher serum lipopolysaccharide-binding protein (LBP), tumor necrosis factor-α, interleukin-6 (IL-6), and ammonia levels than those without HE. Patients with detectable bactDNA had higher white cell counts and serum LBP and IL-6 levels than those without. By contrast, bactDNA, serum LBP, and soluble CD14 levels were comparable between patients with covert HE and those without HE. The multivariate Cox regression analysis revealed that bactDNA translocation (hazard ratio [HR] = 2.49, 95% confidence interval [CI]: 1.22-5.11), Model for End-Stage Liver Disease score (HR = 1.12, 95% CI: 1.09-1.16), age (HR = 1.05, 95% CI: 1.000-1.002), and baseline IL-6 (HR = 1.001, 95% CI: 1.000-1.002) were independent factors associated with 6-month mortality. Apart from hyperammonemia, bactDNA translocation is a possible factor associated with overt HE in cirrhotic patients. BactDNA translocation and IL-6 are independent factors associated with 6-month mortality.

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.

Comparison of 6 tests for diagnosing minimal hepatic encephalopathy and predicting clinical outcome: A prospective, observational study.

Current guidelines recommend the assessment for minimal HE in patients with liver cirrhosis. Various efforts were made to find tools that simplify the diagnosis. Here, we compare the 6 most frequently used tests for their validity and their predictive value for overt hepatic encephalopathy (oHE), rehospitalization, and death. One hundred thirty-two patients with cirrhosis underwent the Portosystemic Encephalopathy-Syndrome-Test yielding the psychometric hepatic encephalopathy score (PHES), Animal Naming Test (ANT), Critical Flicker Frequency (CFF), Inhibitory Control Test (ICT), EncephalApp (Stroop), and Continuous Reaction Time Test (CRT). Patients were monitored for 365 days regarding oHE development, rehospitalization, and death. Twenty-three patients showed clinical signs of HE grade 1-2 at baseline. Of the remaining 109 neurologically unimpaired patients, 35.8% had abnormal PHES and 44% abnormal CRT. Percentage of abnormal Stroop (79.8% vs. 52.3%), ANT (19.3% vs. 51.4%), ICT (28.4% vs. 36.7%), and CFF results (18.3% vs. 25.7%) changed significantly when adjusted norms were used for evaluation instead of fixed cutoffs. All test results correlated significantly with each other ( p <0.05), except for CFF. During follow-up, 24 patients developed oHE, 58 were readmitted to the hospital, and 20 died. Abnormal PHES results were linked to oHE development in the multivariable model. No other adjusted test demonstrated predictive value for any of the investigated endpoints. Where applicable, the diagnosis of minimal HE should be made based on adjusted norm values for the tests, exclusively. The minimal HE tests cannot be equated with one another and have an overall limited value in predicting clinical outcomes.

Metabolic disorder and functional disturbance in the central executive network in minimal hepatic encephalopathy.

The aim of this paper is to investigate dynamical functional disturbance in central executive network in minimal hepatic encephalopathy and determine its association with metabolic disorder and cognitive impairment. Data of magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging were obtained from 27 cirrhotic patients without minimal hepatic encephalopathy, 20 minimal hepatic encephalopathy patients, and 24 healthy controls. Central executive network was identified utilizing seed-based correlation approach. Dynamic functional connectivity across central executive network was calculated using sliding-window approach. Functional states were estimated by K-means clustering. Right dorsolateral prefrontal cortex metabolite ratios (i.e. glutamate and glutamine complex/total creatine, myo-inositol / total creatine, and choline / total creatine) were determined. Neurocognitive performance was determined by psychometric hepatic encephalopathy scores. Minimal hepatic encephalopathy patients had decreased myo-inositol / total creatine and choline / total creatine and increased glutamate and glutamine complex / total creatine in right dorsolateral prefrontal cortex (all P ≤ 0.020); decreased static functional connectivity between bilateral dorsolateral prefrontal cortex and between right dorsolateral prefrontal cortex and lateral-inferior temporal cortex (P ≤ 0.001); increased frequency and mean dwell time in state-1 (P ≤ 0.001), which exhibited weakest functional connectivity. Central executive network dynamic functional indices were significantly correlated with right dorsolateral prefrontal cortex metabolic indices and psychometric hepatic encephalopathy scores. Right dorsolateral prefrontal cortex myo-inositol / total creatine and mean dwell time in state-1 yielded best potential for diagnosing minimal hepatic encephalopathy. Dynamic functional disturbance in central executive network may contribute to neurocognitive impairment and could be correlated with metabolic disorder.

Importance of 1H-MR spectroscopy of the brain to identify the minimal hepatic encephalopathy in different patients with liver cirrhosis: A prospective study.

Liver cirrhosis patients commonly progress to minimal hepatic encephalopathy (MHE) with cognitive impairment and raised blood ammonia and proinflammatory cytokines levels. This study aims to identify the subjects of MHE in patients with liver cirrhosis by hydrogen 1 magnetic resonance (1H-MR) spectroscopy of the brain, serum proinflammatory cytokines, and neuropsychiatric tests. This prospective was carried out on 100 patients of liver cirrhosis without overt hepatic encephalopathy (HE) and compared with 100 healthy controls in a tertiary care hospital in Northeast India between September 2017 and October 2019. The psychometric hepatic encephalopathy score (PHES) neuropsychological tests, cranial MRIwith 1H-MR spectroscopy, and estimation of serum interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were done. The PHES scores and serum proinflammatory markers levels were correlated with the conventional and 1H-MR spectroscopy findings of the brain. The mean PHES score in the case group was -7.58±3.43 (standard deviation [SD]) and the control group was -3.41 ± 3.87 (SD). Patients with Child-Pugh class A (n = 8) had a PHES score of -8.7 ± 2.5 (SD), class B (n = 42) -7.62 ± 3.7 (SD), and class C (n = 50) had a score of -7.36 ± 3.3 (SD). The mean value of IL-6 and TNF-α in the case group was 219 ± 180 (SD) pg/mL and 99 ± 118 (SD) pg/mL and the control group was 67.4 ± 77 (SD) pg/mL and 57.5 ± 76 (SD) pg/mL. Globus pallidus T1-weighted hyperintensities on the visibility scale with a visibility score of 0 were observed in 39 cases, a score of 1 in 38 cases, and a score of 2 in 23 cases. Increased glutamate/glutamine/creatine (Glx/Cr) ratio was identified in the case group on MR spectroscopy as compared to the control (0.95 ± 0.24 vs. 0.31 ± 0.19, P < 0.0005), a decrease of myoinositol/creatine (mI/Cr) ratio (0.11 ± 0.13 vs. 0.30 ± 0.12, P < 0.0005), and increase choline/creatine (Cho/Cr) ratio (0.69 ± 0.26 vs. 0.61 ± 0.20, P < 0.0005). There was a statistically significant difference in Glx/Cr, mI/Cr and Cho/Cr ratio between the case and control groups with P < 0.0005. Predicting the development of MHE in established cases of liver cirrhosis using non-invasive modalities like PHES, IL-6, TNF-α levels, and 1H-MR spectroscopy plays an important role in further progression to overt HE and coma.

Improved cognition after rifaximin treatment is associated with changes in intra- and inter-brain network functional connectivity

BackgroundRifaximin is a non-reabsorbable antibiotic which acts at gut level, and improves cognition and inflammatory parameters in minimal hepatic encephalopathy (MHE) patients, but not all patients show the same level of response. This study aims to assess brain activity, both within and between brain networks, following rifaximin treatment, considering the differences between response groups as well.MethodsTwenty-two healthy controls and 53 patients with cirrhosis (22 without and 31 with MHE, diagnosed by Psychometric Hepatic Encephalopathy Score, PHES) performed psychometric, attention and coordination tests, and blood inflammatory parameters were measured. Resting-state functional magnetic resonance imaging (fMRI) acquisitions were performed on controls and MHE patients. Eighteen MHE patients underwent a rifaximin treatment for 6 months, after which all measures were repeated. fMRI images were analysed and changes after treatment were assessed.ResultsAfter rifaximin treatment, 13 patients improved their PHES score (Responder patients) while 5 did not (Non-responder patients). No significant decrease in blood ammonia was observed after rifaximin treatment, but there was a decrease in plasma inflammatory cytokines in responder patients. A global effect of rifaximin was detected on the sensorimotor and fronto-parietal networks. Responder patients showed a relative increase of thalamic network connectivity in comparison to non-responder patients. Before treatment, responder and non-responder patients showed connectivity differences in basal ganglia network. The connection of the sensorimotor and thalamic networks between them and with other networks suffered changes after treatment. These connections between networks mostly decreased after treatment. All changes and differences showed a significant level of correlation with the performance of psychometric tests and the blood levels of inflammatory biomarkers.ConclusionsThere was an improvement of the communication between executive, motor and attention-related brain areas, and their functional independence following rifaximin treatment. Patients who respond also show a less deteriorated connection involved in these functions before treatment. Results suggest that the improved inflammatory state of MHE patients, following rifaximin treatment would favour the observed changes in brain function and enhanced cognitive performance.

Metabolic alterations in the right anterior insula among patients with cirrhosis without overt hepatic encephalopathy: a magnetic resonance spectroscopy study.

We investigated metabolic alterations in the right anterior insula (rAI) in cirrhotic patients and determined its association with patients' cognitive dysfunction. In this study, 31 healthy controls (HCs) and 32 cirrhotic patients without overt hepatic encephalopathy participated. Both blood ammonia level and Child-Pugh score were measured. The psychometric hepatic encephalopathy score (PHES) was used to evaluate cognitive function. 1H-magnetic resonance spectroscopy (MRS) data located in the rAI were recorded on a commercially available 3T magnetic resonance imaging scanner. The ratios of metabolites were measured, including N-acetylaspartate (NAA)/total creatine (tCr), glutamate plus glutamine (Glx)/tCr, myo-inositol (mI)/tCr, and total choline (tCho)/tCr. We adopted the non-parametric Mann-Whitney U-test for intergroup comparison of metabolic ratios. To determine the association between metabolite concentration and clinical parameters, we performed Spearman correlation analyses. Patients with cirrhosis performed worse on PHES in comparison with HCs (P < 0.001). Patients with cirrhosis had significantly decreased mI/tCr (0.87 ± 0.07 vs. 0.74 ± 0.19, P = 0.025) and increased Glx/tCr (1.79 ± 0.17 vs. 2.07 ± 0.29, P < 0.001) in the rAI. We did not observe any significant between-group differences in tCho/tCr and NAA/tCr. The blood ammonia level was correlated with Glx/tCr (r = 0.405, P = 0.022) and mI/tCr (r = -0.398, P = 0.024) of the rAI. In addition, PHES was negatively correlated with Glx/tCr of the rAI (r = -0.379, P = 0.033). Metabolic disturbance of the rAI, which is associated with ammonia intoxication, might account for the neural substrate of cirrhosis-related cognitive dysfunction to some extent.

Efficacy of psychometric hepatic encephalopathy score versus critical flicker fusion frequency in diagnosing subclinical uremic encephalopathy in patients with chronic kidney disease – A pilot study

Background: Cognitive dysfunction can occur in a significant proportion of patients with chronic kidney disease (CKD). Subclinical uremic encephalopathy (SUE) is defined as cognitive impairment (CI) greater than expected for normal aging and educational level. SUE is characterized by declining cognitive function that becomes irreversible if left untreated. However, there is no specific test to confirm the diagnosis of SUE. Aim and Objectives: To determine the diagnostic accuracy of psychometric hepatic encephalopathy score (PHES) and critical flicker fusion frequency (CFFF) tests in SUE in CKD Stage 5 patients and to estimate the prevalence of CI among CKD patients. Materials and Methods: It was a cross-sectional study conducted at a tertiary care center in Chennai, South India, during September 2022–October 2022, among 35 patients diagnosed with CKD Stage 5. All patients were subjected to MMSE (Mini-mental state examination), PHES test, and CFFF test consecutively and their scores were recorded. The collected data were analyzed with IBM SPSS Statistics for Windows, Version 29.0. The scores of PHES and CFFF were compared against MMSE and their diagnostic accuracy was tested using the receiver operating characteristics curve (ROC) along with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy, and P &lt; 0.05 was considered statistically significant. Results: Of all 35 patients, 19 (54%) were males with a median age of 60 years. Fifteen patients (43%) were on hemodialysis. The prevalence of CI among CKD patients was 60%. CI was detected with MMSE in 21 patients (60%). Out of the 21 patients, 18 were positive with PHES (P &lt; 0.01) and 19 were positive with CFFF (P &lt; 0.05). PHES showed better sensitivity (90.9%), specificity (90.0%), PPV (90.9%), and NPV (90.0%) than CFFF, which showed a sensitivity of (89.7%), specificity (85.3%), PPV (86.8%), and NPV (87.5%). PHES was more accurate (accuracy – 90.5%) than CFFF (85.5%). 29 (83%) patients completed MMSE and 24 (69%) patients completed PHES, whereas all patients (100%) completed CFFF test. The average time taken in minutes to complete MMSE, PHES, and CFFF was 14.68 ± 2.02, 30.11 ± 4.13, and 5.48 ± 1.44 min, respectively. Cognitive function scores did not differ significantly with the duration of CKD and between patients with CKD receiving dialysis. Conclusion: Both PHES and CFFF are effective in detecting impaired cognition and can be used as reliable tools in the diagnosis of SUE. Moreover, CFFF was less time-consuming and easier to complete, making it an ideal bedside test. The prevalence of CI among CKD patients was considerably high (60%). Hence, early detection and treatment would prevent patients from going into overt uremic encephalopathy where CI can become irreversible.

Prevalence and risk factors for minimal hepatic encephalopathy in cirrhotic patients with different etiologies

AbstractAimsMinimal hepatic encephalopathy (MHE) significantly affects the prognosis of patients with cirrhosis. This study was performed to determine whether there is a difference in the prevalence of MHE among patients with cirrhosis of different etiologies and whether the etiology directly influences the occurrence of MHE.MethodsThis multicenter, cross‐sectional study enrolled 1879 patients with confirmed cirrhosis at 40 hospitals from October 25, 2021, to January 10, 2023 (Trial registration: https://clinicaltrials.gov/[NCT05140837]). The patients' demographics, etiologies of cirrhosis, and laboratory test results were collected. The psychometric hepatic encephalopathy score (PHES) was determined in all patients to screen for MHE. Multivariate logistic analyses were performed to identify the risk factors for MHE.ResultsIn total, 736 patients with cirrhosis were analyzed. The prevalence of MHE was 42.0% (n = 309). The primary etiology among all patients was hepatitis B virus (HBV)‐related cirrhosis (71.9% [529/736]). The prevalence of MHE was significantly higher in patients with alcoholic cirrhosis (57.1% [40/70]) than in those with HBV‐related cirrhosis (40.6% [215/529], p = 0.009) or hepatitis C virus (HCV)‐related cirrhosis (38.2% [26/68], p = 0.026). Age (odds ratio [OR], 1.042; 95% confidence interval [CI], 1.024–1.059; p &lt; 0.001), duration of education (OR, 0.935; 95% CI, 0.899–0.971; p = 0.001), etiology (OR, 1.740; 95% CI, 1.028–2.945; p = 0.039), and high MELD‐Na scores (OR, 1.038; 95% CI, 1.009–1.067; p = 0.009) were independent risk factors for MHE. When patients with cirrhosis of different etiologies were analyzed separately, the results showed that age (OR, 1.035; 95% CI, 1.014–1.057; p = 0.001) and duration of education (OR, 0.924; 95% CI, 0.883–0.966; p = 0.001) were risk factors for MHE among patients with HBV‐related cirrhosis, whereas age (OR, 1.138; 95% CI, 1.033–1.254; p = 0.009) and creatinine concentration (OR, 16.487; 95% CI, 1.113–244.160; p = 0.042) were risk factors for MHE in patients with HCV‐related cirrhosis. No risk factors for MHE were found in patients with autoimmune cirrhosis. For patients with alcoholic cirrhosis, the platelet count (OR, 1.014; 95% CI, 1.000–1.027; p = 0.045) was a risk factor for MHE. The PHES subtest results were inconsistent among patients who had MHE with cirrhosis of different etiologies. Patients with HBV‐related cirrhosis performed better on Number Connection Test B and the serial dotting test than those with alcoholic cirrhosis (p = 0.007 and p &lt; 0.001), better on Number Connection Test B than those with HCV‐related cirrhosis (p = 0.020), and better on the line tracing test than those with autoimmune cirrhosis (p = 0.037).ConclusionThe etiology of cirrhosis affected the prevalence of MHE and risk factors for MHE. The domains of major cognitive impairment varied among patients with cirrhosis of different etiologies. Further studies are required to verify these findings.

Covert hepatic encephalopathy is associated with aggressive disease progression and poor survival in patients with cirrhosis.

Covert hepatic encephalopathy (CHE) negatively affects the health-related quality of life and increases the risk of overt HE (OHE) in patients with liver cirrhosis. However, the impact of CHE on long-term patient outcomes remains controversial. This study aimed to explore the association between CHE and disease progression and survival among cirrhotic patients. This was a single-center prospective study that enrolled 132 hospitalized patients with cirrhosis, with an average follow-up period of 45.02 ± 23.06 months. CHE was diagnosed using the validated Chinese standardized psychometric hepatic encephalopathy score. CHE was detected in 35.61% cirrhotic patients. During the follow-up, patients with CHE had a higher risk of developing OHE (log-rank 5.840, P = 0.016), exacerbation of ascites(log-rank 4.789, P = 0.029), and portal vein thrombosis (PVT) (log-rank 8.738, P = 0.003). Cox multivariate regression analyses revealed that CHE was independently associated with the occurrence of OHE, exacerbation of ascites, and PVT. Furthermore, patients with progression of cirrhosis were more likely to be diagnosed as CHE (log-rank 4.462, P = 0.035). At the end of the follow-up, patients with CHE had a lower survival rate compared to those without CHE (log-rank 8.151, P = 0.004). CHE diagnosis (hazard ratio 2.530, P = 0.008), together with elder age and higher Child-Pugh score, were risk factors for impaired survival in cirrhotic patients. CHE is associated with disease progression and poor survival in patients with cirrhosis, indicating that CHE may serve as an independent predictor of poor prognosis among these patients.

Alterations in gut virome are associated with cognitive function and minimal hepatic encephalopathy cross-sectionally and longitudinally in cirrhosis

ABSTRACT Cognitive dysfunction due to minimal hepatic encephalopathy (MHE) adversely impacts patients with cirrhosis and more precise therapies are needed. Gut-brain axis changes are therapeutic targets, but prior studies have largely focused on bacterial changes. Our aim was to determine linkages between individual cognitive testing results and bacteria with the virome using a cross-sectional and longitudinal approach. We included cross-sectional (n = 138) and longitudinal analyses (n = 36) of patients with cirrhosis tested using three cognitive modalities, which were psychometric hepatic encephalopathy score (PHES), inhibitory control test (ICT), Stroop, and all three. Stool metagenomics with virome and bacteriome were analyzed studied cross-sectionally and in a subset followed for development/reversal of MHE repeated at 6 months (longitudinally only using PHES). Cross-sectional: We found no significant changes in α/β diversity in viruses or bacteria regardless of cognitive testing. Cognitively impaired patients were more likely to have higher relative abundance of bacteriophages linked with Streptococcus, Faecalibacterium, and Lactobacillus, which were distinct based on modality. These were also linked with cognition on correlation networks. Longitudinally, 27 patients remained stable while 9 changed their MHE status. Similar changes in phages that are linked with Streptococcus, Faecalibacterium, and Lactobacillus were seen. These phages can influence ammonia, lactate, and short-chain fatty acid generation, which are neuro-active. In conclusion, we found linkages between bacteriophages and cognitive function likely due to impact on bacteria that produce neuroactive metabolites cross-sectionally and longitudinally. These findings could help explore bacteriophages as options to influence treatment for MHE in cirrhosis.

Meta-analysis of the Correlation Between Cognitive Function and Imaging Features in Hepatic Encephalopathy

Objectives: This study aimed to systematically evaluate the correlation between cognitive function and brain imaging findings in patients with hepatic encephalopathy (HE). Methods: We searched PubMed, China National Knowledge Infrastructure, and Wanfang databases to obtain literature on cognitive function and the diagnosis of HE via brain imaging from the establishment of the databases to March 20, 2023. Two researchers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. RevMan v. 5.3 software was used in the meta-analysis. Results: A total of 14 articles were included. The meta-analysis showed that digit symbol test (DST) scores and psychometric HE scores (PHES) were positively correlated with the imaging findings of the frontal lobe in patients with HE, with correlation coefficients of 0.49 (Z = 0.53; 95% confidence interval [CI]: 0.23 ~ 0.83) and 0.52 (Fisher’s Z: 0.58; 95% CI: 0.41 ~ 0.76), respectively. The number connection test-A reaction times were negatively correlated with the signal in the globus pallidus, with a correlation coefficient of -0.23 (Z = - 0.23; 95% CI: - 0.43~ - 0.03); DST scores were positively correlated with the signal in the globus pallidus, with a correlation coefficient of 0.45 (Z = 0.49; 95% CI: 0.29 ~ 0.69); and PHES were positively correlated with the mean peak of grey matter, with a correlation coefficient of 0.52 (Z = 0.57; 95% CI: 0.46 ~ 0.73). Conclusions: Imaging findings are related to the cognitive function of patients with HE. Therefore, they can be used to evaluate the cognitive function of these patients and promptly intervene in and prevent the progression of the disease.

Development and evaluation of a virtual reality driving test for patients with cirrhosis.

Patients with cirrhosis and especially those with HE may have impaired driving skills and may be prone to car accidents. This proof-of-concept study aimed to develop and evaluate the applicability of a virtual reality (VR)-based driving test in patients with cirrhosis. Additionally, the association between the results in the VR test and car accidents was investigated. A short driving test using a VR head-mounted display (HTC Vive Pro Eye) was developed to simulate five hazardous situations. The patient has to pull the brake when the hazardous situations occur. The time from triggering the event to pressing the brake is recorded as reaction time. Total reaction time (TRT) is defined as the combined reaction time to all 5 events. Car accidents were assessed retrospectively (previous 12 months) and patients were followed prospectively for 6 months. Minimal HE (MHE) was diagnosed using Psychometric Hepatic Encephalopathy Score. In total, 112 outpatients with cirrhosis and 52 controls without cirrhosis were recruited. MHE was detected in 14% (n = 15). Patients with cirrhosis and MHE (5.67s) had higher TRTs compared to patients without MHE (5.02s) and controls without cirrhosis above the age of 50 (4.98s) (MHE vs. no MHE or controls p<0.01, no MHE vs. controls: not significant). Seven patients reported car accidents during the twelve months prior to study inclusion. TRTs were numerically higher in patients with reported car accidents (p = 0.099). When patients who stopped driving for HE-related/cirrhosis-related reasons (n = 14) were added to the group of patients with accidents, then a longer TRT was significantly associated with the modeled outcome in univariable (p<0.01) and multivariable analyses (OR 2.83, p<0.01). Two car accidents occurred during follow-up. Both patients had TRTs above the 90th percentile. The VR driving test is easy and rapid to perform in patients with cirrhosis and could be helpful as a point-of-care tool for predicting car accidents.