Acute-on-chronic liver failure (ACLF) is a complicated syndrome associated with high short-term mortality and reversibility. Whether the prior decompensation should be included in the definition of ACLF is controversial.

A total of 532 patients with decompensation (prior or first) of chronic liver disease were retrospectively enrolled and analyzed from January 2018 to June 2023. Clinical data were used to identify the characteristics and determine prognosis.

Of the 532 patients, 99 patients did not meet APASL-ACLF criteria due to the existence of prior decompensation and 433 patients met the Asian Pacific Association for the Study of the Liver (APASL)-ACLF criteria. The two groups had similar characteristics including prognosis scores (Chinese Group on the Study of Severe Hepatitis B (COSSH)-ACLF II score: 7.59 vs. 7.67, p = 0.934; Chronic Liver Failure (CLIF) Consortium ACLF score: 42.90 vs. 44.81, p = 0.273), the distribution of patients with APASL ACLF research consortium score (AARC score) (5-7: 19.2%/12.0%; 8-10: 56.6%/55.0%; 11-15: 24.2%/33.0%, p > 0.05) and the 28-/90-day mortality rates (30.5%/43.2% vs. 36.3%/43.1%, p = 0.267/0.978). In all integrated ACLF patients, Receiver Operating Characteristic (ROC) curve analysis and decision curve analysis (DCA) showed that COSSH-ACLF IIs had higher prognostic efficiency and clinical net benefit than AARC score and CLIF-C ACLFs for 28-/90-day mortality.

Prior decompensated patients exhibited clinical characteristics and high short-term mortality similar to those of first decompensated patients. The COSSH-ACLF IIs demonstrated the highest prognostic efficiency for all integrated ACLF patients. Including prior decompensation in the ACLF definition can help to simplify and improve clinical management.

With progress in basic and clinical research on hepatic encephalopathy in cirrhosis worldwide, the 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." The updated guidelines provide recommendations for the clinical diagnosis, treatment, and both primary and secondary prevention of hepatic encephalopathy in cirrhosis.

To determine the impact of hepatic dysfunction on the motor manifestations of Parkinson's disease.

We conducted a retrospective cohort study using data from the Parkinson's Progression Markers Initiative. Liver fibrosis was defined using the Fibrosis-4 score. Our primary outcome was the association of baseline Fibrosis-4 score with the Movement Disorders Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score. Additional outcomes were MDS-UPDRS part II, MDS-UPDRS part IV, Hoehn and Yahr stage, and levodopa equivalent daily dose. We used linear regression models to evaluate associations at baseline and 5 years after enrollment. We used linear mixed models to evaluate the association of liver fibrosis with the progression of motor dysfunction. Models were adjusted for demographics, comorbidities, alcohol use, time since Parkinson's disease diagnosis, levodopa equivalent daily dose, and genetic predisposition.

We included 360 people with Parkinson's disease with a mean age of 61.8 years (standard deviation 9.7) and 41.1 % women. There was a significant association between liver fibrosis and baseline MDS-UPDRS part III score (β=2.3, 95 % CI: 0.2, 4.5). Liver fibrosis was also correlated with higher interhemispheric signal asymmetry on DAT-SPECT scans in the anterior putamen (p < 0.05 by Wilcoxon rank sum test). There was no correlation with Fibrosis-4 score and any other motor assessment at baseline or after 5 years. Patients with elevated Fibrosis-4 scores had a slower rate of progression in MDS-UPDRS part III scores.

In people with Parkinson's disease, the presence of comorbid liver fibrosis was associated with more severe motor dysfunction early, but not later, within their disease course.

The associations between gray matter (GM) change and neurotransmitter systems in hepatitis B virus-related cirrhosis (HBV-RC) are still poorly understood.

We recruited 60 HBV-RC patients and 60 healthy controls (HCs). Difference of GM volume between HBV-RC and HC groups was evaluated at global and voxel levels. The potential relationship between GM morphology and prognostic models of liver function was evaluated at voxel level in HBV-RC patients. The spatial correspondence between regional GM alteration and the distribution of multiple neurotransmitter systems in HBV-RC compared to healthy controls was assessed by the JuSpace toolbox covering various neurotransmitter maps.

Total GM volume in HBV-RC group was smaller than in HC group (p < 0.05), and the pattern of GM volume alterations showed significantly increased volume in bilateral thalamus and ventral diencephalon and decreased volume in bilateral basal ganglia and cerebellum (p < 0.05, FWE corrected). In HBV-RC group, the volume of left superior frontal gyrus medial segment and right middle frontal gyrus was positively correlated with serum albumin level and negatively correlated with ALBI score, and serum bilirubin level was negatively correlated with right hippocampus and caudate (p < 0.05, FWE corrected). GM alterations in HBV-RC patients relative to HCs were significantly associated with the intrinsic distribution of various neurotransmitter pathways, including GABAergic, cholinergic, serotonergic, and dopaminergic (p < 0.05).

The pattern of GM alteration correlated with liver function and specific neurotransmitter deficits in HBV-RC patients. These findings provide new insight into the complex neuropathogenesis of HBV-RC and the possible therapeutic targets based on neurotransmitter modulation.

In the traditional view, the occurrence of cirrhosis-related complications, such as hepatic encephalopathy, formation of ascites or variceal haemorrhage, marks the transition to the decompensated stage of cirrhosis. Although the dichotomous stratification into a compensated and decompensated state reflects a prognostic water-shed moment and remains to hold its prognostic validity, it represents an oversimplification of clinical realities. A broadening understanding of pathophysiological mechanisms underpinning decompensation have led to the identification of distinct prognostic subgroups, associated with different clinical courses following decompensation. Data provided by the PREDICT study uncovered three distinct sub-phenotypes of acute decompensation (AD). Moreover, acute-on-chronic liver failure (ACLF) has been established as a distinct clinical entity for many years, which is associated with a high short-term mortality. Recently, non-acute decompensation (NAD) has been proposed as a distinct pathway of decompensation, complementing current concepts of the spectrum of decompensation. In contrast to AD, NAD is characterized by a slow and progressive development of complications, which are often presented at first decompensation and/or in patients in an earlier stage of chronic liver disease. Successful treatment of AD or NAD may lead to a clinical stabilization or even the concept of recompensation. This review aims to provide an overview on current concepts of decompensation and to delineate recent advances in our clinical and pathophysiological understanding.

Hepatic encephalopathy (HE) is a mental and neurological complication induced by acute or chronic hepatic failure. Emerging evidence indicates that the farnesoid X receptor (FXR), a multifunctional nuclear receptor and transcription factor, plays a pivotal role in regulating the expression of key genes associated with ammonia metabolism. However, the effect of FXR activation on HE has remained largely uncharted.

We established mouse models of HE by intraperitoneal injection of thioacetamide (TAA) and partial hepatectomy (PHx). Subsequently, we administered obeticholic acid (OCA) to activate FXR and investigated its effects on HE through comprehensive biochemical, biological, histological and behavioral analysis. Additionally, in vitro experiments were conducted to examine the impact of FXR activation on ammonia stress.

In the animal model of HE, activation of FXR upregulated the expression of key enzymes involved in ammonia metabolism pathway within the liver, thereby enhancing urea cycle functionality, reducing plasma ammonia levels, and mitigating liver injury. Furthermore, FXR activation significantly improved behavioral activities in mice and mitigated inflammation in the brain. Finally, our findings demonstrated that activating FXR could enhance ammonia metabolism and ammonia tolerance of C3A cells.

Our data provide novel evidence demonstrating that the activation of FXR by OCA exerts regulatory control over the expression of enzymes involved in ammonia metabolism, thereby effectively alleviating HE. Consequently, FXR could emerge as a promising novel target for HE treatment.

This study was supported by the National Natural Science Foundation of China No: 81970726 (to W-D Chen), and Henan Provincial Key Project of Medical Science and Technology Research No: SBGJ202102215 (to WL Ye).

Portal venous system thrombosis (PVT) outside the setting of cirrhosis is uncommon with limited information available about the etiological and clinical characteristics across varied racial and ethnic groups.

This retrospective cohort study examines the long-term outcomes of non-cirrhotic, Hispanic adults diagnosed with PVT at a single center in Mexico City between January 2000 and August 2023. Patients with conditions predisposing to PVT were excluded.

We included 100 Hispanic adults diagnosed with non-cirrhotic PVT. Thrombophilia was identified in 49 %, with antiphospholipid syndrome (APS) being the most prevalent thrombophilia (23 %), followed by JAK2 mutation (18 %). Chronic PVT, observed in 70 % of cases, predominantly affected the portal vein (50 %), followed by porto-mesenteric (41 %) and porto-splenic (9 %) territories. At diagnosis, 55 % had esophageal varices. Anticoagulant therapy was administered to over half of the patients for >12 months. Over a median follow-up of 55 months, the 5-year risk of re-thrombosis was 24 %, and the 5-year risk of variceal bleeding (VB) was 45 %. The 4-year overall survival (OS) was 97 %. Comparative analysis between thrombophilia-associated and idiopathic PVT did not reveal significant differences in VB, re-thrombosis, and OS.

This study underscores the unique clinical profile of Hispanic patients with non-cirrhotic PVT, highlighting a high prevalence of APS and substantial risks of VB. These findings contribute to a better understanding of PVT in Hispanics and emphasize the importance of tailored management strategies. Our results' generalizability may be limited by the thrombophilia testing approach, the excluded populations, and its retrospective, single center nature.

Many patients with liver diseases are exposed to the risk of hepatic encephalopathy (HE). The incidence of HE in liver patients is high, showing various symptoms ranging from mild symptoms to coma. Liver transplantation is one of the ways to overcome HE. However, not all patients can receive liver transplantation. Moreover, patients who have received liver transplantation have limitations in that they are vulnerable to hepatocellular carcinoma, allograft rejection, and infection. To find other therapeutic strategies, it is important to understand pathological factors and mechanisms that lead to HE after liver disease. Oxidative stress, inflammatory response, hyperammonaemia and metabolic disorders seen after liver diseases have been reported as risk factors of HE. These are known to affect the brain and cause HE. These peripheral pathological factors can impair the blood-brain barrier, cause it to collapse and damage the neurovascular unit component of multiple cells, including vascular endothelial cells, astrocytes, microglia, and neurons, leading to HE. Many previous studies on HE have suggested the impairment of neurovascular unit and cell-cell communication in the pathogenesis of HE. This review focuses on pathological factors that appear in HE, cell type-specific pathological mechanisms, miscommunication/incorrect relationships, and therapeutic candidates between brain cells in HE. This review suggests that regulating communications and interactions between cells may be important in overcoming HE.

This study investigates serum markers for short-term prognosis in hepatic encephalopathy patients.

Patients with hepatic encephalopathy face elevated mortality rates and bleak prognoses. However, effective prognostic models or indicators are lacking. This study aims to explore serum markers for predicting short-term prognosis in these patients.

We conducted a retrospective analysis of 552 patients with hepatic encephalopathy, categorizing 429 individuals meeting exclusion criteria into normal and high activated partial thromboplastin time (APTT) groups. We assessed 12-day and 25-day survival rates using Kaplan-Meier analysis and Cox regression models to examine associations between groups and outcomes.

Upon comparing baseline characteristics, the high APTT group exhibited significant disparities in acute kidney injury, sepsis, coagulation disorders, and ascites (p < 0.05). In the multivariate COX regression model, the hazard ratios [HRs; 95% confidence interval (CI)] of 12- and 25-day mortality were 1.012 (1.001, 1.022, p = 0.033) and 1.010 (1.002, 1.018, p = 0.013), respectively. We discovered that APTT demonstrated an independent association with prognosis. Our findings revealed that the ability of APTT to predict short-term prognosis surpasses that of the traditional MELD model. Regarding 12- and 25-day survival, Kaplan-Meier survival curves from these groups demonstrated a lower survival probability for patients in the high APTT group than the normal group (log-rank p < 0.05). The results of subgroup analysis and interaction analysis indicate that APTT is not influenced by other confounding factors.

A prolonged APTT suggests a poorer short-term prognosis in patients with hepatic encephalopathy.

The role of the gut-liver axis in liver cirrhosis is becoming increasingly recognized. We investigated the fecal microbiome in patients with liver cirrhosis and its potential function as a predictive biomarker of hepatic encephalopathy.

Patients were divided into either a high plasma ammonia (HPA) group or a low plasma ammonia (LPA) group according to the upper limit of normal of plasma ammonia concentration. 16S rRNA sequencing of fecal samples was performed to study how the microbiota affects the clinical symptoms of liver cirrhosis. The Stroop test was used to assess the ability of the brain to inhibit habitual behaviors.

Totally, 21 subjects were enrolled. Among the 18 patients with liver cirrhosis, 14 were male, the age range was 42-56 years, and the plasma ammonia level range was 20-125.9 μmol/l. The Stroop test showed more severe cognitive impairment in HPA than in LPA individuals. At the same time, there were significant differences in fecal microbiome characteristics between the two groups, characterized by a further increase in the abundance of the Proteobacteria phylum in the gut (especially aerobic Enterobacteriaceae). Function predictions of Phylogenetic Investigation of Communities by Reconstruction of Unobserved States in the microbiome further explained the increase in the Enterobacteriaceae-dominated polyamine synthesis pathway in the gut microbiome of HPA groups.

Cirrhotic patients with hyperammonemia have a specific fecal bacterial composition (characterized via expansion of Enterobacteriaceae). The ability to bio-synthesize polyamines that Enterobacteriaceae possesses is likely to be a key factor in the elevation of plasma ammonia.

Pioneered by Thomas Starzl in the early 1970s, liver transplant (LT) is nowadays often considered a final intervention and standard of care to cure many forms of acute and chronic end-stage liver diseases. Started in recipients younger than 60 years old, LT indications are now much broader, and at least, one-fifth of the candidates are older than 65 years. Problems associated with ageing and frailty in LT recipients and their impact on the entire perioperative course are discussed according to a modern anesthesiological perspective and the anesthesiologist covering the role of the perioperative (transplant) physician.

The efficacy of rifaximin in the prevention of overt hepatic encephalopathy (HE) has not been established. The aim of this study was to access the efficacy and safety of rifaximin in the prophylaxis of HE.

We conducted a meta-analysis search of the Cochrane Library, PubMed, ClinicalTrials.gov, Web of Science, and EMBASE as of March 2022. We pooled data by random-effects DerSimonian-Laird models to calculate hazard ratios (relative risks, RRs) for mortality, incidence of HE, and adverse events.

Fourteen randomized controlled trials were included in the study. Rifaximin helped prevent HE (RR = -0.47, 95% confidence interval [CI]: -0.68 to -0.26) in patients with cirrhosis, but did not reduce mortality (RR = 0.03, 95% CI: -0.32 to 0.39) or increase the occurrence of adverse events (RR = -0.08, 95% CI: 0.22-0.07). Subgroup analysis showed that rifaximin was effective in both the primary (RR = 1.17, 95% CI: 1.06-1.29) and secondary (RR = 1.17, 95% CI: 1.06-1.29) prevention of HE. Moreover, subgroup analysis found that rifaximin helped prevent HE in alcohol-related (RR = -0.59, 95% CI: -0.87 to -0.32) or virus-associated (RR = -0.41, 95% CI: -0.71 to -0.11), and underwent transjugular intrahepatic portosystemic shunt (RR = -0.51, 95% CI: -0.76 to -0.27) or non-transjugular intrahepatic portosystemic shunt (RR = -0.35, 95% CI: -0.66 to -0.05) cirrhotic patients. Subgroup analyzed by the intervention, rifaximin versus placebo (RR = -0.43, 95% CI: -0.73 to -0.14) and rifaximin+lactulose versus lactulose (RR = -0.57, 95% CI: -0.68 to -0.26) were statistically significant prevention of HE, rather than rifaximin versus lactulose (RR = -0.44, 95% CI: -1.0 to 0.11).

Rifaximin is beneficial for primary and secondary prevention of HE, but it does not reduce mortality or increase the incidence of adverse events in patients with end-stage cirrhosis caused by virus or alcohol.

Liver disease remains a significant global health concern. In China, the number of patients with liver cirrhosis is estimated to reach 7 million. In addition to the high risk of death, cirrhosis leads to several severe complications. Patients with cirrhosis have significantly longer hospital stays and higher total hospital costs than those without cirrhosis. We aimed to investigate the predictors of readmission among patients with cirrhosis in China.

We conducted a retrospective study to evaluate adult patients with cirrhosis. Data on various sociodemographic, clinical, and hospitalization characteristics were collected. We defined the primary endpoint as the first liver-related readmission occurring within 30-90 days of initial hospitalization. Adult patients with cirrhosis admitted to our hospital between January 2009 and December 2022 were included. Differences between groups were analyzed using Student's t-test and chi-square test. Logistic and multiple linear regression analyses were performed to identify predictors associated with readmission and the length of the first hospitalization.

In total, 1,285 patients were diagnosed with cirrhosis. Among these patients, 767 (59.7%) were males, and the mean age was 58.9 ± 12.3 years. Seventy-two (5.6%) and 154 (12.0%) patients were readmitted within 30 and 90 days, respectively. Compared with those who were not readmitted, patients readmitted at 30-day and 90-day had a higher proportion of males, ascites, spontaneous bacterial peritonitis, electrolyte abnormalities, higher Child-Pugh-Turcotte scores, longer initial hospital stays, and higher initial hospitalization costs. Logistic regression analysis indicated that hepatic encephalopathy, spontaneous bacterial peritonitis, diabetes, and ascites were predictors of 30- and 90-day readmission. Hypertension and spontaneous bacterial peritonitis were significant predictors of the length of the first hospitalization.

Patients with cirrhosis presenting with hepatic encephalopathy, ascites, and spontaneous bacterial peritonitis may have a higher risk of rehospitalization.

The performance of neurodegenerative biomarkers-neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1)-in diagnosing minimal hepatic encephalopathy (MHE) has not been systematically evaluated, simultaneously, nor have their associations with the development of overt hepatic encephalopathy (OHE). This study aimed to evaluate the performance of plasma NfL, GFAP, tau, and UCHL1 in diagnosing MHE and predicting the development of OHE in Chinese patients with hepatic cirrhosis.

In this prospective study, 124 patients with hepatic cirrhosis were recruited. The Psychometric Hepatic Encephalopathy Score was used to diagnose MHE, and OHE development was observed during a 30-day follow-up period. Plasma levels of NfL, GFAP, tau, and UCHL1 were measured using the highly sensitive single-molecule array when MHE was diagnosed. Additionally, serum interleukin-6 (IL-6) levels and the model for end-stage liver disease (MELD) and MELD-Na scores were also measured.

MHE was diagnosed in 57 (46.0%) patients. Patients with MHE had significantly higher plasma levels of NfL and GFAP (34.2 vs. 22.4 pg/mL and 173 vs. 97.6 pg/mL, respectively; both p < 0.001) and lower tau levels (8.4 vs. 11.6 pg/mL, p = 0.048) compared to those without MHE. Plasma NfL (odds ratios = 1.027, 95% confidence interval [CI]: 1.006-1.048; p = 0.013) and serum ammonia levels (odds ratios = 1.021, 95% CI: 1.006-1.036; p = 0.007) were independently associated with MHE occurrence. A combination of NfL, GFAP, tau, and UCHL1 was effective in diagnosing MHE in all cirrhotic patients (area under the receiver operating characteristic curve [hereinafter referred to as AUROC]: 0.748, 95% CI: 0.662-0.821), with an accuracy, sensitivity, and specificity of 71.0%, 71.9%, and 71.6%, respectively. In patients without previous OHE, the combination had an AUROC of 0.764 (95% CI: 0.673-0.840), with an accuracy, sensitivity, and specificity of 72.5%, 71.7%, and 73.0%, respectively. Furthermore, GFAP (hazard ratio (HR) = 1.003, 95% CI: 1.000-1.005; p = 0.044), IL-6 (HR = 1.003, 95% CI: 1.001-1.004; p < 0.001), and MELD score (HR = 1.139, 95% CI: 1.072-1.210; p < 0.001)-but not NfL, tau, and UCHL1-were identified as risk factors for 30-day OHE development.

The combination of plasma levels of NfL, GFAP, tau, and UCHL1 performs well in diagnosing MHE. Additionally, MELD score, IL-6, and GFAP appear to be significant predictors of OHE development in patients with hepatic cirrhosis.

In this article, we provide commentary on the recent article by Zhao et al. We focus on the shifts in the gut microbiota of patients with hepatitis B virus (HBV)-associated cirrhosis/portal hypertension (PH) following transjugular intrahepatic portosystemic shunt (TIPS) and the implications for understanding the mechanisms, diagnosis, and treatment. By comparing the gut microbiota composition and dynamic changes before and after TIPS in patients with and without hepatic encephalopathy, the authors found an increase in non-probiotic bacteria in those who developed hepatic encephalopathy post-TIPS, with Morganella species present only in the hepatic encephalopathy group. The gut microbiota changes post-TIPS among patients without the occurrence of hepatic encephalopathy suggest potential therapeutic benefits through prophylactic microbiome therapies. Furthermore, the specific gut microbiota alterations may hold promise to predict the risk of hepatic encephalopathy in individuals undergoing TIPS for HBV-related PH. Despite these promising findings, future studies are needed to address limitations, including a small sample size, a relatively short evaluation period for gut microbiota alterations, the absence of data on dynamic alterations in gut microbiota post-TIPS and their correlation with blood ammonia levels, and the lack of validation in animal models. In conclusion, Zhao et al's study has shed new light on the link of gut microbiota with post-TIPS hepatic encephalopathy, potentially through the intricate gut-liver axis, and has important clinical implications for improving the management of patients with HBV-related PH.

To investigate the association between overt hepatic encephalopathy (OHE) and liver pathology after transjugular intrahepatic portosystemic shunt (TIPS) creation in cirrhotic patients. From July 2015 to April 2024, 73 patients from 4 hospitals in China who received TIPS creation and liver biopsy were retrospectively enrolled in this study. Based on whether OHE occurred within 3 months after TIPS creation, the patients were categorized into OHE (n = 29) and non-OHE (n = 44) groups. The liver pathology was assessed by hematoxylin-eosin (H&E), Sirius red staining, immunohistochemistry, and immunofluorescence. Liver pathology by H&E staining showed typical features of liver cirrhosis (including disordered structure and pseudolobule formation) in all the patients. No marked difference was observed in extracellular matrix (ECM) deposition between the OHE and non-OHE groups. However, the patients in the OHE group had a higher level of liver and systemic inflammation than in the non-OHE group. And there was a strong correction between intrahepatic macrophage infiltration and serum inflammatory indicators. Additionally, the OHE group had more liver neovascularization, which was consistent with liver inflammation. The emergence of OHE after TIPS creation is closely associated with liver pathology, especially in liver inflammation and angiogenesis, but not in ECM deposition.

Hepatic encephalopathy (HE) is a life-threatening condition where brain function is impaired mainly due to high systemic ammonia levels. HE is associated with a high 1-year mortality. No universally accepted guidelines for the treatment of HE exist. Nitrogen scavengers, such as sodium benzoate (SB), have been proven very effective to treat hyperammonemia in patients with urea cycle defects, in acute and chronic settings. We hypothesized that SB can also be an effective treatment of HE caused by end-stage liver disease or portosystemic shunting, as long as liver function is partially intact. The aim of this meta-analysis is to study the effect of SB in humans and animals with HE due to end-stage liver disease or portosystemic shunting.

Embase, Medline (Ovid and PubMed), Web-of-Science, Cochrane, and Google Scholar were searched on 19 July 2021, both human and animal studies were eligible.

Sixteen studies were included, consisting of four clinical trials, five animal studies, and seven case reports, including 314 subjects. Meta-analysis included 284 subjects. The standardized mean difference (SMD) of SB's ammonia-lowering effect was 0.89 SMD [95% confidence interval (CI): 0.27-1.51] in clinical trials and 1.63 SMD (95% CI: -0.12 to 3.39) in animal studies. Considerable heterogeneity was present in the included studies.

SB seems to be an effective treatment for HE or hyperammonemia caused by end-stage liver disease or portosystemic shunting. However, additional high-quality studies are necessary for more robust conclusions.

Hepatoencephalopathy (HE) is a liver disease that can lead to brain pathology and the impairment of human cognitive abilities. The objective assessment of HE disease severity is difficult due to the lack of reliable diagnostic markers. This paper examines the background to the emergence of HE markers and provides a brief overview of research results indicating the diagnostic value of potential markers isolated from a wide range of metabolites analyzed. It has been suggested that metabolites of the glutamate-glutamine (Glu-Gln) cycle, α-ketoglutarate (αKG), and α-ketoglutaramate (αKGM) can act as such markers of HE. The informative value of these markers was revealed during a comparative analysis of the distribution of αKG and αKGM in samples of the blood plasma and tissues (liver, kidneys, and brain) of rats exposed to the strong hepatotoxin thioacetamide (TAA). A comparative analysis of the balance of αKG and αKGM, as well as their ratio (αKG/αKGM) in the examined samples of blood plasma and animal tissues in these models, revealed their diagnostic value for assessing the severity of HE and/or monitoring the recovery process.

Acute encephalopathy is a common presenting symptom in the emergency room and complicates many hospital and intensive care unit admissions. The evaluation of patients with encephalopathy poses several challenges: limited history and examination due to the patient's mental status, broad differential diagnosis of systemic and neurologic etiologies, low yield of neurodiagnostic testing due to the high base rate of systemic causes, and the importance of identifying less common neurologic causes of encephalopathy that can be life-threatening if not identified and treated. This article discusses the differential diagnosis of acute encephalopathy, presents an approach to the history and examination in a patient with encephalopathy, reviews the literature on the yield of neurodiagnostic testing in this population, and provides a diagnostic framework for the evaluation of patients with altered mental status.

Acute liver failure (ALF) is a fatal clinical syndrome of severe hepatic dysfunction. Chemokines promote liver diseases by recruiting and activating immune cells. We aimed to investigate the role of C-C chemokine ligand 25 (CCL25) in ALF.

An ALF mouse model induced by D-galactosamine/lipopolysaccharide was evaluated through liver hematoxylin and eosin staining and serum transaminase and cytokine measurement. CCL25 expression in serum was analyzed by ELISA and in liver by immunohistochemical staining and western blot. C-C chemokine receptor 9 (CCR9)-expressing cells in the liver were identified by immunofluorescence staining. The effects of anti-CCL25 on ALF were evaluated in vivo. Cytokine expression and migration of CCL25-stimulated RAW264.7 macrophages were studied. We also investigated the role of anti-CCL25 and BMS-345541, an NF-κB signaling inhibitor, in vitro. NF-κB activation was assessed via western blot, and p65 nuclear translocation was detected using cellular immunofluorescence.

ALF mice showed severe histological damage and high serum levels of aminotransferase and inflammatory cytokines. Elevated CCL25 and NF-κB activation was observed in vivo. CCR9 was expressed on macrophages in ALF mouse liver. ALF was suppressed after anti-CCL25 treatment, with significant NF-κB inhibition. In vitro, CCL25 induced strong migration and cytokine release in RAW264.7 macrophages, which were eliminated by anti-CCL25 and BMS-345541. Furthermore, the NF-κB activation and p65 nuclear translocation induced by CCL25 were also inhibited by anti-CCL25 and BMS-345541.

CCL25 contributes to ALF development by inducing macrophage-mediated inflammation via activation of the NF-κB signaling.

Chronic liver diseases and cirrhosis are associated with mood disorders. Regular exercise has various beneficial effects on multiple organs, including the liver and brain. However, the therapeutic effect of exercise on liver fibrosis concomitant with anxiety has not been evaluated. In this study, the effects of exercise training on liver fibrosis-related anxiety-like behaviors were evaluated. Male C57/BL6 mice were divided into four groups: vehicle-sedentary, vehicle-exercise, carbon tetrachloride (CCl4)-sedentary, and CCl4-exercise. Liver fibrosis was induced by CCl4 administration for 8 wk, exercise was applied in the form of voluntary wheel running. After an intervention, anxiety-like behavior was assessed using the elevated plus maze. CCl4 increased liver and serum fibrotic markers, as measured by blood analysis, histochemistry, and qRT-PCR, and these changes were attenuated by exercise training. CCl4 induced anxiety-like behavior, and the anxiolytic effects of exercise occurred in both healthy and liver-fibrotic mice. In the hippocampus, CCl4-induced changes in neuronal nitric oxide synthase (nNOS) were reversed by exercise, and exercise enhanced brain-derived neurotrophic factor (BDNF) induction, even in a state of severe liver fibrosis. These results suggested that hepatic fibrosis-related anxiety-like behaviors may be induced by excess hippocampal nNOS, and the beneficial effects of exercise could be mediated by increases in BDNF and reductions in nNOS. The percentage of fibrotic area was negatively correlated with antianxiety behavior and positively associated with hippocampal nNOS protein levels. Liver fibrosis-related anxiety-like behaviors could be alleviated through the regulation of hippocampal BDNF and nNOS via exercise training. These results support the therapeutic value of exercise by targeting the mechanisms underlying liver fibrosis and associated anxiety.NEW & NOTEWORTHY This study explores how exercise affects liver fibrosis-related anxiety in mice. Researchers found that regular exercise reversed carbon tetrachloride (CCl4)-induced liver fibrosis and reduced anxiety, even in mice with liver fibrosis. Exercise increased brain-derived neurotrophic factor (BDNF) and decreased neuronal nitric oxide synthase (nNOS) in the hippocampus. These findings suggest that exercise has therapeutic potential for treating anxiety associated with chronic liver disease by modulating specific brain factors.

Hepatic encephalopathy is a severe complication with high mortality in patients with hepatopathy and/or portosystemic shunts, partly due to the presence of hyperammonemia because of defective hepatic detoxification. Diagnosis is essentially clinical, characterized by various neuropsychiatric symptoms, possibly associated with hyperammonemia. Complementary tests, such as electroencephalogram to identify metabolic encephalopathy, or specific abnormalities on cerebral magnetic resonance imagery, may also support the diagnosis. Management is essentially based on treatment of triggering factors such as ionic disorders or sepsis, and symptomatic therapy with non-absorbable disaccharides (notably lactulose) or polyethylene glycol, possibly combined with rifaximin. Progression varies according to the initial severity and management of hepatic encephalopathy, but this condition is potentially reversible with treatment.

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.

Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms.

Acute liver dysfunction commonly leads to rapid increases in ammonia concentrations in both the serum and the cerebrospinal fluid. These elevations primarily affect brain astrocytes, causing modifications in their structure and function. However, its impact on neurons is not yet fully understood. In this study, we investigated the impact of elevated ammonium chloride levels (NH4Cl, 5 mM) on synaptic transmission onto CA1 pyramidal neurons in mouse organotypic entorhino-hippocampal tissue cultures. We found that acute exposure to NH4Cl reversibly reduced excitatory synaptic transmission and affected CA3-CA1 synapses. Notably, NH4Cl modified astrocytic, but not CA1 pyramidal neuron, passive intrinsic properties. To further explore the role of astrocytes in NH4Cl-induced attenuation of synaptic transmission, we used methionine sulfoximine to target glutamine synthetase, a key astrocytic enzyme for ammonia clearance in the central nervous system. Inhibition of glutamine synthetase effectively prevented the downregulation of excitatory synaptic activity, underscoring the significant role of astrocytes in adjusting excitatory synapses during acute ammonia elevation.

Computed tomography of the head (CT head) is frequently used for patients with cirrhosis presenting with suspected hepatic encephalopathy (HE).

The primary aims of this study were to assess the frequency of CT head usage in this patient population and to determine whether these scans yielded significant findings. Our secondary aims were to identify factors associated with the decision to order CTs and whether patients who received CTs had different outcomes.

A single-centre, retrospective chart review was performed. Patients presenting to the University of Alberta Hospital with cirrhosis and common liver disease aetiologies over a 27-month period were identified via discharge diagnosis codes. Charts of patients with suspected HE were manually identified. The use of a CT head was documented, as were patient demographics, cirrhosis aetiology, MELD, and outcomes. Comparisons were made between patients with and without CT head.

A total of 119 encounters from 100 patients met our inclusion criteria. In 57% of encounters, a CT scan was performed on presentation. None of these CT scans had significant findings. Patient factors associated with the decision to order CT included older age, more preserved liver function, and longer length of time between patient's current and previous presentations. Patients who did not receive CT head had higher in-hospital mortality, which was likely reflective of more severe underlying liver dysfunction in this group.

The frequency of CT head usage in the studied patient population was high while the yield was low. This calls into question the usefulness of CT head in this population.

Acute liver injury (ALI) that progresses into acute liver failure (ALF) is a life-threatening condition with an increasing incidence and associated costs. Acetaminophen (N-acetyl-p-aminophenol, APAP) overdosing is among the leading causes of ALI and ALF in the Northern Hemisphere. Brain dysfunction defined as hepatic encephalopathy is one of the main diagnostic criteria for ALF. While neuroinflammation and brain metabolic alterations significantly contribute to hepatic encephalopathy, their evaluation at early stages of ALI remained challenging. To provide insights, we utilized post-mortem analysis and non-invasive brain micro positron emission tomography (microPET) imaging of mice with APAP-induced ALI.

Male C57BL/6 mice were treated with vehicle or APAP (600 mg/kg, i.p.). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver damage (using H&E staining), hepatic and serum IL-6 levels, and hippocampal IBA1 (using immunolabeling) were evaluated at 24h and 48h. Vehicle and APAP treated animals also underwent microPET imaging utilizing a dual tracer approach, including [11C]-peripheral benzodiazepine receptor ([11C]PBR28) to assess microglia/astrocyte activation and [18F]-fluoro-2-deoxy-2-D-glucose ([18F]FDG) to assess energy metabolism. Brain images were pre-processed and evaluated using conjunction and individual tracer uptake analysis.

APAP-induced ALI and hepatic and systemic inflammation were detected at 24h and 48h by significantly elevated serum ALT and AST levels, hepatocellular damage, and increased hepatic and serum IL-6 levels. In parallel, increased microglial numbers, indicative for neuroinflammation were observed in the hippocampus of APAP-treated mice. MicroPET imaging revealed overlapping increases in [11C]PBR28 and [18F]FDG uptake in the hippocampus, thalamus, and habenular nucleus indicating microglial/astroglial activation and increased energy metabolism in APAP-treated mice (vs. vehicle-treated mice) at 24h. Similar significant increases were also found in the hypothalamus, thalamus, and cerebellum at 48h. The individual tracer uptake analyses (APAP vs vehicle) at 24h and 48h confirmed increases in these brain areas and indicated additional tracer- and region-specific effects including hippocampal alterations.

Peripheral manifestations of APAP-induced ALI in mice are associated with brain neuroinflammatory and metabolic alterations at relatively early stages of disease progression, which can be non-invasively evaluated using microPET imaging and conjunction analysis. These findings support further PET-based investigations of brain function in ALI/ALF that may inform timely therapeutic interventions.

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.

Breath analysis, despite being an overlooked biomatrix, has a rich history in disease diagnosis. However, volatile organic compounds (VOCs) have yet to establish themselves as clinically validated biomarkers for specific diseases. As focusing solely on late-stage or malignant disease biomarkers may have limited relevance in clinical practice, the objective of this review is to explore the potential of VOC breath tests for the diagnosis of non-cancer diseases: (1) Precancerous conditions like gastro-esophageal reflux disease (GERD) and Barrett's esophagus (BE), where breath tests can complement endoscopic screening; (2) endoluminal diseases associated with autoinflammation and dysbiosis, such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and coeliac disease, which currently rely on biopsy and symptom-based diagnosis; (3) chronic liver diseases like cirrhosis, hepatic encephalopathy, and non-alcoholic fatty liver disease, which lack non-invasive diagnostic tools for disease progression monitoring and prognostic assessment. A literature search was conducted through EMBASE, MEDLINE, and Cochrane databases, leading to an overview of 24 studies. The characteristics of these studies, including analytical platforms, disorder type and stage, group size, and performance evaluation parameters for diagnostic tests are discussed. Furthermore, how VOCs can be utilized as non-invasive diagnostic tools to complement existing gold standards is explored. By refining study designs, sampling procedures, and comparing VOCs in urine and blood, we can gain a deeper understanding of the metabolic pathways underlying VOCs. This will establish breath analysis as an effective non-invasive method for differential diagnosis and disease monitoring.

Cirrhosis with complications of liver decompensation and hepatocellular carcinoma (HCC) constitute a leading cause of morbidity and mortality worldwide. Portal hypertension is central to the progression of liver disease and decompensation. The most recent Baveno VII guidance included revision of the nomenclature for chronic liver disease, termed compensated advanced chronic liver disease, and leveraged the use of liver stiffness measurement to categorize the degree of portal hypertension. Additionally, non-selective beta blockers, especially carvedilol, can improve portal hypertension and may even have a survival benefit. Procedural techniques with interventional radiology have become more advanced in the management of refractory ascites and variceal bleeding, leading to improved prognosis in patients with decompensated liver disease. While lactulose and rifaximin are the preferred treatments for hepatic encephalopathy, many alternative treatment options may be used in refractory cases and even procedural interventions such as shunt embolization may be of benefit. The approval of terlipressin for the treatment of hepatorenal syndrome (HRS) in the USA has improved the way in which HRS is managed and will be discussed in detail. Malnutrition, frailty, and sarcopenia lead to poorer outcomes in patients with decompensated liver disease and should be addressed in this patient population. Palliative care interventions can lead to improved quality of life and clinical outcomes. Lastly, the investigation of systemic therapies, in particular immunotherapy, has revolutionized the management of HCC. These topics will be discussed in detail in this review.

The liver, the largest organ in the human body, plays a multifaceted role in digestion, coagulation, synthesis, metabolism, detoxification, and immune defense. Changes in liver function often coincide with disruptions in both the central and peripheral nervous systems. The intricate interplay between the nervous and immune systems is vital for maintaining tissue balance and combating diseases. Signaling molecules and pathways, including cytokines, inflammatory mediators, neuropeptides, neurotransmitters, chemoreceptors, and neural pathways, facilitate this complex communication. They establish feedback loops among diverse immune cell populations and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems within the liver. In this concise review, we provide an overview of the structural and compositional aspects of the hepatic neural and immune systems. We further explore the molecular mechanisms and pathways that govern neuroimmune communication, highlighting their significance in liver pathology. Finally, we summarize the current clinical implications of therapeutic approaches targeting neuroimmune interactions and present prospects for future research in this area.

Multiple organs and tissues coordinate to respond to dietary and environmental challenges. It is interorgan crosstalk that contributes to systemic metabolic homeostasis. The liver and brain, as key metabolic organs, have their unique dialogue to transmit metabolic messages. The interconnected pathogenesis of liver and brain is implicated in numerous metabolic and neurodegenerative disorders. Recent insights have positioned the liver not only as a central metabolic hub but also as an endocrine organ, capable of secreting hepatokines that transmit metabolic signals throughout the body via the bloodstream. Metabolites from the liver or gut microbiota also facilitate a complex dialogue between liver and brain. In parallel to humoral factors, the neural pathways, particularly the hypothalamic nuclei and autonomic nervous system, are pivotal in modulating the bilateral metabolic interplay between the cerebral and hepatic compartments. The term "liver-brain axis" vividly portrays this interaction. At the end of this review, we summarize cutting-edge technical advancements that have enabled the observation and manipulation of these signals, including genetic engineering, molecular tracing, and delivery technologies. These innovations are paving the way for a deeper understanding of the liver-brain axis and its role in metabolic homeostasis.

Renal replacement therapy (RRT) is used in hyperammonemia to reduce the concentration of ammonia in the blood. In the case of plasma hyperosmolarity, RRT can also rapidly decrease plasma osmolarity, which may increase cerebral edema in these patients and favor the occurrence of brain herniation.

We conducted a retrospective clinical study in a tertiary care university-affiliated hospital. All patients admitted in a Pediatric Intensive Care Unit (PICU), less than 18 years old with ammonemia >150 µmol/L and who underwent RRT between January 2015 and June 2023 were included. We collected data on plasma osmolarity levels, osmolar gap and blood ammonia levels before and during RRT.

Eleven patients were included (10 with acute liver failure and 1 with a urea cycle disorders). Their mean age was 36.2 months. Before RRT, the median highest measured osmolarity was 320 (305-324) mOsm/L, whereas the median calculated osmolarity was 303 (293-314) mOsm/L, corresponding to an osmolar gap of 14 mOsm/L. Ammonia blood level over 400 µmol/L are significantly associated with higher plasma osmolarity (P-Value <0.001). In one case, a patient had a brain herniation episode after a quick osmolar drop. This episode was reversed by the administration of hyperosmolar agents and the temporary suspension of RRT.

This study highlights the hyperosmolarity and high osmolar gap that occur in children with hyperammonemia. A careful monitoring and control of plasma osmolarity evolution may alert clinician on the risk of occurrence of neurological complication such as brain herniation.

Acute confusional state (ACS) is a common cause of admission to the emergency department (ED). It can be related to numerous etiologies. Electroencephalography (EEG) can show specific abnormalities in cases of non-convulsive status epilepticus (NCSE), or metabolic or toxic encephalopathy. However, up to 80% of patients with a final diagnosis of NCSE have an ACS initially attributed to another cause. The exact place of EEG in the diagnostic work-up remains unclear.

Data of consecutive patients admitted to the ED for an ACS in a two-year period and who were referred for an EEG were collected. The initial working diagnosis was based on medical history, clinical, biological and imaging investigations allowing classification into four diagnostic categories. Comparison to the final diagnosis was performed after EEG recordings (and sometimes additional tests) were performed, which allowed the reclassification of some patients from one category to another.

Seventy-five patients (mean age: 71.1 years) were included with the following suspected diagnoses: seizures for 8 (11%), encephalopathy for 14 (19%), other cause for 34 (45%) and unknown for 19 (25%). EEG was recorded after a mean of 1.5 days after symptom onset, and resulted in the reclassification of patients as follows: seizure for 15 (20%), encephalopathy for 15 (20%), other cause for 29 (39%) and unknown cause for 16 (21%). Moreover, ongoing epileptic activity (NCSE or seizure) and interictal epileptiform activity were found in eight (11%) patients initially diagnosed in another category.

In our cohort, EEG was a key examination in the management strategy of ACS in 11% of patients admitted to the ED. It resulted in a diagnosis of epilepsy in these patients admitted with unusual confounding presentations.

Cardiovascular disease is the leading cause of mortality among nonalcoholic steatohepatitis (NASH) patients who undergo liver transplants. In the present study, machine learning algorithms were used to identify important risk factors for cardiovascular death and to develop a prediction model. The Standard Transplant Analysis and Research data were gathered from the Organ Procurement and Transplantation Network. After cleaning and preprocessing, the dataset comprised 10,871 patients and 92 features. Recursive feature elimination (RFE) and select from model (SFM) were applied to select relevant features from the dataset and avoid overfitting. Multiple machine learning algorithms, including logistic regression, random forest, decision tree, and XGBoost, were used with RFE and SFM. Additionally, prediction models were developed using a support vector machine, Gaussian naïve Bayes, K-nearest neighbors, random forest, and XGBoost algorithms. Finally, SHapley Additive exPlanations (SHAP) were used to increase interpretability. The findings showed that the best feature selection method was RFE with a random forest estimator, and the most critical features were recipient and donor blood type, body mass index, recipient and donor state of residence, serum creatinine, and year of transplantation. Furthermore, among all the outcomes, the XGBoost model had the highest performance, with an accuracy value of 0.6909 and an area under the curve value of 0.86. The findings also revealed a predictive relationship between features and cardiovascular death after liver transplant among NASH patients. These insights may assist clinical decision-makers in devising strategies to prevent cardiovascular complications in post-liver transplant NASH patients.

The metabolic signals that regulate sleep and the metabolic functions that occur during sleep are active areas of research. Prior studies have focused on sugars and nucleotides but new genetic evidence suggests novel functions of lipid and amino acid metabolites in sleep. Additional genetic studies of energetic signaling pathways and the circadian clock transcription factor network have increased our understanding of how sleep responds to changes in the metabolic state. This review focuses on key recent insights from genetic experiments in humans and model organisms to improve our understanding of the interrelationship between metabolism and sleep.

Quantitative susceptibility mapping (QSM) is a unique technique for providing quantitative information on tissue magnetic susceptibility using phase image data. QSM can provide valuable information regarding physiological and pathological processes such as iron deposition, hemorrhage, calcification, and myelin. QSM has been considered for use as an imaging biomarker to investigate physiological status and pathological changes. Although various studies have investigated the clinical applications of QSM, particularly regarding the use of QSM in clinical practice, have not been examined well. This review provides on an overview of the basics of QSM and its clinical applications in neuroradiology. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Disturbance of the blood‒brain barrier (BBB) and associated inflammatory responses are observed in patients with hepatic encephalopathy (HE) and can cause long-term complications. Dahuang-Wumei decoction (DWD) is a renowned traditional Chinese herbal medicine with a long history of clinical use and has been widely employed as an effective treatment for hepatic encephalopathy (HE). Despite its established efficacy, the precise mechanisms underlying the therapeutic effects of DWD have not been fully elucidated.

The present study aimed to comprehensively explore the potential effects and underlying molecular mechanisms of DWD on HE through an integrated investigation that included both in vivo and in vitro experiments.

In the present study, carbon tetrachloride (CCl4) and thioacetamide (TAA) were used to establish an HE model in mice. The therapeutic effects of DWD on liver injury, fibrosis, brain injury, behaviour, and consciousness disorders were evaluated in vivo. C8-D1A and bEnd.3 cells were used to construct a BBB model in vitro. The effects of DWD on proinflammatory factor expression, BBB damage and the Wnt/β-catenin pathway were detected in vivo and in vitro.

Our results showed that DWD can improve liver injury and fibrosis and brain damage and inhibit neurofunctional and behavioural disorders in mice with HE. Afterwards, we found that DWD decreased the levels of proinflammatory factors and suppressed BBB disruption by increasing the levels of junction proteins in vivo and vitro. Further studies verified that the Wnt/β-catenin pathway may play a pivotal role in mediating the inhibitory effect of DWD on HE.

These results demonstrated that DWD can treat HE by preventing BBB disruption, and the underlying mechanisms involved were associated with the activation of the Wnt/β-catenin pathway and the inhibition of inflammatory responses.

MELD 3.0 introduces changes to address waitlist disparities for liver transplant (LT) candidates. Ascites and hepatic encephalopathy (HE) are important milestones in the natural history of cirrhosis regardless of the Model for End-Stage Liver Disease (MELD) score. We aim to assess the impact of ascites and HE and its interaction with MELD 3.0 on waitlist mortality.

This is a retrospective study of patients listed for LT in the Organ Procurement and Transplantation Network database from 2016 to 2021. The primary outcome was waitlist mortality (death/delisting for too sick to LT). Ascites/HE were classified as moderate ascites without moderate HE (mAscites), moderate HE without moderate ascites (mHE), both moderate ascites/HE (mBoth), and neither. MELD 3.0 scores were categorized as <20, 20-29, 30-39, and ≥40.

Of 39 025 candidates, 29% had mAscites, 3% mHE, and 8% mBoth. One-year waitlist mortality was 30%, 38%, and 47%, respectively, compared with 17% (all P < 0.001) for those with neither. In multivariable Cox regression, the adjusted risk of waitlist mortality associated with mAscites (versus neither) was a hazard ratio (HR) of 1.76 (95% confidence interval [CI], 1.55-2.00) when the MELD 3.0 score was <20, significantly higher than when the MELD 3.0 score was 20-29 (HR 1.40; 95% CI, 1.27-1.54), 30-39 (HR 1.19; 95% CI, 1.04-1.35), and ≥40 (HR 1.14; 95% CI, 0.91-1.43, interaction P < 0.05 for all). A similar pattern was observed by MELD 3.0 for both moderate ascites/HE.

The presence of moderate ascites alone, or combined with moderate HE, not only increases the risk of waitlist mortality but also has a differential effect by MELD 3.0, especially at lower MELD scores. Earlier strategies addressing this group and improving treatment plans or access to LT regardless of MELD remain needed.

We describe the endovascular embolization of a 65-year-old man with chronic hepatic encephalopathy. A contrast-enhanced computed tomography demonstrated a splenorenal shunt and a recanalized paraumbilical vein as a continuous portal shunt connecting the left branch of the portal vein and the right common femoral vein. A 2-session embolization was performed for the splenorenal shunt. First, the transvenous approach was used for coil embolization of the splenorenal shunt. It was difficult to advance the catheter system to the embolization site, and it was unstable during coil placement. Second, the paraumbilical venous approach was used to place additional coils. The catheter system had good maneuverability and easily reached the embolization site. Additionally, the stable system allowed for densely packed additional coil implantations. This report demonstrated the paraumbilical venous approach's effectiveness in catheter maneuverability and system stability during coil embolization.

Management of hepatic encephalopathy relies on self-titration of lactulose. In this feasibility trial, we assess an artificial intelligence-enabled tool to guide lactulose use through a smartphone application.

Subjects with hepatic encephalopathy on lactulose captured bowel movement pictures during lead-in and intervention phases. During the intervention phase, daily feedback on lactulose titration was delivered through the application. Goals were determined according to number of bowel movement and Bristol Stool Scale reports.

Subjects completed the study with more than 80% satisfaction. In the lead-in phase, less compliant subjects achieved Bristol Stool Scale goal on 62/111 (56%) of days compared with 107/136 (79%) in the intervention phase ( P = 0.041), while the most compliant subjects showed no difference. Severe/recurrent hepatic encephalopathy group achieved Bristol Stool Scale goal on 80/104 (77%) days in the lead-in phase and 90/110 (82%) days in the intervention phase ( P = NS), compared with 89/143 (62%) days and 86/127 (68%) days in the stable group.

Dieta application is a promising tool for objective Bowel Movement/Bristol Stool Scale tracking for hepatic encephalopathy and may potentially be used to assist with lactulose titration.

The pathophysiology of hepatic encephalopathy (HE) is complex, with hyperammonemia playing a central role in its development. Traditional therapies for HE have targeted ammonia and include medications such as lactulose and rifaximin. Although these agents are considered standard of care, nontraditional treatments seek to affect other factors in the pathogenesis of HE. Finally, procedural therapies include albumin dialysis, shunt closure, and the ultimate cure for HE, which is liver transplant. The treatments discussed provide alternative options for patients who have failed standard of care. However, more high-quality studies are needed to routinely recommend many of these agents.