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Alcohol use, while commonly associated with liver damage, also has significant neurologic implications, which often mimic hepatic encephalopathy and complicate diagnosis and management. Alcohol mediates its acute central nervous system effects by altering neurotransmitter balance, notably between gamma-aminobutyric acid and glutamate. Its chronic neurotoxicity, compounded by thiamine deficiency, results in chronic neurologic complications. Clinically, alcohol-related neurologic disorders present a spectrum from acute intoxication and withdrawal to chronic conditions like Korsakoff syndrome, dementia, cerebellar degeneration, and peripheral neuropathy. This review underscores differentiating these conditions from hepatic encephalopathy and highlights the importance of history-taking and physical examination in clinical practice., Competing Interests: Disclosure All authors have no commercial or financial conflicts of interest to disclose. There are no funding sources to disclose for this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Dementia and hepatic encephalopathy (HE) have symptom overlap and are challenging to differentiate. The presence of undiagnosed cirrhosis may lead to missed opportunities to treat HE, which was found in a veterans database. This needs validation in a non-veteran cohort., Methods: A retrospective cohort study was conducted between 2009 and 2019 using national non-Veteran patient data from the multi-center TriNetX database. Participants included 68,807 patients with a dementia diagnosis at ≥2 visits, no prior diagnosis of cirrhosis, and with sufficient laboratory test results to calculate the Fibrosis-4 (FIB-4) index, which indicates liver disease. Prevalences of high FIB-4 scores (>2.67 and >3.25) were measured within the cohort, and associations between high FIB-4 and comorbidities/demographics were examined., Results: Within the cohort (44.7% male, 78.0% White, mean age 72.73 years (±11.09), 7.6% (n = 5815) had a FIB-4 index > 3.25 and 12.8% (n = 8683) had FIB-4 > 2.67. In multivariable logistic regression models, FIB-4 > 3.25 was associated with male gender (OR: 1.42 [1.33-1.51]), congestive heart failure (OR: 1.73 [1.59-1.87]), viral hepatitis (OR: 2.23 [1.84-2.68]), alcohol use disorder (OR: 1.39 [1.22-1.58]), and chronic kidney disease (OR: 1.38 [1.28-1.48]), and inversely associated with White race (OR: 0.76 [0.71-0.82]) and diabetes (OR: 0.82 [0.77-0.88]). Similar findings were associated with the FIB-4 > 2.67 threshold., Conclusion: The findings of this national cohort suggest that the FIB-4 index could be utilized to screen for potential undiagnosed cirrhosis in patients with dementia, and that hepatic encephalopathy might be misdiagnosed as dementia or cause worsening of cognitive function in patients with dementia., (Published by Elsevier Inc.)

Introduction and Objectives: Although 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 Methods: This 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., Results: Of 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., Conclusions: These 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., Competing Interests: Conflicts of interest None., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Hyperammoniemic encephalopathy is part of the differential -diagnosis in the presence of an acute confusional state. Although associated with liver dysfunction in the majority of cases, it can be observed in many other clinical situations. Often not investigated, the dosage of ammonium in the blood should be integrated in the biological work-up of encephalopathy of unknown origin. Mana-gement focused on etiology is paramount and usually allows for the rapid normalization of ammonium levels and resolution of the clinical syndrome., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Cirrhosis is a prevalent, chronic condition with an asymptomatic compensated phase, in which patients may feel well, and a decompensated phase that begins with the onset of complications (eg hepatic encephalopathy, ascites, and/or variceal bleeding). Because patients with cirrhosis may appear healthy with normal liver enzymes, alkaline phosphatase, and serum bilirubin levels, awareness of clinical signals is important. For example, patients with thrombocytopenia should be evaluated for chronic liver disease and cirrhosis. Early recognition and management of cirrhosis-related complications (eg hepatic encephalopathy, ascites, and/or variceal bleeding) are important, given their association with hospitalization and poor prognosis (eg increased odds of short-term mortality). Hepatic encephalopathy can be the most subtle cirrhosis-related complication and associated cognitive impairment may be misdiagnosed. Because hepatic encephalopathy can be associated with hospital readmissions, reducing readmission rates after hepatic encephalopathy-related hospitalizations is critical. This includes incorporating ongoing therapy (eg rifaximin plus lactulose) in postdischarge management plans to reduce the risk of hepatic encephalopathy recurrence. Strategies that mitigate cirrhosis progression and prevent the development of cirrhosis-related complications are key to improving patient outcomes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute hyperammonaemia is a medical emergency as it can progress to cerebral oedema, seizures, coma and death. Hepatic encephalopathy secondary to cirrhotic disease or portosystemic shunting are relatively well-known causes, but non-cirrhotic aetiologies of acute hyperammonaemia are less well-known, especially in the emergency department. However, an elevated ammonia is not required to make the diagnosis of hepatic encephalopathy. Although measurement of plasma ammonia is recommended for patients with acute, unexplained, altered mental status, as early identification allows early effective management which may prevent irreversible brain damage, there is currently reduced awareness among physicians of the non-cirrhotic aetiologies of acute hyperammonaemia. Furthermore, measurement of ammonia in patients with cirrhosis has been shown to have low sensitivity and specificity, and not to have altered management in the majority of cases; thus, measurement of ammonia is currently not recommended in guidelines for management of hepatic encephalopathy. We sought to describe the pathophysiology of hyperammonaemia and review the non-cirrhotic causes. This was achieved by review of MEDLINE, PubMed and Web of Science databases to include published English literature within the last 20 years. We also present a framework for investigating the acute non-cirrhotic causes of hyperammonaemia to assist both chemical pathologists and clinicians managing these often challenging cases., (Copyright © 2024 Royal College of Pathologists of Australasia. All rights reserved.)

Background and Aims: 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., Methods: 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., Results: 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., Conclusions: 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.

With the progress of basic and clinical research on hepatic encephalopathy in cirrhosis over the world, Chinese Society of Hepatology of the Chinese Medical Association has invited experts in relevant fields to revise the 2018 "Chinese Guidelines on the Management of Hepatic Encephalopathy in Cirrhosis". New guideline provides the recommendations for clinical diagnosis, treatment, primary and secondary prevention of hepatic encephalopathy in 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.

Background and Objectives: Emerging research suggests that hyperammonemia may enhance the probability of hepatic encephalopathy (HE), a condition associated with elevated levels of circulating ammonia in patients with cirrhosis. However, some studies indicate that blood ammonia levels may not consistently correlate with the severity of HE, highlighting the complex pathophysiology of this condition., Methods: A systematic review and meta-analysis through PubMed, Scopus, Embase, Web of Science, and Virtual Health Library were conducted to address this complexity, analyzing and comparing published data on various laboratory parameters, including circulating ammonia, blood creatinine, albumin, sodium, and inflammation markers in cirrhotic patients, both with and without HE., Results: This comprehensive review, which included 81 studies from five reputable databases until June 2024, revealed a significant increase in circulating ammonia levels in cirrhotic patients with HE, particularly those with overt HE. Notably, significant alterations were observed in the circulating creatinine, albumin, sodium, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα) in HE patients., Conclusions: These findings suggest an association between ammonia and HE and underscore the importance of considering other blood parameters such as creatinine, albumin, sodium, and pro-inflammatory cytokines when devising new treatment strategies for HE., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2024 Sepehrinezhad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Liver diseases are a significant global cause of morbidity and mortality. Liver cirrhosis can result in severe complications such as bleeding, hepatic encephalopathy (HE), and infections. Implementing a clear strategy for intensive care unit (ICU) admission management improves patient outcomes. Hemodynamically significant esophageal/gastric variceal bleeding (E/GVB) and grade 4 HE, when accompanied by the need for renal replacement therapy (RRT), are definitive indications for ICU admission. E/GVB, spontaneous bacterial peritonitis (SBP), and infections with multidrug-resistant organisms (MDRO) require close and stringent critical assessment. Patients with severe hepatorenal syndrome (HRS) or respiratory failure have increased baseline mortality and most likely benefit from early ICU treatment. Rapid identification of sepsis in patients with liver cirrhosis is a crucial criterion for ICU admission. Prioritizing cases based on mortality risk and clinical urgency enables efficient resource utilization and optimizes patient management. In addition, "Liver Units" provide an intermediate care (IMC) level for patients with liver diseases who require close monitoring but do not need immediate intensive care., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: There are a lack of data describing outcomes and follow-up after hospital discharge for patients with newly diagnosed cirrhosis with complication on index admission. This study examines factors that influence outcomes such as readmission, follow-up, and mortality for patients with newly diagnosed cirrhosis., Methods: We conducted a single-center retrospective chart review study of 230 patients with newly diagnosed cirrhosis from January 1st, 2020 through December 31st, 2021. We obtained demographics, clinical diagnoses, admission, and discharge MELD-Na, disposition, mortality, appointment requests rate, appointment show rate, and readmission., Results: The primary complications on admission were GI bleed (27%), ascites (25.7%), and hepatic encephalopathy (HE) (10.4%). Overall, the median length of stay (LOS) was 6 days, and the readmission rate was 27%. Out of 230 patients, 25 (10.9%) patients died while hospitalized while another 43 (18.6%) died after initial discharge within the two-year study period. Although there was a significant reduction of the MELD-Na from admission to discharge (p < 0.05), admission MELD-Na did not correlate with LOS and discharge MELD-Na did not predict readmission. Patients with HE had the highest median LOS, while patients with ascites had the highest readmission rate. The median time to an appointment was 32 days. When comparing discharge destinations, most patients were discharged to home (63%), to facilities (13.9%), or expired (10.9%). The average appointment show rate was 38.5%, although 70% of patients had appointment requests. Readmission rate and mortality did not differ based on appointment requests. No significant differences in outcomes were observed based on race, sex, or insurance status., Conclusion: New diagnosis of decompensated was found to have high mortality and high readmission rates. Higher MELD-Na score was seen in patients who died within 30 days. Routine appointment requests did not significantly improve readmission, mortality, increase appointment show rate, or decrease time to appointment. A comprehensive and specialized hepatology-specific program may have great benefits after cirrhotic decompensation, especially for those with newly diagnosed cirrhosis., (© 2024. The Author(s).)

Although ammonia is involved in the pathophysiology of hepatic encephalopathy (HE), the use of ammonia levels in clinical practice is problematic. 1-3 For example, in a study of 551 patients with overt HE (OHE) receiving lactulose who had ammonia levels tested, only 60% had an increased ammonia level (defined as >72 μmol/L). 2 Overall, there was no correlation observed between lactulose dose and whether ammonia levels were obtained (ie, presence/absence of increased ammonia level did not guide therapy), or between time to OHE resolution and ammonia levels. 2 Additionally, there is substantial interlaboratory variability in sample handling and processing, which may affect ammonia measurements. 4 ., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Hepatic encephalopathy (HE) is a serious complication of acute-on-chronic liver failure (ACLF) that requires early detection and intervention to positively impact patient prognosis. This study aimed to develop a reliable model to predict HE in ACLF patients during hospitalization., Methods: Retrospectively recruiting 255 hepatitis B-related ACLF patients, including 67 who developed HE during hospitalization, the study analysed clinical data and biochemical indices collected during the first week of admission. The least absolute shrinkage and selection operator (LASSO) was used to identify characteristic predictors for hospitalization HE events, and a logistic regression model was subsequently developed. Receiver operating characteristic (ROC) curves, calibration curves, and bootstrap resampling were used to evaluate the model's discrimination, consistency, and accuracy, and a nomogram was created to visualize the model. An external validation cohort of 236 liver failure patients collected from the same medical centre between 2007 and 2010 was used to validate the model., Results: The study found that blood urea nitrogen (BUN), alpha-fetoprotein (AFP), international normalized ratio (INR), serum ammonia, and infection complications during hospitalization were risk factors for HE in ACLF patients. The new model predicted the development of HE in ACLF patients with an area under the receiver operating characteristic curve (AUROC) of 85.2%, which was superior to other models. The best threshold for the new model was 0.28, resulting in a specificity of 81.4% and a sensitivity of 80.6%. In the validation group, the new model showed similar results, with an AUROC of 79% and a specificity of 83.6% and a sensitivity of 56.6%., Conclusion: This study developed and validated a new prediction model for HE in ACLF patients offering a useful tool for early identification of patients with a high risk of HE in clinical settings. However, to ascertain the model's general effectiveness, future prospective multicentre studies are warranted.

Objective: The aim of this study was to compare the predictive power of optic nerve sheath diameter (ONSD) measured by brain computed tomography (CT) in patients diagnosed with hepatic encephalopathy (HE) in the emergency department, with other factors for mortality and disease severity., Materials and Methods: A total of 217 patients aged 18 years and older with acute decompensation of cirrhosis diagnosed with HE in the emergency department were included in the study. To compare with patients diagnosed with HE, a total of 217 individuals were included in the study as the healthy control group. ONSD measurements were performed on both the HE patients and the healthy control group in the brain CT., Results: The mortality rate of HE patients was 32.7%. Regarding the severity of the disease, 53% of the patients had late-stage HE. The presence of acute-on-chronic liver failure was detected in 51.4% of patients. The mortality rate among acute-on-chronic liver failure patients was 56.6%. According to the study data, ONSD, creatinine, lactate, and procalcitonin were independent predictors of mortality. Meanwhile, Child-Pugh score, direct bilirubin, ONSD, ammonia, and total bilirubin were independent predictors of disease severity. In the receiver operating characteristic curve analysis, the ONSD had the highest predictive power for mortality and disease severity among the determined predictive values., Conclusion: The data from the study suggests that assessing the ONSD through brain CT scans in individuals diagnosed with HE in the emergency department may provide valuable insights for clinicians, aiding in the prediction of both mortality rates and the severity of the disease., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2024. The Author(s).)

Introduction: Little has been reported about the clinical relevance and trajectories of symptoms in end-stage liver disease (ESLD). The purpose of this prospective study was to identify trajectories of change in symptom burden over the course of 12 months in adults with ESLD., Methods: Patients were recruited from hepatology clinics at 2 healthcare systems. Validated measures were used to assess physical and psychological symptoms. Latent growth mixture modeling and survival and growth modeling were used to analyze the survey data., Results: Data were available for 192 patients (mean age 56.5 ± 11.1 years, 64.1% male, mean Model for ESLD (MELD) 3.0 19.2 ± 5.1, ethyl alcohol as primary etiology 33.9%, ascites 88.5%, encephalopathy 70.8%); there were 38 deaths and 39 liver transplantations over 12 months. Two symptom trajectories were identified: 62 patients (32.3%) had high and unmitigated symptoms, and 130 (67.7%) had lower and improving symptoms. Patients with high and unmitigated symptoms had twice the hazard of all-cause mortality (subhazard ratio 2.53, 95% confidence interval: 1.32-4.83) and had worse physical ( P < 0.001) and mental quality of life ( P = 0.012) compared with patients with lower and improving symptoms. Symptom trajectories were not associated with MELD 3.0 scores ( P = 0.395). Female sex, social support, and level of religiosity were significant predictors of symptom trajectories ( P < 0.05 for all)., Discussion: There seems to be 2 distinct phenotypes of symptom experience in patients with ESLD that is independent of disease severity and associated with sex, social support, religiosity, and mortality. Identifying patients with high symptom burden can help optimize their care., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ammonia is a product of amino acid metabolism that accumulates in the blood of patients with cirrhosis and plays a pivotal role in the pathogenesis of hepatic encephalopathy (HE). Despite being one of the main drivers of brain dysfunction, for many years international societies stated that increased blood ammonia does not add any diagnostic, staging, or prognostic value for HE in patients with cirrhosis. Nonetheless, in the last decades, evidence is emerging that supports the utility of ammonia for risk stratification, but its role in guiding HE diagnosis, staging, and treatment is unclear and there is equipoise in its use in clinical practice. This review provides the latest evidence on the value of ammonia as a biomarker in patients with cirrhosis. Although correct measurement of ammonia requires disciplined sample collection, it provides extremely useful clinical guidance for the diagnosis of HE, offers prognostic information, and it defines a therapeutic target., Competing Interests: Rajiv Jalan has research collaborations with Yaqrit. Rajiv Jalan is the inventor of OPA, which has been patented by UCL and licensed to Mallinckrodt Pharma. He is also the founder of Yaqrit Ltd, a spin out company from University College London, Cyberliver Ltd and Hepyx Ltd. The other authors declare no conflicts of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background and Aims: 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., Approach and Results: 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., Conclusions: 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., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Introduction: Hepatic encephalopathy (HE) is a frequent complication of cirrhosis, leading to preventable hospitalizations and increased mortality. Despite the availability of validated neuro-psychometric tests to diagnose HE, only 10% of clinicians regularly screen for HE due to lack of time, equipment, and trained personnel., Materials and Methods: We studied the association between patient-reported cognitive function and the National Institutes of Health Toolbox Cognition Battery (a validated measure of HE) in patients with cirrhosis. A single-center prospective study of adult patients undergoing liver transplantation evaluation was performed from 10/2020 to 12/2021. Cognition was assessed using the National Institutes of Health Toolbox Cognition Battery and a brief Patient-Reported Outcomes Measurement Information System (PROMIS) survey., Results: Twenty-three liver transplantation candidates were enrolled; the mean age was 56.4 (±9.7) years, 39% were female and the most common etiologies of cirrhosis were primary biliary cirrhosis/primary sclerosing cholangitis/overlap syndrome (30%), hepatitis C (22%) and alcohol-associated liver disease (22%). The mean MELD-Na was 14.9 (±6.4). The mean PROMIS Cognitive Function T-score (PROMIS CF ) was 49.2 (±9.6). The mean T-scores for the List Sort Working Memory test, Flanker Inhibitory Control and Attention test, and Pattern Comparison Processing Speed test were 46.4 (±9.9), 37.8 (±6.2), and 50.22 (±16.4), respectively. PROMIS CF correlated with the List Sort Working Memory test (r = 0.45, P = .03). The mean hospitalization rate was 1.6 days admitted per month. On adjusted multivariate analysis, PROMIS CF predicted total hospitalization days (P < .001), hospital admissions (P = .01), and hospitalization rate (P < .001)., Conclusions: A brief survey can screen for HE and predict hospitalizations in patients with cirrhosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/aims: Quick sequential organ failure assessment (qSOFA) is believed to identify patients at risk of poor outcomes in those with suspected infection. We aimed to evaluate the ability of modified qSOFA (m-qSOFA) to identify high-risk patients among those with acutely deteriorated chronic liver disease (CLD), especially those with acute-onchronic liver failure (ACLF)., Methods: We used data from both the Korean Acute-on-Chronic Liver Failure (KACLiF) and the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) cohorts. qSOFA was modified by replacing the Glasgow Coma Scale with hepatic encephalopathy, and an m-qSOFA ≥2 was considered high., Results: Patients with high m-qSOFA had a significantly lower 1-month transplant-free survival (TFS) in both cohorts and higher organ failure development in KACLiF than those with low m-qSOFA (Ps<0.05). Subgroup analysis by ACLF showed that patients with high m-qSOFA had lower TFS than those with low m-qSOFA. m-qSOFA was an independent prognostic factor (hazard ratios, HR=2.604, 95% confidence interval, CI 1.353-5.013, P=0.004 in KACLiF and HR=1.904, 95% CI 1.484- 2.442, P<0.001 in AARC). The patients with low m-qSOFA at baseline but high m-qSOFA on day 7 had a significantly lower 1-month TFS than those with high m-qSOFA at baseline but low m-qSOFA on day 7 (52.6% vs. 89.4%, P<0.001 in KACLiF and 26.9% vs. 61.5%, P<0.001 in AARC)., Conclusion: Baseline and dynamic changes in m-qSOFA may identify patients with a high risk of developing organ failure and short-term mortality among CLD patients with acute deterioration.

Background: In India, cirrhosis is becoming a growing concern, leading to an unmet need for new non-invasive markers to assess the severity of liver disease. Serum prolactin is one such marker., Aim: To determine the association between serum prolactin, the severity of liver cirrhosis, and its complications such as ascites, hepatic encephalopathy, and esophageal varices., Methods: This cross-sectional study involved 117 patients with liver cirrhosis. They were evaluated for some complications such as ascites, esophageal varices, and hepatic encephalopathy, as well as for severity by using the Child-Turcotte-Pugh (CTP) score. Serum prolactin levels were measured, and their relationship with both the severity and complications of liver cirrhosis was determined. A P value of < 0.05 was considered significant., Results: The mean age of the patients was 48.3 ± 12.08 years, and the majority (80.3%) were males. Seventy-one percent of the patients had elevated serum prolactin levels (>19.40 ng/mL). Elevated serum prolactin was found in approximately 95.0% and 86.8% of patients with hepatic encephalopathy and ascites, respectively. The median serum prolactin levels were significantly associated with esophageal varices grades (P = 0.043) and hepatic encephalopathy (P < 0.001). The sensitivity and specificity of serum prolactin for predicting severe CTP scores were 81.6% and 91.2%, respectively, with a diagnostic accuracy of 87.2%. On multivariate regression analysis, ascites (AOR = 3.8, 95%CI = 1.29-10.98, P = 0.015), hepatic encephalopathy (AOR = 6.1, 95%CI = 0.68-53.78, P = 0.012), CTP class B (AOR = 5.9, 95%CI = 1.39-24.68, P = 0.016), and CTP class C (AOR = 13.4, 95%CI = 2.25-82.21, P = 0.004) were significantly associated with elevated serum prolactin levels., Conclusion: There was a significant association between serum prolactin levels and CTP classes, esophageal varices, ascites, and hepatic encephalopathy in patients with liver cirrhosis., (Copyright © 2024 Copyright: © 2024 Nigerian Journal of Clinical Practice.)

Managing cirrhosis complications is an important measure for improving patients' clinical outcomes. Therefore, in order to provide a complete disease assessment and comprehensive treatment, improve quality of life, and improve the prognosis for patients with cirrhosis, it is necessary to pay attention to complications such as thrombocytopenia and portal vein thrombosis in addition to common or severe complications such as ascites, esophagogastric variceal bleeding, hepatic encephalopathy, and hepatorenal syndrome. The relevant concept that an effective albumin concentration is more helpful in predicting the cirrhosis outcome is gradually being accepted; however, the detection method still needs further standardization and commercialization.

In recent years, the pathophysiological concept of decompensated liver cirrhosis has undergone significant changes. Until a few years ago, the focus of pathophysiological considerations was on the hyperdynamic circulation resulting from portal hypertension. In recent years, emerging data suggests that increased bacterial translocation leading to systemic inflammation plays an important role in patients with decompensated liver cirrhosis. This inflammation affects a variety of extrahepatic organs. Nowadays, liver cirrhosis is considered not only a condition confined to the liver but rather an inflammatory-triggered multisystem disease. The existing inflammation serves as the common pathophysiological explanation for the diverse impact of liver cirrhosis on several extrahepatic organs. It plays a significant role in the development of conditions such as hepatorenal syndrome, cirrhotic cardiomyopathy, hepatopulmonary syndrome, hepatic encephalopathy, and even in the emergence of cirrhosis-associated relative adrenal insufficiency. These new pathophysiological insights hold clinical significance as they influence the prophylaxis and treatment of patients with decompensated liver cirrhosis., Competing Interests: DB: Vortragstätigkeit: Falk Foundation, W. L. Gore & Associates; Reisesponsering: Gilead Science; Forschungsförderung: Dr. Rolf M. Schwiete-Stiftung MS: Vortragstätigkeit für Falk Foundation e.V., W. L. Gore & Associates, Bentley InnoMed GmbH, (Thieme. All rights reserved.)

Introduction: Classically, clinical practice guidelines and expert recommendations have focused on the management of decompensated cirrhotic patients, so we focused this review on improving care for compensated cirrhotic patients who are followed up in outpatient clinics., Areas Covered: We reviewed the current methods for establishing liver function, the diagnosis and management of advanced chronic liver disease and clinically significant portal hypertension as well as the prevention of its complications, with special attention to covert hepatic encephalopathy, we also paid attention to the extrahepatic complications of cirrhosis and the palliative care. All this from the perspective of evidence-based medicine and trying to empower precision medicine. The literature search was undertaken by PubMed with 'cirrhosis,' 'advanced chronic liver disease,' 'liver function,' 'portal hypertension,' 'covert hepatic encephalopathy,' 'minimal hepatic encephalopathy,' 'palliative care' as MeSH terms., Expert Opinion: We must offer compensated cirrhotic patients specific care and measures to prevent the progression of the disease and the appearance of its complications beyond the calculation of liver function and imaging screening for hepatocellular carcinoma that we perform every six months. Entities that have typically received little attention, such as covert hepatic encephalopathy, extrahepatic complications and symptoms of cirrhosis, and palliative care, must come to the spotlight.

Background: Frailty increases the vulnerability to internal and external stressors and may therefore be an indicator of a higher frequency of cirrhosis complications. We aimed to investigate the association of the Clinical Frailty Scale (CFS) with covert (CHE) and overt HE (OHE) development in patients with cirrhosis., Methods: This study analyzed data of 228 patients with cirrhosis. Frailty was assessed using CFS. Patients were examined for the presence of CHE (using PHES) at study inclusion and followed for OHE., Results: Median CFS was 3 and 26 (11 %) patients were at least pre-frail (CFS>3). In multivariable logistic regression analysis in patients without a history of OHE (n = 195), a higher CFS was associated with the presence of CHE at baseline (OR 1.6, p = 0.039). During follow-up, 42 (18 %) patients developed an episode of OHE. In multivariable competing risk regression analyses, a higher CFS was independently associated with the development of an OHE episode in the total cohort (sHR 1.97, p < 0.001) and in the subcohort of patients without a history of OHE (sHR 1.88, p = 0.008)., Conclusion: CFS appears to be a reliable tool to identify patients at higher risk of HE in whom intensified monitoring and treatment may be justified., Competing Interests: Conflict of interest Leonard Kaps reports travel support from Gilead Sciences. Jörn M. Schattenberg reports consultancy to BMS, Boehringer Ingelheim, Echosens, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Nordic Bioscience, Novartis, Pfizer, Roche, Sanofi, Siemens Healthcare GmbH and research funding from Gilead Sciences, Boehringer Ingelheim, and Siemens Healthcare GmbH, all unrelated to this research. Simon Gairing reports receiving travel and accommodation expenses from Ipsen. Christian Labenz reports travel expenses and consulting honoraria from Norgine and Merz Pharmaceuticals, lecture fee from Norgine, Intercept Pharmaceuticals/Advanz Pharma, Gilead Sciences and Merz Pharmaceuticals, and research grants from Norgine and Merz Pharmaceuticals, all unrelated to this research. The other authors disclose no potential financial or non-financial conflict of interests regarding this study., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Liver disease is increasingly common, estimated to affect over 25% of the world's population. Failure of the liver to maintain a normal metabolic milieu leads to impaired brain function (hepatic encephalopathy), and conditions that cause liver disease can themselves predispose to neurological disease. As neurologists' involvement with the acute take increases, it is important that we are familiar with the neurological complications of liver disease, their investigation and management, and to know which other neurological diseases occur in this patient population. In this article, we review the causes, presentation and treatment of hepatic encephalopathy, and discuss important differential diagnoses in patients with liver disease who present with neurological disturbance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that is observed primarily in patients with liver disease. The pathophysiology is complex and involves many factors including ammonia toxicity, dysregulation of central nervous system activity, and excess inflammatory cytokines. Symptoms of HE range from subclinical to debilitating. HE can be difficult to treat and represents a large burden to patients, their caregivers, and the health-care system because of associated resource utilization. This review article provides an overview of the current understanding of the pathophysiology behind HE and where the current research and treatments are pointing toward., Competing Interests: Disclosure No conflicts of interest, financial or otherwise, are declared by the authors. Funding: This study received no external funding., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Minimal hepatic encephalopathy (MHE) is a pervasive frequent complication of cirrhosis of any etiology. The diagnosis of MHE is difficult as the standard neurologic examination is essentially within normal limits. None of the symptoms and signs of overt HE is present in a patient with MHE, such as confusion, disorientation, or asterixis. Progress has been made in diagnostic tools for detection of attention and cognitive deficits at the point of care of MHE. The development of MHE significantly impacts quality of life and activities of daily life in affected patients including driving motor vehicles and machine operation., Competing Interests: Disclosure The authors have no commercial conflicts of interest and no funding sources connected with this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hepatic encephalopathy (HE) can occur as a complication of chronic liver disease as well as acute liver failure. HE is associated with significantly increased morbidity and worse patient outcomes. The clinical manifestation of HE ranges from early less-severe presentations that may only be accurately detected on dedicated psychomotor diagnostic testing to overt alterations in cognition and mental status to the most severe form of coma. Greater awareness of the clinical manifestations of HE across the spectrum of symptom severity is critical for early identification and timely initiation of appropriate therapy to improve patient outcomes., Competing Interests: Disclosure No relevant disclosures for all authors., (Published by Elsevier Inc.)

Background and Study Aims: The mechanism of hepatic encephalopathy is complex and has not been conclusively established. Recent studies support lower serum 25-Hydroxy Vitamin D [25(OH) D] levels in patients with hepatic encephalopathy. This study aimed to evaluate the association between serum 25(OH) D and hepatic encephalopathy in patients with decompensated cirrhosis of liver., Patients and Methods: A total of 70 cirrhosis patients (35 cases of hepatic encephalopathy and 35 patients without encephalopathy as control, mean age 53.07 ± 12.99 years, 67 % male) were recruited for this study. Assessment of the severity of cirrhosis was done by using a model for end-stage liver disease(MELD) and Child Turcotte Pugh (CTP) scores, and assessment of the severity of hepatic encephalopathy was done according to West Haven criteria. Serum 25 (OH) D level was measured by Chemiluminescent Microparticle Immuno Assay(CMIA)., Results: The mean serum 25(OH) D level among hepatic encephalopathy patients was significantly lower in comparison to the control group without encephalopathy (18.76 ± 8.84 nmol/L vs 31.19 ± 13.9 nmol/L, P<0.0001). 91.4 % of hepatic encephalopathy patients had moderate to severe 25(OH)D deficiency as compared to 51.4 % in the control group. There was a significant correlation observed between the severity of the 25 (OH) D deficiency and the severity of liver disease (r =  - 0.35, P = 0.002). No statistically significant difference in serum 25(OH) D levels was found among patients with different hepatic encephalopathy grades (P = 0.416)., Conclusion: A significant association was found between a low serum 25(OH) D leveland hepatic encephalopathy. It requires further large-scale multicenter studies to establish it as a risk factor and predictor of hepatic encephalopathy., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

A 63-year-old man with type 2 diabetes mellitus, alcohol consumption in moderation, and three episodes of hepatic encephalopathy presented with symmetrical lower limb distal weakness, sensory ataxia, thickened palpable nerves, mood disturbances for seven years, and a family history of schizophreniform disorders. Nerve conduction studies showed demyelinating sensorimotor polyradiculoneuropathy. CSF analysis showed mild albumino-cytological dissociation. MRI brain and lumbosacral plexus showed thickened fifth cranial nerves and lumbosacral roots. He was treated with steroids for a provisional diagnosis of chronic inflammatory polyneuropathy and became encephalopathic. EEG showed triphasic waves. Serum ammonia was 201 micrograms/dL. Further evaluation suggested ornithine transcarbamylase (OTC) deficiency. The patient underwent hemodialysis with a low protein diet, rifaximin, and sodium benzoate, with subsequent recovery., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hepatic encephalopathy (HE) remains both a clinical diagnosis and one of exclusion. Laboratory testing is largely focused on identifying precipitating factors. Ammonia levels in the blood can be helpful for the diagnosis of HE but are not required for confirmation. More recent literature is lending support to the prognostic capabilities of ammonia in cirrhosis, both in predicting future HE events and in determining outcomes in hospitalized patients. Accurate ammonia testing requires strict protocols to avoid common pitfalls in the measurement of this labile analyte. Future studies investigating the utility of other laboratory testing to diagnose, stage, or predict HE are encouraged., Competing Interests: Disclosure R.T. Frederick serves as an investigator for Salix Pharmaceuticals/Bausch Health, Mallinckrodt, Astra Zeneca, River 2 Renal; a consultant for Mallinckrodt, Seal Rock Therapeutics, Tennor Therapeutics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction and Objectives: Hepatic encephalopathy (HE) is a frequent complication of cirrhosis and may cause cerebral damage. Neurodegenerative diseases can induce the release of neuroproteins like neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in body fluids, including blood plasma. We investigated whether NfL and GFAP could serve as potential diagnostic plasma biomarkers for overt HE (oHE)., Materials and Methods: We included 85 patients from three prospective cohorts with different stages of liver disease and HE severity. The following patients were included: 1) 34 patients with primary sclerosing cholangitis (PSC) with compensated disease; 2) 17 patients with advanced liver disease without oHE before elective transjugular intrahepatic portosystemic shunt (TIPS) placement; 3) 17 intensive care unit (ICU) patients with oHE and 17 ICU patients without cirrhosis or oHE. Plasma NfL and GFAP were measured using single molecule assays., Results: ICU oHE patients had higher NfL concentrations compared to pre-TIPS patients or ICU controls (p < 0.05, each). Median GFAP concentrations were equal in the ICU oHE and pre-TIPS patients or ICU controls. Plasma NfL and GFAP concentrations correlated with Model for End-Stage Liver Disease (MELD) scores (R = 0.58 and R = 0.40, p < 0.001, each)., Conclusions: Plasma NfL deserves further evaluation as potential diagnostic biomarker for oHE and correlates with the MELD score., Competing Interests: Declaration of interests None., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Liver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD)., Methods/design: The BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18 years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25 mg (a NSBB) or a matched placebo, once or twice daily, for 36 months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD. The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child-Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival., Discussion: The BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care., Ethics and Dissemination: The trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website ( www.boppp-trial.org ) and partners in the British Liver Trust (BLT) organisation., Trial Registration: EUDRACT reference number: 2018-002509-78. ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019., (© 2024. The Author(s).)

Objectives: Hepatitis A virus (HAV) is the commonest cause for pediatric acute liver failure (PALF) in India. The objective of the study was to identify the predictors of mortality and to evaluate the utility of Peds-HAV model in a cohort of non-LT HAV-PALF., Methods: The study included HAV-related PALF from two non-transplant centers. The predictors of outcome were identified by univariate analysis followed by Cox regression analysis. The prognostic accuracy of Peds-HAV model, King's College Hospital (KCH) criteria and pediatric end-stage liver disease score (PELD) were evaluated., Results: As many as 140 children with PALF were included, of whom 96 (68.6%) children had HAV-PALF. On Cox regression analysis, international normalized ratio (INR) (p < 0.001), jaundice to encephalopathy (JE) interval (p < 0.001) and hepatic encephalopathy (HE) grade 3/4 (p = 0.01) were independent predictors of mortality. The mortality rates were 0% (0/42), 14.3% (3/21), 60% (9/15) and 94.4% (17/18) when none, 1, 2 or 3 criteria of the Peds-HAV were met, respectively. Peds-HAV model at a listing cut-off of  ≥ 2 criteria predicted death with 89.7% sensitivity and 89.6% specificity. In contrast, KCH criteria had a lower sensitivity of 62.1%. PELD score had a sensitivity of 89.7% and specificity of 85.1% at a cut-off of 30. The overall prognostic accuracy of Peds-HAV model (89.6%) was higher than those of KCH (83.3%) and PELD (86.5%)., Conclusion: INR, HE grade and JE interval were independent predictors of mortality. The study provides an external validation of Peds-HAV model as a prognostic score in HAV-PALF., Clinical Trial Registry Number: Not applicable as this is a retrospective study., (© 2024. Indian Society of Gastroenterology.)

Pediatric acute liver failure (PALF) is a catastrophic clinical condition with very high morbidity and mortality without early detection and intervention. It is characterized by the acute onset of massive hepatocellular injury that releases circulating inflammatory mediators, resulting in metabolic disturbances, coagulopathy, hepatic encephalopathy and multi-organ failure. The etiological spectrum is dominated by hepatotropic viruses, drug-induced liver injury, metabolic and genetic disorders and immune-mediated diseases. Unlike adults, indeterminate causes for acute liver failure constitute a considerable proportion of cases of acute liver failure in children in the west. The heterogeneity of age and etiology in PALF has led to difficulties in developing prognostic scoring. The recent guidelines emphasize prompt identification of PALF, age-appropriate evaluation for hepatic encephalopathy and laboratory evaluation with careful monitoring. Current therapy focuses on supporting the failing liver and other organs, pending either spontaneous recovery or liver transplantation. Targeted therapy is available for a select group of etiologies. Liver transplantation can be lifesaving and a plan for the same should be organized, whenever indicated. The aim of this review is to define PALF, understand its etiopathogenesis, address the challenges encountered during the management and update the latest advances in liver transplantation and non-transplant treatment options in PALF., (© 2024. Indian Society of Gastroenterology.)

Cirrhosis-related neurocognitive impairment caused by covert or minimal hepatic encephalopathy (CHE) affects psychosocial function, increases risk of overt hepatic encephalopathy (OHE) development, and worsens survival. 1,2 However, detection in clinical practice is challenging. 2 One modality used for screening and prediction of outcomes related to cirrhosis is the EncephalApp Stroop, but it can require up to 10 minutes. Furthermore, the assessment comprises of distinct stages of difficulty, with an easier "Off" stage and a more challenging "On" stage. 3 To alleviate these concerns, QuickStroop, which takes <1 minute, was developed. This uses only the first 2 runs of the Off stage of the EncephalApp Stroop, where number signs presented in red, green, or blue need to be matched quickly to their respective colors. 4 A prior study showed these versions were comparable cross-sectionally to diagnose CHE. 4 However, the utility of QuickStroop to predict cirrhosis-related outcomes is unclear. 5-7 Our aim was to determine the ability of QuickStroop to determine time to development of OHE and OHE-related hospitalizations, all-cause hospitalizations, and death in outpatients with cirrhosis., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Hepatic encephalopathy (HE) is a debilitating complication associated with both acute and chronic liver injury. It is associated with a greater risk of death than any other significant hepatic decompensation event. It manifests as a wide spectrum of neuropsychological abnormalities ranging from subtle impairments in higher cognitive function, to confusion and coma. The pathophysiological role of ammonia in the development of HE is well known, but there is increasing recognition that the gut microbiome, gut-derived systemic inflammation and development of infection can serve as drivers of HE in patients with cirrhosis. The development of HE portents to the severity of cirrhosis and the prognosis is poor without liver transplantation. A referral for liver transplantation should therefore be considered early in those who are eligible. This review covers the pragmatic assessment of HE in patients with cirrhosis, as well as the current evidence base for the best practice management of HE in such patients., (© 2024 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Hepatic encephalopathy, characterized by mental status changes and neuropsychiatric impairment, is associated with chronic liver disease as well as acute liver failure. In children, its clinical manifestations can be challenging to pinpoint. However, careful assessment for the development of hepatic encephalopathy is imperative when caring for these patients as progression of symptoms can indicate impending cerebral edema and systemic deterioration. Hepatic encephalopathy can present with hyperammonemia, but it is important to note that the degree of hyperammonemia is not indicative of severity of clinical manifestations. Newer forms of assessment are undergoing further research, and include imaging, EEG and neurobiomarkers. Mainstay of treatment currently includes management of underlying cause of liver disease, as well as reduction of hyperammonemia with either enteral medications such as lactulose and rifaximin, or even with extracorporeal liver support modalities., (© 2023. The Author(s).)

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., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Number connection test A (NCT-A) and digit symbol test (DST), the preferential neuropsychological tests to detect minimal hepatic encephalopathy (MHE) in China, haven't been standardized in Chinese population. We aimed to establish the norms based on a multi-center cross-sectional study and to detect MHE in cirrhotic patients. NCT-A and DST were administered to 648 healthy controls and 1665 cirrhotic patients. The regression-based procedure was applied to develop demographically adjusted norms for NCT-A and DST based on healthy controls. Age, gender, education, and age by education interaction were all predictors of DST, while age, gender, and education by gender interaction were predictors of log 10 NCT-A. The predictive equations for expected scores of NCT-A and DST were established, and Z-scores were calculated. The norm for NCT-A was set as Z ≤ 1.64, while the norm for DST was set as Z ≥ - 1.64. Cirrhotic patients with concurrent abnormal NCT-A and DST results were diagnosed with MHE. The prevalence of MHE was 8.89% in cirrhotic patients, and only worse Child-Pugh classification (P = 0.002, OR = 2.389) was demonstrated to be the risk factor for MHE. The regression-based normative data of NCT-A and DST have been developed to detect MHE in China. A significant proportion of Chinese cirrhotic patients suffered from MHE, especially those with worse Child-Pugh classification., (© 2024. The Author(s).)

Introduction: Hepatic encephalopathy (HE) is prevalent and is associated with increased morbidity and mortality among patients with cirrhosis. On October 1, 2022, a new, specific International Classification of Diseases-10 code for HE, K76.82, was introduced. We aimed to analyze the diagnostic accuracy of K76.82., Methods: Diagnostic performance of K76.82 for HE (sensitivity, specificity, positive predictive ratio, and negative predictive ratio) was evaluated in 2 large health systems compared with lactulose, rifaximin, and K72.90., Results: A total of 2,483 patients were analyzed. The combination term "lactulose or rifaximin" showed the highest sensitivity of >98% while K76.82 demonstrated a specificity of >87% in all cohorts., Discussion: Although K76.82 is promising, the combination term "lactulose or rifaximin" identified patients with HE more accurately., (Copyright © 2023 by The American College of Gastroenterology.)

Importance: Dementia and hepatic encephalopathy (HE) are challenging to distinguish clinically. Undiagnosed cirrhosis in a patient with dementia can lead to missed opportunities to treat HE., Objective: To examine the prevalence and risk factors of undiagnosed cirrhosis and therefore possible HE in veterans with dementia., Design, Setting, and Participants: A retrospective cohort study was conducted between 2009 and 2019 using data from the Veterans Health Administration (VHA) and 2 separate validation cohorts from the Richmond Veterans Affairs Medical Center. Data analysis was conducted from May 20 to October 15, 2023. Participants included 177 422 US veterans with a diagnosis of dementia at 2 or more clinic visits, no prior diagnosis of cirrhosis, and with sufficient laboratory test results to calculate the Fibrosis-4 (FIB-4) score., Exposures: Demographic and clinical characteristics., Main Outcomes and Measures: An FIB-4 score (>2.67 suggestive of advanced fibrosis and >3.25 suggestive of cirrhosis), capped at age 65 years even for those above this cutoff who were included in the analysis., Results: Among 177 422 veterans (97.1% men; 80.7% White; mean (SD) age, 78.35 [10.97] years) 5.3% (n = 9373) had an FIB-4 score greater than 3.25 and 10.3% (n = 18 390) had an FIB-4 score greater than 2.67. In multivariable logistic regression models, FIB-4 greater than 3.25 was associated with older age (odds ratio [OR], 1.07; 95% CI, 1.06-1.09), male gender (OR, 1.43; 95% CI, 1.26-1.61), congestive heart failure (OR, 1.48; 95% CI, 1.43-1.54), viral hepatitis (OR, 1.79; 95% CI, 1.66-1.91), Alcohol Use Disorders Identification Test score (OR, 1.56; 95% CI, 1.44-1.68), and chronic kidney disease (OR, 1.11; 95% CI, 1.04-1.17), and inversely associated with White race (OR, 0.79; 95% CI, 0.73-0.85), diabetes (OR, 0.78; 95% CI, 0.73-0.84), hyperlipidemia (OR, 0.84; 95% CI, 0.79-0.89), stroke (OR, 0.85; 95% CI, 0.79-0.91), tobacco use disorder (OR, 0.78; 95% CI, 0.70-0.87), and rural residence (OR, 0.92; 95% CI, 0.87-0.97). Similar findings were associated with the FIB-4 greater than 2.67 threshold. These codes were associated with cirrhosis on local validation. A local validation cohort of patients with dementia showed a similar percentage of high FIB-4 scores (4.4%-11.2%)., Conclusions and Relevance: The findings of this cohort study suggest that clinicians encountering patients with dementia should be encouraged to screen for cirrhosis using the FIB-4 score to uncover reversible factors associated with cognitive impairment, such as HE, to enhance outcomes.

Patients with cirrhosis who have cognitive complaints are presumed to have hepatic encephalopathy (HE), which leads to unwarranted medications while ignoring the underlying disease process causing these complaints. Since neuropsychological testing, the current gold standard for HE diagnosis, is not readily available, an orderable test is needed. We aimed to develop and validate a rapid gut microbiota test to exclude HE and determine stakeholder input on this approach. Stool was collected from two cohorts: a two-center training cohort ( n  = 305, on/not on HE-related therapy) and a multicenter validation cohort ( n  = 30, on HE treatment). Stool microbiota was analyzed rapidly using nanopore analysis. Stakeholder (patients and clinicians) needs assessment was evaluated using semi-quantitative questionnaires. In the training cohort, machine learning using neural network identified a 20-species signature that differentiated HE vs no-HE with 84% specificity compared to the gold standard neuropsychological testing. This high specificity persisted regardless of whether patients were on HE-related therapy or not. In the validation cohort, application of this profile led to reevaluation of the HE diagnosis and treatment in > 40% of the patients. This approach was acceptable to patients (Veterans in the validation cohort) and clinician ( n  = 40 nationwide) stakeholders. We conclude that a machine learning stool signature based on 20 microbial species developed in a training set and validated in a separate multicenter prospective cohort differentiated those with vs. without HE, identified patients misdiagnosed with HE, and was acceptable to patients and clinician stakeholders.

Competing Interests: Declaration of Competing Interest None of the authors reports conflict of interest regarding this work.