Assessment of Cirrhotic Patients by the EncephalApp Fails to Predict Low-Grade Hepatic Encephalopathy.

INTRODUCTION: An early detection of low-grade hepatic encephalopathy (HE) is of high importance. The aim of the study was to compare a neuropsychological with a psychophysical test on the basis of the psychometric hepatic encephalopathy score (PHES) regarding effectiveness in diagnosing minimal HE (MHE). METHODS: In our prospective controlled observational study, we examined a total of 103 patients with liver cirrhosis for HE. The PHES, CFF, and EncephalApp were performed in all patients. Graduation was based on the result of the PHES. Patients without evidence for HE 1&2 according to the mental state (West-Haven criteria) with a PHES <-4 value points and no clinical symptoms were defined as having MHE. Patients were considered as HE0 when in the PHES none of the psychometric subtest results was abnormal or with a PHES ≥-4 value points. Patients with clinical symptoms were considered HE 1&2 patients. Different cut-off values were determined, and their specificity and sensitivity were calculated. RESULTS: Ninety-six of the involved patients had liver cirrhosis and 25 acted as a healthy control group. The ROC analysis for the classification resulted in an AUC of 0.806, with the highest Youden index for the cut-off time >224 s, for which the sensitivity was 82% and the specificity 75%. Cases of withdrawals were seen in 10.74% of all tested patients. CONCLUSION: The EncephalApp distinguishes well between HE0 and MHE but has its limitations in grading higher forms of HE. Diagnosis using only the EncephalApp is not sufficient.

Minimal hepatic encephalopathy is associated with a higher risk of overt hepatic encephalopathy and poorer survival.

BACKGROUND AND AIMS: Minimal hepatic encephalopathy (MHE) is a frequent complication in patients with liver cirrhosis. Its impact on predicting the development of overt hepatic encephalopathy (OHE) and survival has not been studied in large multicenter studies. METHODS: Data from patients recruited at eight centers across Europe and the United States were analyzed. MHE was detected using the psychometric hepatic encephalopathy score (PHES). A subset was also tested with the simplified animal naming test (S-ANT1). Patients were followed for OHE development and death/liver transplantation (LTx). RESULTS: A total of 1462 patients with a median model of end-stage liver disease of 11 were included (Child-Pugh (CP) stages: A 47%/B 41%/C 12%). Median follow-up time was 19 months, during which 336 (23%) patients developed an OHE episode and 464 (32%) reached the composite end point of death/LTx (369 deaths, 95 LTx). In multivariable analyses, MHE (defined by PHES) was associated with the development of OHE (subdistribution hazard ratio 1.74, p < 0.001) and poorer LTx-free survival (hazard ratio 1.53, p < 0.001) in the total cohort as well as in the subgroup of patients without a history of OHE. In subgroup analyses, MHE (defined by PHES) was associated with OHE development in patients with CP B, whereas there was no association in patients with CP A or C. In the subgroup of patients with available S-ANT1, MHE (defined by S-ANT1) was independently associated with OHE development. Combined testing (PHES+S-ANT1) was superior to single testing for predicting OHE and poorer LTx-free survival. CONCLUSIONS: This large multicenter study demonstrates that screening for MHE is a useful tool for predicting OHE and poorer survival.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Performance of EncephalApp Stroop Test in Cirrhotic Patients for Evaluating Covert Hepatic Encephalopathy.

BACKGROUND: Covert hepatic encephalopathy (HE) is the mildest HE spectrum that is difficult to detect, but associated with significant decrease in quality of life. Currently, there is no gold standard to detect covert HE. EncephalApp Stroop Test as a newer diagnostic tool is easier, faster and its ease of availability in various health institutions is expected to be applied in Indonesia for covert HE detection. This study aimed to validate and test the reliability and diagnostic ability of EncephalApp Stroop Test to diagnose covert HE, compared to the Psychometric Hepatic Encephalopathy Score (PHES) and critical flicker frequency (CFF). METHODS: This study is a cross-sectional test, conducted from August to September 2018, targeted at patient with cirrhosis in Jakarta, to obtain Area Under The Curve (AUC), sensitivity, specificity, cut-off point, predictive value, likelihood ratio, and post-test probability of the EncephalApp Stroop Test, compared to PHES and CFF. The Validity and reliability tests were done before diagnostic study. Translation of the EncephalApp Stroop Test were first carried out using WHO protocol. All patients first underwent a Mini Mental State Examination and Ishihara Test to rule out color blindness. RESULTS: Thirty subjects participated in validity and reliability tests, and eighty in diagnostic tests. The translated application showed excellent internal consistency (Chronbach's Alpha of 0.942) and correlation coefficient of 0.82. The diagnostic study showed OnTime + OffTime as the best parameter (AUC: 0.897 (95% CI: 82.9% - 96.5%); sensitivity: 88.6%; specificity: 80%; positive predictive value (PPV): 0.77; negative predictive value (NPV): 0.9; positive likelihood ratio (LK+): 4.4; negative likelihood ratio (LK-): 1.4; positive post-test probability: 0,775; negative post-test probability: 0,1; and cut-off point ≥ 188.8 seconds. CONCLUSION: The EncephalApp Stroop Test is valid and reliable, with good AUC value, sensitivity, specificity, PPV, NPV and likelihood ratio in diagnosing covert hepatic encephalopathy in patients with cirrhosis in Indonesia.

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

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/ß 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.

[Impact of different diagnostic criteria for assessing mild micro-hepatic encephalopathy in liver cirrhosis: an analysis based on a prospective, multicenter, real-world study].

Objective: To compare the differences in the prevalence of mild micro-hepatic encephalopathy (MHE) among patients with cirrhosis by using the psychometric hepatic encephalopathy score (PHES) and the Stroop smartphone application (Encephal App) test. Methods: This prospective, multi-center, real-world study was initiated by the National Clinical Medical Research Center for Infectious Diseases and the Portal Hypertension Alliance and registered with International ClinicalTrials.gov (NCT05140837). 354 cases of cirrhosis were enrolled in 19 hospitals across the country. PHES (including digital connection tests A and B, digital symbol tests, trajectory drawing tests, and serial management tests) and the Stroop test were conducted in all of them. PHES was differentiated using standard diagnostic criteria established by the two studies in China and South Korea. The Stroop test was evaluated based on the criteria of the research and development team. The impact of different diagnostic standards or methods on the incidence of MHE in patients with cirrhosis was analyzed. Data between groups were differentiated using the t-test, Mann-Whitney U test, and χ (2) test. A kappa test was used to compare the consistency between groups. Results: After PHES, the prevalence of MHE among 354 cases of cirrhosis was 78.53% and 15.25%, respectively, based on Chinese research standards and Korean research normal value standards. However, the prevalence of MHE was 56.78% based on the Stroop test, and the differences in pairwise comparisons among the three groups were statistically significant (kappa = -0.064, P < 0.001). Stratified analysis revealed that the MHE prevalence in three groups of patients with Child-Pugh classes A, B, and C was 74.14%, 83.33%, and 88.24%, respectively, according to the normal value standards of Chinese researchers, while the MHE prevalence rates in three groups of patients with Child-Pugh classes A, B, and C were 8.29%, 23.53%, and 38.24%, respectively, according to the normal value standards of Korean researchers. Furthermore, the prevalence rates of MHE in the three groups of patients with Child-Pugh grades A, B, and C were 52.68%, 58.82%, and 73.53%, respectively, according to the Stroop test standard. However, among the results of each diagnostic standard, the prevalence of MHE showed an increasing trend with an increasing Child-Pugh grade. Further comparison demonstrated that the scores obtained by the number connection test A and the number symbol test were consistent according to the normal value standards of the two studies in China and South Korea (Z = -0.982, -1.702; P = 0.326, 0.089), while the other three sub-tests had significant differences (P < 0.001). Conclusion: The prevalence rate of MHE in the cirrhotic population is high, but the prevalence of MHE obtained by using different diagnostic criteria or methods varies greatly. Therefore, in line with the current changes in demographics and disease spectrum, it is necessary to enroll a larger sample size of a healthy population as a control. Moreover, the establishment of more reliable diagnostic scoring criteria will serve as a basis for obtaining accurate MHE incidence and formulating diagnosis and treatment strategies in cirrhotic populations.

Development and validation of the AMMON-OHE model to predict risk of overt hepatic encephalopathy occurrence in outpatients with cirrhosis.

BACKGROUND & AIMS: Neuropsychological and psychophysical tests are recommended to assess the risk of overt hepatic encephalopathy (OHE), but their accuracy is limited. Hyperammonaemia is central in the pathogenesis of OHE, but its predictive utility is unknown. In this study, we aimed to determine the role of neuropsychological or psychophysical tests and ammonia, and to develop a model (AMMON-OHE) to stratify the risk of subsequent OHE development in outpatients with cirrhosis. METHODS: This observational, prospective study included 426 outpatients without previous OHE from three liver units followed for a median of 2.5 years. Psychometric hepatic encephalopathy score (PHES) <-4 or critical flicker frequency (CFF) <39 was considered abnormal. Ammonia was normalized to upper limit of normal (AMM-ULN) at the respective reference laboratory. Multivariable frailty competing risk and random survival forest analyses were performed to predict future OHE and to develop the AMMON-OHE model. External validation was carried out using 267 and 381 patients from two independent units. RESULTS: Significant differences were found in time-to-OHE (log-rank p <0.001) according to PHES or CFF and ammonia, with the highest risk in patients with abnormal PHES plus high AMM-ULN (hazard ratio 4.4; 95% CI 2.4-8.1; p <0.001 compared with normal PHES and AMM-ULN). On multivariable analysis, AMM-ULN but not PHES or CFF was an independent predictor of the development of OHE (hazard ratio 1.4; 95% CI 1.1-1.9; p = 0.015). The AMMON-OHE model (sex, diabetes, albumin, creatinine and AMM-ULN) showed a C-index of 0.844 and 0.728 for the prediction of a first episode of OHE in two external validation cohorts. CONCLUSIONS: In this study, we developed and validated the AMMON-OHE model, comprising readily available clinical and biochemical variables that can be used to identify outpatients at the highest risk of developing a first episode of OHE. IMPACT AND IMPLICATIONS: In this study, we aimed to develop a model to predict which patients with cirrhosis are at risk of developing overt hepatic encephalopathy (OHE). Using data from three units and including 426 outpatients with cirrhosis, we developed the AMMON-OHE model - comprising sex, diabetes, albumin, creatinine and ammonia levels - which demonstrated good predictive ability. The AMMON-OHE model performs better than PHES and CFF to predict the first episode of OHE in outpatients with cirrhosis. This model was validated in 267 and 381 patients from two independent liver units. The AMMON-OHE model is available online for clinical use.

Current vision on diagnosis and comprehensive care in hepatic encephalopathy.

The first clinical guidelines on hepatic encephalopathy were published in 2009. Almost 14 years since that first publication, numerous advances in the field of diagnosis, treatment, and special condition care have been made. Therefore, as an initiative of the Asociación Mexicana de Gastroenterología A.C., we present a current view of those aspects. The manuscript described herein was formulated by 24 experts that participated in six working groups, analyzing, discussing, and summarizing the following topics: Definition of hepatic encephalopathy; recommended classifications; epidemiologic panorama, worldwide and in Mexico; diagnostic tools; conditions that merit a differential diagnosis; treatment; and primary and secondary prophylaxis. Likewise, these guidelines emphasize the management of certain special conditions, such as hepatic encephalopathy in acute liver failure and acute-on-chronic liver failure, as well as specific care in patients with hepatic encephalopathy, such as the use of medications and types of sedation, describing those that are permitted or recommended, and those that are not.

Prevalence and risk factors of covert hepatic encephalopathy in cirrhotic patients: A multicenter study in China.

OBJECTIVE: We aimed to investigate the prevalence of covert hepatic encephalopathy (CHE) in cirrhotic patients in China and its risk factors. METHODS: A multicenter prospective observational study was conducted from January 2021 to March 2022 at 16 medical centers across China to investigate the risk factors of CHE and establish a prediction model for CHE episodes. RESULTS: A total of 528 patients were enrolled in the study. Based on both the psychometric hepatic encephalopathy score and Stroop test results, the prevalence of CHE was 50.4% (266/528), and the consistency between these two tests was 68.9%. Multivariate analysis showed that age (odds ratio [OR] 1.043, 95% confidence interval [CI] 1.022-1.063, P < 0.001), duration of education (OR 0.891, 95% CI 0.832-0.954, P = 0.001), comorbidities of cardiovascular diseases, hypertension, cerebral apoplexy or diabetes mellitus (OR 2.072, 95% CI 1.370-3.133, P < 0.001), Child-Pugh score (OR 1.142, 95% CI 1.029-1.465, P = 0.025), and blood urea nitrogen concentration (OR 1.126, 95% CI 1.038-1.221, P = 0.004) were associated with CHE episodes. According to the Chronic Liver Disease Questionnaire, CHE patients had lower scores for abdominal symptoms and systemic symptoms (P < 0.001), indicating a poor health-related quality of life. Based on a stepwise Cox regression hazard model, we established a nomogram for determining the probabilities of CHE episodes, and the area under the receiver operating characteristic curve was 0.733 (95% CI 0.679-0.788) and 0.713 (95% CI 0.628-0.797) in the training and validation cohorts. CONCLUSIONS: CHE is a common complication of cirrhosis in China. Large-scale studies with long-term follow-up are needed to determine the natural history of Chinese CHE patients.

Elevated serum levels of glial fibrillary acidic protein are associated with covert hepatic encephalopathy in patients with cirrhosis.

Background & Aims: Blood biomarkers facilitating the diagnosis of covert hepatic encephalopathy (CHE) in patients with cirrhosis are lacking. Astrocyte swelling is a major component of hepatic encephalopathy. Thus, we hypothesised that glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes, might facilitate early diagnosis and management. This study aimed to investigate the utility of serum GFAP (sGFAP) levels as a biomarker of CHE. Methods: In this bicentric study, 135 patients with cirrhosis, 21 patients with ongoing harmful alcohol use and cirrhosis, and 15 healthy controls were recruited. CHE was diagnosed using psychometric hepatic encephalopathy score. sGFAP levels were measured using a highly sensitive single-molecule array (SiMoA) immunoassay. Results: In total, 50 (37%) people presented with CHE at study inclusion. Participants with CHE displayed significantly higher sGFAP levels than those without CHE (median sGFAP, 163 pg/ml [IQR 136; 268] vs. 106 pg/ml [IQR 75; 153]; p <0.001) or healthy controls (p <0.001). sGFAP correlated with results in psychometric hepatic encephalopathy score (Spearman's ρ = -0.326, p <0.001), model for end-stage liver disease score (Spearman's ρ = 0.253, p = 0.003), ammonia (Spearman's ρ = 0.453, p = 0.002), and IL-6 serum levels (Spearman's ρ = 0.323, p = 0.006). Additionally, sGFAP levels were independently associated with the presence of CHE in multivariable logistic regression analysis (odds ratio 1.009; 95% CI 1.004-1.015; p <0.001). sGFAP levels did not differ between patients with alcohol-related cirrhosis vs. patients with non-alcohol-related cirrhosis or between patients with ongoing alcohol use vs. patients with discontinued alcohol use.Conclusions: sGFAP levels are associated with CHE in patients with cirrhosis. These results suggest that astrocyte injury may already occur in patients with cirrhosis and subclinical cognitive deficits and that sGFAP could be explored as a novel biomarker. Impact and implications: Blood biomarkers facilitating the diagnosis of covert hepatic encephalopathy (CHE) in patients with cirrhosis are lacking. In this study, we were able to demonstrate that sGFAP levels are associated with CHE in patients with cirrhosis. These results suggest that astrocyte injury may already occur in patients with cirrhosis and subclinical cognitive deficits and that sGFAP could be explored as a novel biomarker.

Psychometric Hepatic Encephalopathy Score for the Diagnosis of Minimal Hepatic Encephalopathy in Thai Cirrhotic Patients.

The psychometric hepatic encephalopathy score (PHES) is the gold standard for diagnosing minimal hepatic encephalopathy (MHE). Screening for MHE is frequently overlooked in clinical practice due to time constraints. Furthermore, the simplified animal naming test (S-ANT1) is a new simple tool for evaluating MHE in cirrhotic patients. The purpose of this study was to standardize the PHES in a healthy Thai population, assess the prevalence of MHE, and validate the S-ANT1 in detecting MHE in patients with cirrhosis. The study included 194 healthy controls and 203 cirrhotic patients without overt HE. Psychometric tests and the S-ANT1 were administered to all participants. Multiple linear regression was used to analyze factors related to PHES results, and formulas were developed to predict the results for each PHES subtest. In healthy controls, age and education were predictors of all five subtests. The PHES of the control group was −0.26 ± 2.28 points, and the threshold for detecting MHE was set at ≤ −5 points. The cirrhotic group had PHES values of −2.6 ± 3.1 points. Moreover, MHE was found to be present in 26.6% of cirrhotic patients. S-ANT1 had a moderate positive correlation with PHES (r = 0.44, p < 0.001). S-ANT1 < 22 named animals detected MHE with a sensitivity of 71.2%, specificity of 65%, and area under the receiver operating curve of 0.68 (p < 0.001). In conclusion, Thai PHES normative data have been developed to detect MHE in cirrhotic patients who do not have overt HE. The optimal cutoff for detecting MHE in Thai cirrhotic patients was PHES ≤ −5 points and S-ANT1 < 22 named.

QuickStroop, a Shortened Version of EncephalApp, Detects Covert Hepatic Encephalopathy With Similar Accuracy Within One Minute.

BACKGROUND & AIMS: Covert hepatic encephalopathy (CHE) is associated with poor outcomes but is often not diagnosed because of the time requirement. Psychometric hepatic encephalopathy score (PHES) is the gold standard against which EncephalApp Stroop has been validated. However, EncephalApp (5 runs each in "Off" and "On" state) can take up to 10 minutes. This study sought to define the smallest number of EncephalApp runs needed for comparable accuracy to the total EncephalApp using CHE on PHES as gold standard. METHODS: A derivation and a validation cohort of outpatients with cirrhosis who underwent PHES (gold standard) and total EncephalApp was recruited. Data were analyzed for individual runs versus total EncephalApp time versus PHES-CHE. The derivation cohort (n = 398) was split into training (n = 299) and test (n = 99) sets. From the training data set a regression model was created with age, gender, education, and various sums of the "Off" settings. After this, a K-fold cross-validation on the test dataset was performed for both total EncephalApp time and individual Off runs and for the validation cohort. RESULTS: In both cohorts, Off runs 1 + 2 had statistically similar area under the receiver operating curve and P value to the total EncephalApp for PHES-CHE prediction. The adjusted (age, gender, education) regression formula from the derivation cohort showed an accuracy of 84% to diagnose PHES-CHE in the validation cohort. Time for CHE diagnosis decreased from 203.7 (67.82) to 36.8 (11.25) seconds in the derivation and from 178.2 (46.19) to 32.9 (9.94) seconds in the validation cohort. CONCLUSIONS: QuickStroop, which is completed within 1 minute, gives an equivalent ability to predict CHE on the gold standard compared with the entire EncephalApp time.

Validation of EncephalApp_Stroop as screening tool for the detection of minimal hepatic encephalopathy in German patients with liver cirrhosis.

BACKGROUND: In contrast to overt hepatic encephalopathy (OHE), the diagnosis of minimal HE (MHE) is challenging in patients with cirrhosis requiring elaborate, specialized testing. The EncephalApp_Stroop is a smartphone-based application established as screening tool for the diagnosis of MHE but has not yet been validated in a German cohort and country specific cut-offs are currently missing. METHODS: 93 patients with cirrhosis were enroled into this study. Psychometric hepatic encephalopathy score (PHES) was used to detect MHE, and a subset of the patients was tested with critical flicker frequency (CFF). All patients underwent testing with EncephalApp_Stroop. Cut-off thresholds for EncephalApp_Stroop were calculated according to Youden's Index and a separate cut-off was determined with focus on sensitivity. RESULTS: 24 (26%) patients had MHE according to PHES. EncephalApp_Stroop had a strong correlation with PHES (r=-0.76, p<0.001), while there was only a modest correlation with CFF (r=-0.51, <0.001). On time as well as on+off time discriminated best between patients with and without MHE with AUROCS of 0.87 for both measures. According to Youden's index, a cut-off of >224.7 s (sec) (on+off time) discriminated best between patients with and without MHE with a sensitivity of 71% and a specificity of 88%. The adjusted cut-off value for on+off time with focus on sensitivity (sensitivity:specificity weighed 2:1) was 185.1 s, yielding an optimized sensitivity of 92% and a negative predictive value of 96%. By using this cut-off as a pre-screening test in a stepwise diagnosis algorithm, elaborate testing with PHES could have been avoided in 49% of all patients. CONCLUSION: EncephalApp_Stroop may be useful in a stepwise diagnosis algorithm or even as a stand-alone screening tool to detect MHE in German patients with cirrhosis.

A prospective multicenter and real-world study on the diagnostic value of combination of number connection test-B and line tracing test in mild hepatic encephalopathy / 中华消化杂志

Objective:To investigate the diagnostic value of independent and combined subtests of the psychometric hepatic encephalopathy score (PHES) in mild hepatic encephalopathy(MHE) of patients with liver cirrhosis, so as to optimize the PHES.Methods:This was a prospective, multicenter and real-world study which was sponsored by the National Clinical Research Center of Infectious Diseases and the Portal Hypertension Consortium. Twenty-six hospitals from 13 provinces, autonomous regions and municipalities countrywide participated in this study, induding Tianjin Third Central Hospital, the Fourth People′s Hospital of Qinghai Province, the Second Affiliated Hospital of Baotou Medical College, the Third People′s Hospital of Taiyuan, the Fifth Medical Center of PLA General Hospital and so on. From October 2021 to February 2022, outpatients and hospitalized patients with liver cirrhosis and no obvious hepatic encephalopathy were consecutively enrolled. All patients received 5 PHES subjects in the same order: number connection test(NCT)-A, NCT-B, digit symbol test(DST), line tracing test(LTT) and serial dotting test(SDT), and the scores were calculated. The total score of PHES <-4 was taken as the cut-off value for diagnosing MHE. Compare the differences in each subtest between MHE group and non-MHE group. Receiver operating characteristic curve(ROC) and area under the curve(AUC) was performed to assess the diagnostic value of independent and combined subtests in MHE. Mann-Whitney U test and DeLong test were used for statistical analysis. Results:A total of 581 patients with liver cirrhosis were enrolled, 457 were diagnosed as MHE, and the incidence of MHE was 78.7%. The results of NCT-A, NCT-B, SDT, LTT, DST of MHE group were 60.00 s(47.01 s, 88.00 s), 90.45 s(69.32 s, 125.35 s), 74.00 s(57.65 s, 96.60 s), 74.72(60.00, 98.61) and 27.00(20.00, 36.00), respectively. Compared those of non-MHE group(34.00 s(29.15 s, 44.48 s), 50.00 s(40.98 s, 60.77 s), 50.00 s(41.07 s, 63.03 s), 46.23(38.55, 59.42) and 42.00(34.00, 50.75)), the differences were statistically significant( Z=12.37, 12.98, 9.83, 11.56, 10.66; all P<0.001). The AUC(95% confidence interval(95% CI)) of subtests of PHES NCT-B, NCT-A, LTT, DST and SDT alone in MHE diagnosis were 0.880(0.849 to 0.910), 0.862(0.828 to 0.896), 0.838(0.799 to 0.877), 0.812(0.772 to 0.851) and 0.788(0.743 to 0.832), respectively. The combination of 2 PHES subtests significantly increased the diagnostic efficacy. Among them the diagnostic efficacy of the combination of NCT-B and LTT was the best, the AUC(95% CI) was 0.924(0.902 to 0.947), the specificity was 91.9% and the sensitivity was 79.2%, which was better than a single PHES subtest (NCT-A, NCT-B, SDT, LTT and DST) and the combination of NCT-A and DST(AUC was 0.879, 95% CI0.847 to 0.910) which was recommended by guidelines on the management of hepatic encephalopathy in cirrhosis, the differences were statistically significant ( Z=3.78, 3.83, 5.57, 5.51, 5.38, 2.93; all P<0.01). Furthermore, compared between the combination of NCT-B and LTT and the combination of 3 subests of PHES, only the diagnostic efficacy of combination of NCT-B, LTT and SDT (AUC was 0.936, 95% CI 0.916 to 0.956) was better than that of the combination of NCT-B and LTT, the difference was statistically significant( Z=2.32, P=0.020). Conclusion:Based on the diagnostic efficacy and clinical feasibility of PHES subtests and their combinations, the combination of NCT-B and LTT is recommended for the diagnosis of MHE.

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

INTRODUCTION: Minimal hepatic encephalopathy (MHE) represents one of the most overlooked complications of liver cirrhosis. AIM OF THE STUDY: To compare the utility and efficacy of different MHE diagnostic modalities. MATERIAL AND METHODS: This 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). RESULTS: CFF 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. CONCLUSIONS: 3-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.

Liver Transplant Is Associated with Sustained Improvement in Tandem Gait and Risk of Falls.

BACKGROUND: Cirrhosis is associated with poor health-related quality of life (HRQOL), cognitive dysfunction (CD), and lack of coordination leading to falls. Tandem gait (TG; heel-toe) can be used to assess coordination. The impact and relationship between CD, TG and falls pre-/post-liver transplant (LT) is unclear. We aimed to determine the impact of LT on CD, abnormal TG, and HRQOL in cirrhosis. METHODS: We analyzed patients who underwent complete neurological examination, cognitive testing by psychometric hepatic encephalopathy score (PHES), and HRQOL assessment using sickness impact profile (SIP). All patients were followed for 1 post-LT visit at 6 or 12 months post-LT for clinical course and falls. Change in CD, TD, and falls pre-/post-LT were compared. RESULTS: Off 131 recruited, 61 patients completed all visits. Majority were men (84%), with HCV etiology (34%). Pre-LT: Abnormal TG trended towards increased falls (OR 3.3, P = 0.08). Forty-nine % had abnormal TG, 61% had CD, 32.7% had CD + abnormal TG, 62% had prior OHE, and 14.7% had falls. Abnormal and normal TG patients had similar ages, BMI, sex, education level, and MELD scores. Abnormal TG group had higher prior overt HE (P = 0.03) and worse physical SIP score (P = 0.008). Post-LT: There was sustained improvement in CD, HRQOL, falls, and TG post-LT more at 12 than 6 months in all patients. Patients who had abnormal TG pre-LT continued to have a worse PHES (P = 0.0064) and physical SIP score (P = 0.008) compared to normal pre-LT TG patients. CONCLUSION: After LT, there is a sustained improvement in coordination measured via tandem gait, accompanied by a lower rate of falls.

Factors Affecting Psychological Burden on the Informal Caregiver of Patients With Cirrhosis: Looking Beyond the Patient.

BACKGROUND AND AIMS: Cirrhosis leads to considerable morbidity and mortality, compromises quality of life, and often necessitates assistance in activities of daily living. An informal caregiver bears the psychological burden of coping with the needs of the patient and the knowledge of morbid prognosis of a loved one. This aspect is rarely recognized and almost never addressed in a clinical practice. METHODS: This cross-sectional study assessed the factors influencing psychological burden of cirrhosis on the caregivers in a predominantly lower-middle socioeconomic class Indian population. Patients underwent psychometric tests [Psychometric Hepatic Encephalopathy Score (PHES)], and questionnaires for quantifying caregiver burden [Perceived Caregiver Burden (PCB) and Zarit Burden Interview (ZBI)] and assessing depression [Beck Depression Inventory (BDI)] and anxiety [Beck Anxiety Inventory (BAI)] were administered. RESULTS: One hundred patients with cirrhosis [70% male, 27% with past hepatic encephalopathy (HE), and 53% with minimal HE] and their caregivers (66% women, 81% spouse, 26.51 years of mean relationship) were evaluated. Caregiver burden scores were higher in patients with previous overt HE than in those without previous overt HE [PCB (74.63 vs. 66.15, P = 0.001), ZBI (27.93 vs. 21.11, P = 0.023), BDI (11.63 vs. 8.96, P = 0.082), and BAI (11.37 vs. 8.12, P = 0.027)]. Similarly, caregivers of patients with minimal HE had higher caregiver burden that those of patients who did not have minimal HE [PCB (70.74 vs. 65.85, P = 0.027), ZBI (26 vs. 19.51, P = 0.015)]. Burden scores correlated well with each other and with liver disease severity scores and negatively correlated with socioeconomic status. Repeated hospital admissions, alcohol as etiology, and lower socioeconomic status were the independent predictors of caregiver burden. CONCLUSION: Higher perceived burden is common in caregivers of patients with cirrhosis. Repeated hospital admissions, alcoholism, and lower socioeconomic status influence caregiver burden.

Combined Scores from the EncephalApp Stroop Test, Number Connection Test B, and Serial Dotting Test Accurately Identify Patients With Covert Hepatic Encephalopathy.

BACKGROUND & AIMS: The EncephalApp Stroop test is a high-sensitivity but low-specificity test that has been used to identify patients with covert hepatic encephalopathy (CHE). We aimed to develop a new strategy to detect CHE, combining EncephalApp Stroop test score with scores from subtests of the psychometric hepatic encephalopathy scoring system (PHES). METHODS: We performed a survey of 569 adult volunteers (229 men) in 9 communities in Shanghai, China, administering the EncephalApp Stroop test to determine the range of scores in the general population. Data from the standard PHES, including the number connection test-A, number connection test-B (NCT-B), line tracing test, serial dotting test (SDT), and digit symbol test, were used as the reference standard for diagnosis of CHE. A combination of the EncephalApp Stroop with subtests of the PHES was used to establish a new strategy for CHE diagnosis. We validated our findings using data from 160 patients with cirrhosis from 5 centers China. RESULTS: We determined the range of EncephalApp Stroop test scores for the volunteers of different decades of age, education levels, and sexes. Age, education level, and sex were independently associated with EncephalApp Stroop test scores. A combination of scores from the EncephalApp Stroop test, the NCT-B, and the SDT identified patients with CHE with the highest level of accuracy, when the standard PHES was used as the reference standard. A combination of scores of 187 sec for the EncephalApp Stroop test and below -1 for the NCT-B or below -1 for the SDT identified patients with CHE with an area under the curve (AUC) of 0.86, 81.0% sensitivity, and 91.9% specificity, and 87.5% accuracy. In the validation cohort, these cutoff scores identified patients with CHE with an AUC of 0.88, 97.1% sensitivity, 79.3% specificity, and 86.9% accuracy. The average time to calculate this score was 374±140 sec, compared 424±115 sec for the entire PHES. CONCLUSION: Scores from the EncephalApp Stroop test, NCT-B, and SDT identify patients with CHE with approximately 87% accuracy, and in a much shorter time than the standard PHES. This score combination could be a valid and convenient method for identifying patients with CHE. chictr.org.cn number, ChiCTR-EDC-17012007, ChiCTR1800019954.

Prevalence of Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis: A Cross-Sectional, Clinicoepidemiological, Multicenter, Nationwide Study in India: The PREDICT Study.

BACKGROUND: The study aimed at assessing the prevalence and clinical profile of minimal hepatic encephalopathy (MHE) in patients with cirrhosis using neuropsychological assessment and at understanding the management practices of MHE in the Indian clinical setting. METHODS: This cross-sectional, clinicoepidemiological study conducted at 20 sites enrolled liver cirrhosis patients with Grade 0 hepatic encephalopathy according to West-Haven Criteria. Patients were subjected to mini-mental state examination and those with a score of ≥24 were assessed using psychometric hepatic encephalopathy score. Short Form-36 questionnaire was administered to assess the impact on health-related quality of life. RESULTS: Of the 1260 enrolled patients, 1114 were included in the analysis. The mean age was 49.5 years and majority were males (901 [81%]). The prevalence of MHE was found to be 59.7% (665/1114) based on the psychometric hepatic encephalopathy score of ≤-5. Alcohol-related liver disease was the most common etiology (482 [43.27%]) followed by viral infection (239 [21.45%]). Past smokers as well as those currently smoking were more likely to have MHE than nonsmokers. A significant association was found between tobacco chewing, smoking, alcohol consumption, diabetes, and the presence of MHE. Multivariable analysis revealed smoking as the only parameter associated with MHE. A total of 300 (26.9%) patients were on prophylaxis with lactulose/lactitol or rifaximin. These patients were less likely to have MHE as compared to those not on prophylaxis (odds ratio, 0.67; 95% confidence interval, 0.50-0.88; P = 0.005). CONCLUSION: The disease burden of MHE is quite substantial in patients with cirrhosis with no apparent cognitive defect. Smoking, whether past or current, has significant association with the presence of MHE. Although MHE has been shown to adversely affect quality of life, prophylaxis for MHE is not routinely practiced in the Indian setting.The study has been registered under clinical trials registry of India (CTRI/2014/01/004306).

Outcomes in Clinical Trials Evaluating Interventions for the Prevention and Treatment of Hepatic Encephalopathy.

Randomised clinical trials and systematic reviews of research findings can provide high-quality evidence for decision-making in the management of patients with hepatic encephalopathy. A large number of clinical trials have been undertaken, over the last 50 years, relative to the prevention and treatment of this condition. However, changes have been made, during this time, in the classification of hepatic encephalopathy, diagnostic criteria and assessment measures. These temporally based changes and the consequent lack of standardisation make it difficult to compare interventions and to evaluate their comparative efficacy and safety. While some consensus has been reached in relation to the diagnostic evaluation, classification and monitoring of patients in clinical trials, there is less surety about the choice of clinical endpoints. These outcome measures should be universally applicable, easily measured and clinically relevant. This article reviews the current recommendations regarding outcome selection and outlines some of the potential problems and pitfalls inherent in clinical trial evaluating interventions for the management of hepatic encephalopathy.