Hepatic encephalopathy (HE) is one of the major complications of cirrhosis, and its presence is associated with poor survival. Several risk factors for HE are well established, including age, history of HE, portosystemic shunts, or poorer liver function. In recent years, diabetes mellitus (DM) has emerged as another potential risk factor for the development of HE. This may be important for many patients, as the incidence of type 2 DM (T2DM) is increasing worldwide and, consequently, the incidence of NAFLD-related cirrhosis is rising simultaneously. In addition, DM is a critical factor in the progression of other liver diseases, such as alcohol-related liver disease. Thus, the number of patients with cirrhosis and comorbid T2DM will also increase. To date, the prevalence of DM already ranges between 22 - 40% in patients with cirrhosis. DM-associated factors that may influence the risk of HE include systemic inflammation, insulin resistance with increased muscle protein breakdown as well as autonomic dysfunction with prolonged intestinal transit time and small intestinal bacterial overgrowth. Currently, the evidence for an association between DM and both minimal and overt HE is weak and it seems likely that only poor glycemic control has an impact on HE risk. In addition, there are some early signs indicating that DM may impair the response of patients with HE to pharmacological therapies such as rifaximin. Thus, improvements in the management of glycemic control may be a candidate future target to reduce the risk of HE. In this concise review, we summarize the current evidence on the association between DM and HE and its potential future implications.

INTRODUCTION: Frailty is common in patients with cirrhosis and increases the vulnerability to internal and external stressors. This study aimed to investigate the impact of frailty, as defined by the Clinical Frailty Scale (CFS), on the risk of acute kidney injury (AKI) and hepatorenal syndrome (HRS-AKI) in hospitalized patients with liver cirrhosis. METHODS: We analyzed data of 201 nonelectively hospitalized patients with cirrhosis and without higher-grade chronic kidney disease. Patient characteristics were captured within the first 24 hours of hospital admission, and frailty was assessed using the CFS. Patients were followed for the development of AKI and/or HRS-AKI during the hospital stay. RESULTS: In the total cohort, median CFS was 3 (interquartile range 3–4), and 34 (16.9%) patients were frail (CFS >4). During the hospital stay, 110 (54.7%) and 49 (24.3%) patients developed AKI or HRS-AKI, respectively. Patients with AKI or HRS-AKI had a significantly higher CFS than patients without kidney injury (P < 0.001 each). In multivariable analyses, a higher CFS was independently associated with the development of AKI (odds ratio [OR] 1.467, 95% confidence interval (CI) 1.065–2.021) in the total cohort and HRS-AKI (OR 1.809, 95% CI 1.263–2.591) in the subcohort of patients with a history of ascites. In addition, there was a strong association between frailty (OR 3.717, 95% CI 1.456–9.491) and HRS-AKI. DISCUSSION: Frailty in patients with cirrhosis is associated with AKI and HRS-AKI. In this context, CFS appears to be a reliable tool to identify patients at high risk for developing AKI or HRS-AKI on hospital admission.

Background: ADVanced Organ Support (ADVOS) is a novel type of extracorporeal albumin dialysis that supports multiorgan function in patients with acute-on-chronic liver failure (ACLF). No data exist on whether ADVOS affects inflammatory cytokine levels, which play a relevant role in ACLF. Aim: Our aim was to quantify cytokine levels both before and after a single ADVOS treatment in patients with ACLF at a regular dialysis ward. Methods and results: In this prospective study, 15 patients (60% men) with ACLF and an indication for renal replacement therapy were included. Patient liver function was severely compromised, reflected by a median CLIF-consortium ACLF score of 38 (IQR 35; 40). Blood samples were directly taken before and after ADVOS dialysis. The concentration of cytokines for IL-1β, IFN-α2, IFN-γ, TNF-α, MCP-1, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23, IL-33 were quantified via a cytometric bead array. We found no significant (p > 0.05) change in cytokine levels, even when patients were stratified for dialysis time (<480 min versus ≥480 min). The relevance of the assessed cytokines in contributing to systemic inflammation in ACLF was demonstrated by Ingenuity pathway analysis^®. Conclusion: Concentrations of pathomechanistically relevant cytokines remained unchanged both before and after ADVOS treatment in patients with ACLF.

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

The presynaptic protein Mover/TPRGL/SVAP30 is absent in Drosophila and C. elegans and differentially expressed in synapses in the rodent brain, suggesting that it confers specific functions to subtypes of presynaptic terminals. In order to investigate how the absence of this protein affects behavior and learning, Mover knockout mice (KO) were subjected to a series of established learning tests. To determine possible behavioral and cognitive alterations, male and female 8-week-old KO and C57Bl/6J wildtype (WT) control mice were tested in a battery of memory and anxiety tests. Testing included the cross maze, novel object recognition test (NOR), the Morris water maze (MWM), the elevated plus maze (EPM), and the open field test (OF). Mover KO mice showed impaired recognition memory in the NOR test, and decreased anxiety behavior in the OF and the EPM. Mover KO did not lead to changes in working memory in the cross maze or spatial reference memory in the MWM. However, a detailed analysis of the swimming strategies demonstrated allocentric-specific memory deficits in male KO mice. Our data indicate that Mover appears to control synaptic properties associated with specific forms of memory formation and behavior, suggesting that it has a modulatory role in synaptic transmission.