Enters the CNS and reverses the inhibitory effects of neuroactive steroids on brain function in humans 9 Normalizes an elevated GABAergic tone, independent of ammonia 9 Improves cognitive function Cirrhosisis a growing problem and an end-stage disease Current drugs are targeting elevated ammonia levels Increased production of allopregnanolone Ammonia, inflammation Golexanolone: the only HE drug directly targeting CNS Golexanolone in HE CNS-related disorders Excessive GABAergic inhibition is a central driver of HE Excessive GABAergic tone Cirrhosis HighlightsHerein, we report findings from a pilot phase IIa study of golexanolone, a GABA-A receptor-modulating steroid antagonist, in clinical development for HE.Golexanolone was generally well tolerated and seemed to improve neuropsychiatric performance.These findings support a role for neurosteroids in the pathogenesis of HE-related sleepiness and vigilance.The results also suggest a role for golexanolone in the treatment of neurosteroid-mediated vigilance and cognitive disorders including HE.

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INTRODUCTION:The prevalence of minimal hepatic encephalopathy (MHE), in particular in different subgroups, remains unknown. This study aimed to analyze the prevalence of MHE in different subgroups to identify patients at high risk and to pave the way for personalized screening approaches.METHODS:In this study, data of patients recruited at 10 centers across Europe and the United States were analyzed. Only patients without clinical signs of hepatic encephalopathy were included. MHE was detected using the Psychometric Hepatic Encephalopathy Score (PHES, cut-off < or ≤−4 depending on local norms). Clinical and demographic characteristics of the patients were assessed and analyzed.RESULTS:In total, 1,868 patients with cirrhosis with a median model for end-stage liver disease (MELD) of 11 were analyzed (Child-Pugh [CP] stages: A 46%, B 42%, and C 12%). In the total cohort, MHE was detected by PHES in 650 patients (35%). After excluding patients with a history of overt hepatic encephalopathy, the prevalence of MHE was 29%. In subgroup analyses, the prevalence of MHE in patients with CP A was low (25%), whereas it was high in CP B or C (42% and 52%). In patients with a MELD score <10, the prevalence of MHE was only 25%, but it was 48% in patients with a MELD score ≥20. Standardized ammonia levels (ammonia level/upper limit of normal of each center) correlated significantly, albeit weakly with PHES (Spearman ρ = −0.16, P < 0.001).DISCUSSION:The prevalence of MHE in patients with cirrhosis was high but varied substantially between diseases stages. These data may pave the way for more individualized MHE screening approaches.

Background and Aims: The occurrence of overt hepatic encephalopathy (HE) marks a significant progression in the natural history of liver disease. The aims of the present study were to: 1) describe a large cohort of patients with cirrhosis in terms of neuropsychological or neurophysiological HE indices, and 2) test if the severity of liver disease and/or any such indices [Psychometric Hepatic Encephalopathy Score (PHES), Scan test, electroencephalography (EEG)] predicted mortality/HE risk in a subgroup of such cohort. Method: Four hundred and sixty-one patients with cirrhosis (59 ± 10 years; 345 males) were included; information on previous overt HE episodes was available in 407. Follow-up information on mortality/HE-related hospitalization in 134/127 respectively. Information on previous overt HE episodes and both mortality and HErelated hospitalization over the follow-up in 124.Results: Patients with a history of overt HE (60%) had poorer liver function, worse neuropsychiatric indices, higher ammonia levels and higher prevalence of portal-systemic shunt. The risk of HE-related hospitalization over the follow-up was higher in patients with higher MELD score and worse Scan performance. Mortality was higher in those with higher MELD. Among patients without a history of overt HE, those with worse PHES had higher HE risk. Among patients with a history, those with higher MELD, better PHES and worse Scan performance had higher HE risk. Conclusions:In patients without previous overt HE episodes, neuropsychological and neurophysiological tests predict HE, while in those with previous overt HE episodes, HE development largely depends on the severity of liver dysfunction.