Professor Sara Montagnese

Management of hepatic encephalopathy (HE) remains challenging from a medical and psychosocial perspective. Members of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recognized 5 key unresolved questions in HE management focused on (i) driving, (ii) ammonia levels in clinical practice, (iii) testing strategies for covert or minimal HE, (iv) therapeutic options, and (v) nutrition and patient-reported outcomes. The consensus document addresses these topical issues with a succinct review of the literature and statements that critically evaluate the current science and practice, laying the groundwork for future investigations.

IntroductionHepatic encephalopathy (HE) affects the survival and quality of life of patients with cirrhosis. However, longitudinal data on the clinical course after hospitalization for HE are lacking. The aim was to estimate mortality and risk for hospital readmission of cirrhotic patients hospitalized for HE.MethodsWe prospectively enrolled 112 consecutive cirrhotic patients hospitalized for HE (HE group) at 25 Italian referral centers. A cohort of 256 patients hospitalized for decompensated cirrhosis without HE served as controls (no HE group). After hospitalization for HE, patients were followed-up for 12 months until death or liver transplant (LT).ResultsDuring follow-up, 34 patients (30.4%) died and 15 patients (13.4%) underwent LT in the HE group, while 60 patients (23.4%) died and 50 patients (19.5%) underwent LT in the no HE group. In the whole cohort, age (HR 1.03, 95% CI 1.01–1.06), HE (HR 1.67, 95% CI 1.08–2.56), ascites (HR 2.56, 95% CI 1.55–4.23), and sodium levels (HR 0.94, 95% CI 0.90–0.99) were significant risk factors for mortality. In the HE group, ascites (HR 5.07, 95% CI 1.39–18.49) and BMI (HR 0.86, 95% CI 0.75–0.98) were risk factors for mortality, and HE recurrence was the first cause of hospital readmission.ConclusionIn patients hospitalized for decompensated cirrhosis, HE is an independent risk factor for mortality and the most common cause of hospital readmission compared with other decompensation events. Patients hospitalized for HE should be evaluated as candidates for LT.

Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis.

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.

Few data on hepatic encephalopathy (HE) over time are available, thus our aim was to study its evolution in patients with varying degree of HE on first assessment. Eighty-six patients with cirrhosis (age = 58 ± 11 years; males = 72) were evaluated 2–10 times for liver transplantation selection purposes, differential diagnosis or treatment optimization. The presence/severity of HE was assessed by clinical and neuropsychiatric indices [ Psychometric Hepatic Encephalopathy Score (PHES) and electroencephalography (EEG)] and the severity of liver disease by the Model for End-Stage Liver Disease (MELD) score. Treatment was instituted/modified after each evaluation. Amongst 23 unimpaired patients, 56/6% remained unimpaired, 35/3% developed covert HE, 9/0% developed overt HE on second/third evaluation. Amongst 32 patients with covert HE, 25/10% became unimpaired, 44/19% remained covert, 31/13% developed overt HE. Finally, amongst 32 patients with overt HE, 19/16% became unimpaired, 25/13 % became covert and 56/25% remained overt. PHES results improved in patients with overt HE and EEG worsened over time (despite remaining normal) in unimpaired patients. In patients with multiple evaluations, HE evolution was manifold and difficult to predict. HE evolution over time is variable and largely dependent on HE history/management. These data support the concept that HE is an essentially reversible condition.

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. 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. 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

The formation of a collateral circulation is a direct consequence of portal hypertension. Various types of collateral circulation may develop during the course of the disease, but from a clinical point of view the most important is the gastroesophageal collateral circulation, which results in the formation of gastroesophageal varices. Varices are a very specific index of the presence of portal hypertension, but they are not sensitive, since patients with portal hypertension may develop collateral vessels other than esophageal varices. Once varices are formed, they progress from small to large, and eventually bleed. The risk of bleeding increases according to the size of the varices, the presence of red marks, and the severity of the underlying liver disease. Available strategies for preventing variceal formation and growth, with the aim of decreasing the risk of variceal bleeding, are discussed based on the available evidence.

Hyperammonaemia/mild hepatic encephalopathy (HE) can be simulated by the oral administration of a so-called amino acid challenge (AAC). This study sought to assess the effects of the AAC alone and in combination with either ammonia-lowering [L-ornithine-L-aspartate (LOLA)] or vigilance-enhancing medication (caffeine). Six patients with cirrhosis (5 males; 61.3 ± 9.2 years; 5 Child A, 1 Child B) and six healthy volunteers (5 males; 49.8 ± 10.6 years) were studied between 08:00 and 19:00 on Monday of three consecutive weeks. The following indices were obtained: hourly capillary ammonia, hourly subjective sleepiness, paper & pencil/computerized psychometry and wake electroencephalography (EEG) at 12:00, i.e. at the time of the maximum expected effect of the AAC. RESULTS On average, patients had worse neuropsychological performance and slower EEG than healthy volunteers in all conditions but differences did not reach significance. In healthy volunteers, the post-AAC increase in capillary ammonia levels was contained by both the administration of LOLA and of caffeine (significant differences between 10:00 and 14:00 h). The administration of caffeine also resulted in a reduction in subjective sleepiness and in the amplitude of the EEG on several frontal/temporal-occipital sites (p 

Chronobiology is not routinely taught to biology or medical students in most European countries. Here we present the results of the chronobiology practicals of a group of students of the University of Padova, with a view to highlight some interesting features of this group, and to share a potentially interesting cross-faculty teaching experience. Thirty-eight students (17 males; 22.9 ± 1.6 yrs) completed a set of self-administered electronic sleep quality [Pittsburgh Sleep Quality Index (PSQI)], chronotype and sleepiness [Epworth Sleepiness Scale (ESS)] questionnaires. They then went on to complete sleep diaries for two weeks. Sixteen also wore an actigraph, 8 wore wireless sensors for skin temperature, and 8 underwent a course of chronotherapy aimed at anticipating their sleep-wake timing. Analyses were performed as practicals, together with the students. Average PSQI score was 5.4 ± 1.9, with 15 (39%) students being poor sleepers. Average ESS score was 6.5 ± 3.3, with 3 (8%) students exhibiting excessive daytime sleepiness. Seven classified themselves as definitely/moderately morning, 25 as intermediates, 6 as moderately/definitely evening. Students went to bed/fell asleep significantly later on weekends, it took them less to fall asleep and they woke up/got up significantly later. Diary-reported sleep onset time coincided with the expected decrease in proximal skin temperature. Finally, during chronotherapy they took significantly less time to fall asleep. In conclusion, significant abnormalities in the sleep-wake patterns of a small group of university students were observed, and the students seemed to benefit from chronotherapy. We had a positive impression of our teaching experience, and the chronobiology courses obtained excellent student feedback.

Up to 50–65% of patients with cirrhosis exhibit interrupted night sleep, delayed sleep habits and excessive daytime sleepiness. These have been variously attributed to disease complications (i.e. ascites, pruritus), hepatic encephalopathy or impaired hepatic melatonin metabolism, but the understanding of their pathophysiology remains limited and their treatment problematic. In addition, use of common hypnotics is contraindicated in these patients because of impaired hepatic disposition and increased cerebral sensitivity to psychoactive medication. Sleep is regulated by the interaction of a homeostatic and a circadian process. The homeostatic process determines sleep propensity in relation to sleep history, so that the need to sleep increases in parallel with the duration of the wake period. The circadian process, which is marked by the 24-h rhythm of the hormone melatonin, is responsible for the alternation of high/low sleep propensity in relation to dark/light cues. Circadian sleep regulation has been studied in some depth in patients with cirrhosis, who show considerable delays in the 24-h melatonin rhythm, mostly in relation to impaired sensitivity to light cues. However, while circadian abnormalities are associated with delayed sleep habits, they do not offer a comprehensive explanation to the sleep–wake changes exhibited by these patients. Limited data are available on homeostatic sleep control in patients with cirrhosis, which is worthy of further study.

The terms minimal hepatic encephalopathy and covert hepatic encephalopathy are defined. Clinical assessment is unreliable and both require the use of diagnostic tools. Of these, psychometric tests are the most widely used. They require proper standardization and may be biased by patient cooperation or lack thereof. The measure of the critical flicker frequency and of the electroencephalogram, possibly quantified, are also useful. The alteration of any of them is not strictly parallel in size and may vary from patient to patient. When possible, the use of multiple measures might increase diagnostic reliability. These functional measures should be interpreted within the clinical/biochemical profile of the patient to exclude other disorders. A flow chart for treatment is proposed on the basis of current knowledge.

OBJECTIVE: To study the effect of hyperammonaemia on the wake electroencephalogram (EEG) of patients with cirrhosis and healthy volunteers. METHODS: Wake EEGs were recorded prior to and after the induction of controlled hyperammonaemia in 10 patients with cirrhosis and 10 matched healthy volunteers. RESULTS: At baseline, patients had higher ammonaemia than healthy volunteers and their dominant EEG rhythm was slower and of higher amplitude. Induced hyperammonaemia resulted in increased spectral power over most of the scalp in healthy volunteers and decreased frequency along the anterior-posterior midline in patients. CONCLUSIONS: These findings suggest different effects of hyperammonaemia on the wake EEG in relation to baseline/peak ammonia levels. SIGNIFICANCE: The wake EEG is sensitive to hyperammonaemia and power-based EEG parameters may help in its neurophysiological definition, which, to date, has generally been based on EEG frequency indices.

The EASL Clinical Practice Guidelines (CPGs) on the management of hepatic encephalopathy (HE) present evidence-based answers to a set of relevant questions (where possible, formulated in PICO [patient/population, intervention, comparison and outcomes] format) on the definition, diagnosis, differential diagnosis and treatment of HE. The document does not cover the pathophysiology of HE and does not cover all available treatment options. The methods through which it was developed and any information relevant to its interpretation are also provided.

Background Daily rhythms are observed in humans and almost all other organisms. Most of these observed rhythms reflect both underlying endogenous circadian rhythms and evoked responses from behaviours such as sleep/wake, eating/fasting, rest/activity, posture changes and exercise. For many research and clinical purposes, it is important to understand the contribution of the endogenous circadian component to these observed rhythms. Content The goal of this manuscript is to provide guidance on best practices in measuring metrics of endogenous circadian rhythms in humans and promote the inclusion of circadian rhythms assessments in studies of health and disease. Circadian rhythms affect all aspects of physiology. By specifying minimal experimental conditions for studies, we aim to improve the quality, reliability and interpretability of research into circadian and daily (i.e., time-of-day) rhythms and facilitate the interpretation of clinical and translational findings within the context of human circadian rhythms. We describe protocols, variables and analyses commonly used for studying human daily rhythms, including how to assess the relative contributions of the endogenous circadian system and other daily patterns in behaviours or the environment. We conclude with recommendations for protocols, variables, analyses, definitions and examples of circadian terminology. Conclusion Although circadian rhythms and daily effects on health outcomes can be challenging to distinguish in practice, this distinction may be important in many clinical settings. Identifying and targeting the appropriate underlying (patho)physiology is a medical goal. This review provides methods for identifying circadian effects to aid in the interpretation of published work and the inclusion of circadian factors in clinical research and practice.

Circadian clocks orchestrate a variety of physiological and behavioural functions within the 24-h day. These timekeeping systems have also been implicated in developmental and reproductive processes that span more (or less) than 24 h. Whether natural alleles of cardinal clock genes affect entire sets of life-history traits (i.e., reproductive arrest, developmental time, fecundity), thus providing a wider substrate for seasonal adaptation, remains unclear. Here we show that natural alleles of the timeless (tim) gene of Drosophila melanogaster, previously shown to modulate flies’ propensity to enter reproductive dormancy, differentially affect correlated traits such as early-life fecundity and developmental time. Homozygous flies expressing the shorter TIM isoform (encoded by the s-tim allele) not only show a lower dormancy incidence compared to those homozygous for ls-tim (which produce both the short and an N-terminal additional 23-residues longer TIM isoform), but also higher fecundity in the first 12 days of adult life. Moreover, s-tim homozygous flies develop faster than ls-tim homozygous flies at both warm (25°C) and cold (15°C) temperatures, with the gap being larger at 15°C. In summary, this phenotypic analysis shows that natural variants of tim affect a set of life-history traits associated with reproductive dormancy in Drosophila. We speculate that this provides further adaptive advantage in temperate regions (with seasonal changes) and propose that the underlying mechanisms might not be exclusively dependent on photoperiod, as previously suggested.

The relationship between hepatic encephalopathy (HE) and the sleep-wake disturbances exhibited by patients with cirrhosis remains debated. The aim of this study was to examine the usefulness of sleep-wake interview within the context of HE assessment. One-hundred-and-six cirrhotic patients were asked three yes/no questions investigating the presence of difficulty falling asleep, night awakenings and daytime sleepiness. All underwent formal HE assessment, quantitative electroencephalography and standardised psychometry. Fifty-eight were monitored for 8 ± 6 months in relation to the occurrence of HE. Patients complaining of daytime sleepiness (n = 75, 71 %) had slower EEGs than those who did not report it (relative alpha power: 37 ± 19 vs. 48 ± 17 %, p  

Details of two patients with chronic hepatitis C infection who developed features of Parkinsonism when treated with IFN-α2b and ribavirin are reported. The symptoms resolved when treatment was discontinued in one patient but not in the other. Physicians should be alert to the possibility that drug-related Parkinsonism may complicate treatment of hepatitis C infection with antiviral agents; the agent most likely responsible is IFN-α2b. Prompt withdrawal of treatment is mandatory but does not always guarantee reversal of the Parkinsonian features.

This narrative review briefly describes the mammalian circadian timing system, the specific features of the liver clock, also by comparison with other peripheral clocks, the role of the liver clock in the preparation to food intake, and its relationship with energy metabolism. It then goes on to provide a chronobiological perspective of the pathophysiology and management of several types of liver disease, with particular focus on metabolic-associated fatty liver disease (MAFLD), decompensated cirrhosis and liver transplantation. Finally, it provides some insight into the potential contribution of circadian principles and circadian hygiene practices in preventing MAFLD, improving the prognosis of advanced liver disease and modulating liver transplantation outcomes.

Objective: Intra-individual variability (IIV) of response reaction times (RTs) and psychomotor slowing were proposed as markers of brain dysfunction in patients with minimal hepatic encephalopathy (MHE), a subclinical disorder of the central nervous system frequently detectable in patients with liver cirrhosis. However, behavioral measures alone do not enable investigations into the neural correlates of these phenomena. The aim of this study was to investigate the electrophysiological correlates of psychomotor slowing and increased IIV of RTs in patients with MHE. Methods: Event-related potentials (ERPs), evoked by a stimulus-response (S-R) conflict task, were recorded from a sample of patients with liver cirrhosis, with and without MHE, and a group of healthy controls. A recently presented Bayesian approach was used to estimate single-trial P300 parameters. Results: Patients with MHE, with both psychomotor slowing and higher IIV of RTs, showed higher P300 latency jittering and lower single-trial P300 amplitude compared to healthy controls. In healthy controls, distribution analysis revealed that single-trial P300 latency increased and amplitude decreased as RTs became longer; however, in patients with MHE the linkage between P300 and RTs was weaker or even absent. Conclusions: These findings suggest that in patients with MHE, the loss of the relationship between P300 parameters and RTs is related to both higher IIV of RTs and psychomotor slowing. Significance: This study highlights the utility of investigating the relationship between single-trial ERPs parameters along with RT distributions to explore brain functioning in normal or pathological conditions.

Circadian desynchrony and sleep deprivation related to the Spring transition to Daylight Saving Time (DST) have been associated with several unfavorable outcomes, including an increase in road traffic accidents. As previous work has mainly focused on analyzing historical crash/hospitalization data, there is virtually no literature investigating the effects of DST on specific driving performance indicators. Here, the effect of the Spring transition to DST on driving performance was investigated by means of a driving simulator experiment, in which participants completed two trials (one week distance, same time and day of the week) on exactly the same simulated route, the second trial taking place in the week after the transition to DST. Results were compared to those of a control group (who also underwent two trials, both before the DST transition), and documented significant worsening of driving performance after DST, as measured by a comprehensive set of simulator-derived indices. [Display omitted] •A simulator was used to study the effects of DST transition on driving behavior•Several driving variables were negatively affected by DST transition•These included reaction times, situation awareness and risk behavior•DST-related circadian desynchrony is likely to result in driving impairment Human activity in medical context; Biological sciences; Chronobiology

Patients with cirrhosis exhibit features of circadian disruption. Hyperammonaemia has been suggested to impair both homeostatic and circadian sleep regulation. Here, we tested if hyperammonaemia directly disrupts circadian rhythm generation in the central pacemaker, the suprachiasmatic nuclei (SCN) of the hypothalamus. Wheel-running activity was recorded from mice fed with a hyperammonaemic or normal diet for similar to 35 days in a 12:12 light-dark (LD) cycle followed by similar to 15 days in constant darkness (DD). The expression of the clock protein PERIOD2 (PER2) was recorded from SCN explants before, during and after ammonia exposure, +/- glutamate receptor antagonists. In LD, hyperammonaemic mice advanced their daily activity onset time by similar to 1 h (16.8 +/- 0.3 vs. 18.1 +/- 0.04 h, p = .009) and decreased their total activity, concentrating it during the first half of the night. In DD, hyperammonaemia reduced the amplitude of daily activity (551.5 +/- 27.7 vs. 724.9 +/- 59 counts, p = .007), with no changes in circadian period. Ammonia (>= 0.01 mM) rapidly and significantly reduced PER2 amplitude, and slightly increased circadian period. The decrease in PER2 amplitude correlated with decreased synchrony among circadian cells in the SCN and increased extracellular glutamate, which was rescued by AMPA glutamate receptor antagonists. These data suggest that hyperammonaemia affects circadian regulation of rest-activity behaviour by increasing extracellular glutamate in the SCN.

Hepatic encephalopathy is a neuropsychiatric syndrome that occurs in patients with liver disease. This Primer discusses the epidemiology, pathophysiology, diagnosis and treatment of hepatic encephalopathy, and discusses how this disorder affects the quality of life of patients. Hepatic encephalopathy (HE) is a prognostically relevant neuropsychiatric syndrome that occurs in the course of acute or chronic liver disease. Besides ascites and variceal bleeding, it is the most serious complication of decompensated liver cirrhosis. Ammonia and inflammation are major triggers for the appearance of HE, which in patients with liver cirrhosis involves pathophysiologically low-grade cerebral oedema with oxidative/nitrosative stress, inflammation and disturbances of oscillatory networks in the brain. Severity classification and diagnostic approaches regarding mild forms of HE are still a matter of debate. Current medical treatment predominantly involves lactulose and rifaximin following rigorous treatment of so-called known HE precipitating factors. New treatments based on an improved pathophysiological understanding are emerging.

A frequent complication in liver cirrhosis is malnutrition, which is associated with the progression of liver failure, and with a higher rate of complications including infections, hepatic encephalopathy and ascites. In recent years, the rising prevalence of obesity has led to an increase in the number of cirrhosis cases related to non-alcoholic steatohepatitis. Malnutrition, obesity and sarcopenic obesity may worsen the prognosis of patients with liver cirrhosis and lower their survival. Nutritional monitoring and intervention is therefore crucial in chronic liver disease. These Clinical Practice Guidelines review the present knowledge in the field of nutrition in chronic liver disease and promote further research on this topic. Screening, assessment and principles of nutritional management are examined, with recommendations provided in specific settings such as hepatic encephalopathy, cirrhotic patients with bone disease, patients undergoing liver surgery or transplantation and critically ill cirrhotic patients.

Hepatic encephalopathy (HE) is a form of brain dysfunction that is caused by liver insufficiency and/or portal-systemic shunting. The exact nature of HE is debated; as such, conflicting uses of the term "HE" may cause inconsistencies in its detection and management. This review highlights the meaning of the term "HE" on the basis of its historical origins and current consensus. It also provides criteria for the diagnosis of the condition based on its phenotypes and risk factors for its occurrence. The procedure for differential diagnosis from other conditions which result in similar phenotypes is considered, together with precipitants and confounders. Finally, the current multidimensional approach for the correct clinical reporting of HE episodes is discussed.

Background: We evaluated a modified Roche NH3L method developed by our group that significantly reduced the error flag "> ABS (> Absorbance)" on the COBAS 6000 (c501 module) automated platform. Methods: Our study was finalized to validate the NH3L open method on COBAS 6000 (c501 module) with imprecision and correlation tests. In addition, the NH3L open method was evaluated for determination of lower limit of blank (LoB), lower limit of detection (LoD), and accuracy. Results: The imprecision test showed good results with CV for all samples tested < 3 and < 5 for within-run and between-run assays. Correlation tests of NH3L classic and NH3L open method showed good correlation with R square = 0.95. "> ABS" obtained with the NH3L open were only 2% compared to NH3L classic method. Conclusions: Our study shows that the NH3L open method is reproducible and stable, providing values which correlate with those obtained by the traditional method. The ability to reduce the alarm > ABS by more than 95% thanks to lower background absorbance values makes this method reliable, avoiding re-testing or the need for sample dilutions.

Hepatic encephalopathy (HE) is a common complication of advanced liver disease which has profound implications in terms of the patients' ability to fulfil their family and social roles, to drive and to provide for themselves. Recurrent and persistent HE is still a serious management challenge, translating into a significant burden for patients and their families, health services and society at large. The past few years have been characterized by significantly more attention towards HE and its implications; its definition has been refined and a small number of new drugs/alternative management strategies have become available, while others are underway. In this narrative review we summarize them in a pragmatic and hopefully useful fashion.

The COVID-19 pandemic had a huge impact on national and regional health systems. The impact of SARS-CoV-2 on the quality of care for patients with liver disease is still unknown. The Italian Association for the Study of the Liver (AISF) conducted a survey to assess the impact of SARS-CoV-2 on hepatology units activities in Italy. A prospective web-based survey was proposed to all AISF active members. The survey was available online from April 8 2020, to May 3 2020, (lockdown phase in Italy). 194 AISF members answered the questionnaire, most of whom were specialists in Gastroenterology (41%) or Internal Medicine (28%), and worked in Northern Italy (51%). 26% of hepatology wards had been converted into COVID-19 wards, and 33% had bed reductions. All hepatological activities, including the management of patients with decompensated liver disease, liver transplant and HCC had been significantly reduced/stopped. The number of physicians answering that their practices had not been modified ranged between 0.6% (for chronic hepatitis) to 47% (for the execution of paracentesis). The recorded answers were consistent among different regions, and did not show any north-south gradient COVID-19 outbreak significantly impacted on hepatological clinical activity. This survey can serve as a basis to compare the impact of future measures aimed at delivering an acceptable level of liver care during a national pandemic or crisis.

Alcohol dependence is a common, complex and debilitating disorder with genetic and environmental influences. Here we show that alcohol consumption increases following mutations to the gamma-aminobutyric acid(A) receptor (GABA(A)R) beta 1 subunit gene (Gabrb1). Using N-ethyl-N-nitrosourea mutagenesis on an alcohol-averse background (F1 BALB/cAnN x C3H/HeH), we develop a mouse model exhibiting strong heritable preference for ethanol resulting from a dominant mutation (L285R) in Gabrb1. The mutation causes spontaneous GABA ion channel opening and increases GABA sensitivity of recombinant GABA(A)Rs, coupled to increased tonic currents in the nucleus accumbens, a region long-associated with alcohol reward. Mutant mice work harder to obtain ethanol, and are more sensitive to alcohol intoxication. Another spontaneous mutation (P228H) in Gabrb1 also causes high ethanol consumption accompanied by spontaneous GABA ion channel opening and increased accumbal tonic current. Our results provide a new and important link between GABA(A)R function and increased alcohol consumption that could underlie some forms of alcohol abuse.

The number of orthotopic liver transplantation performed each year is increasing due to increased safety and logistic facilities. Therefore, the importance of reducing adverse events is progressively growing. To review present knowledge on the neurological complications of orthotopic liver transplantation. The epidemiology, the clinical features and the pathophysiology of the neurological complications of orthotopic liver transplants, resulting from a systematic review of the literature in the last 25 years, are summarized. The review highlights that a relevant variety of neurological adverse events can occur in patients undergoing orthotopic liver transplantation. The knowledge of neurological complications of orthotopic liver transplantation is important for transplantation teams to reduce their prevalence and improve their management. In addition, the likelihood of neurological adverse effects provides evidence for the need of a careful cognitive and neurological work up of patients in the orthotopic liver transplantation waiting list, in order to recognize and interpret neurological dysfunction occurring after orthotopic liver transplantation.

Background & Aims: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis. Methods: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks' dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days. Results: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well. Conclusion: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone. Lay summary: Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

Spectral EEG analysis in hepatic encephalopathy (HE) is usually performed disregarding the effect of epoch length, statistical errors and equipment noise. A study on these items was carried out. In addition, spectral analysis and a new analysis, performed in time domain, were compared in the assessment of HE. The EEG tracings of 73 cirrhotic patients with HE were analyzed. Artifact-free periods of about 1 min were selected. Equipment noise was measured by short-circuiting all the electrodes. The equipment noise was notable below 1.5 Hz; the best epoch length was 4 s and the statistical errors were minimal for the band with the highest relative power. Nineteen per cent of the tracings were unstable. The spectral values were found to be related to liver function and to the degree of HE, whereas the relationship with psychometric variables was poor. The indexes computed by time-domain analysis were found to be better related to psychometric findings. We have provided information on the optimisation of spectral EEG analysis and presented a time-domain analysis giving results related to psychometric tests and liver function.

Background A healthy individual has a high degree of functional connectivity between organ systems, which can be represented graphically in a network map. Disruption of this system connectivity is associated with mortality in life-threatening acute illnesses, demonstrated by a network approach. However, this approach has not been applied to chronic multisystem diseases and may be more reliable than conventional individual organ prognostic scoring methods. Cirrhosis is a chronic disease of the liver with multisystem involvement. Development of an efficient model for prediction of mortality in cirrhosis requires a profound understanding of the pathophysiologic processes that lead to poor prognosis. In the present study, we use a network approach to evaluate the differences in organ system connectivity between survivors and non-survivors in a group of well-characterized patients with cirrhosis. Methods 201 patients with cirrhosis originally referred to the Clinic five at the University Hospital of Padova, with 13 clinical variables available representing hepatic, metabolic, haematopoietic, immune, neural and renal organ systems were retrospectively enrolled and followed up for 3, 6, and 12 months. Software was designed to compute the correlation network maps of organ system interaction in survivors and non-survivors using analysis indices: A. Bonferroni corrected Pearson's correlation coefficient and B. Mutual Information. Network structure was quantitatively evaluated using the measures of edges, average degree of connectivity and closeness, and qualitatively using clinical significance. Pair-matching was also implemented as a further step after initial general analysis to control for sample size and Model for End-Stage Liver Disease (MELD-Na) score between the groups. Results There was a higher number of significant correlations in survivors, as indicated by both the analysis indices of Bonferroni corrected Pearson's correlation coefficient and the Mutual Information analysis. The number of edges, average degree of connectivity and closeness were significantly higher in survivors compared to non-survivors group. Pair-matching for MELD-Na was also associated with increased connectivity in survivors compared to non-survivors over 3 and 6 months follow up. Conclusion This study demonstrates the application of a network approach in evaluating functional connectivity of organ systems in liver cirrhosis, demonstrating a significant degree of network disruption in organ systems in non-survivors. Network analysis of organ systems may provide insight in developing novel prognostic models for organ allocation in patients with cirrhosis.

The contemporary European genetic makeup formed in the last 8,000 years when local Western Hunter-Gatherers (WHGs) mixed with incoming Anatolian Neolithic farmers and Pontic Steppe pastoralists.1–3 This encounter combined genetic variants with distinct evolutionary histories and, together with new environmental challenges faced by the post-Neolithic Europeans, unlocked novel adaptations.4 Previous studies inferred phenotypes in these source populations, using either a few single loci5–7 or polygenic scores based on genome-wide association studies,8–10 and investigated the strength and timing of natural selection on lactase persistence or height, among others.6,11,12 However, how ancient populations contributed to present-day phenotypic variation is poorly understood. Here, we investigate how the unique tiling of genetic variants inherited from different ancestral components drives the complex traits landscape of contemporary Europeans and quantify selection patterns associated with these components. Using matching individual-level genotype and phenotype data for 27 traits in the Estonian biobank13 and genotype data directly from the ancient source populations, we quantify the contributions from each ancestry to present-day phenotypic variation in each complex trait. We find substantial differences in ancestry for eye and hair color, body mass index, waist/hip circumferences, and their ratio, height, cholesterol levels, caffeine intake, heart rate, and age at menarche. Furthermore, we find evidence for recent positive selection linked to four of these traits and, in addition, sleep patterns and blood pressure. Our results show that these ancient components were differentiated enough to contribute ancestry-specific signatures to the complex trait variability displayed by contemporary Europeans. •Ancient groups differentially contributed to complex traits in contemporary Europeans•In contemporary Estonians 11 out of 27 traits show association with some ancestry•Hunter-Gatherer and Yamnaya ancestries divergently influence cholesterol levels•Post-admixture selection is not necessary to have trait-ancestry associations Marnetto e al. quantitatively analyze how ancient populations differentially contributed to the complex trait variability in contemporary Europeans. Using the Estonian biobank as case study, they find that 11 out of 27 traits show association with some ancestral European group, including anthropometric, pigmentation, and metabolic traits.

Background Reduced heart rate variability (HRV) is an independent predictor of mortality in patients with cirrhosis. However, conventional HRV indices can only be interpreted in individuals with normal sinus rhythm. In patients with recurrent premature ventricular complexes (PVCs), the predictive capacity of conventional HRV indices is compromised. Heart Rate Turbulence (HRT) represents the biphasic change of the heart rate after PVCs. This study was aimed to define whether HRT parameters could predict mortality in cirrhotic patients. Materials and Methods 24 h electrocardiogram recordings were collected from 40 cirrhotic patients. Turbulence Onset was calculated as HRT indices. The enrolled patients were followed up for 12 months after the recruitment in relation to survival and/or transplantation. Results During the follow-up period, 21 patients (52.5%) survived, 12 patients (30%) died and 7 patients (17.5%) had liver transplantation. Turbulence Onset was found to be strongly linked with mortality on Cox regression (Hazard ratio = 1.351, p < 0.05). Moreover, Turbulence Onset predicted mortality independently of MELD and Child-Pugh's Score. Conclusion This study provides further evidence of autonomic dysfunction in cirrhosis and suggests that HRT is reliable alternative to HRV in patients with PVCs.

The gamma aminobutyric acid (GABA) system has been implicated in the susceptibility to develop alcohol dependence and in determining electroencephalogram (EEG) beta activity. The role of the GABA receptor alpha-2 gene (GABRA2) in human alcohol dependence was determined in a genetic and electrophysiological study. The study population comprised 586 white UK individuals with alcohol dependence but a very low prevalence of co-morbid drug dependence, and 603 ancestrally matched healthy controls. Genotyping for seven GABRA2 single nucleotide polymorphisms (SNPs), identified from the literature as positively associated with alcohol dependence, was performed with success rates of 90% or greater. EEGs were available in 32 selected patients who had been abstinent from alcohol for a minimum of 24 months and in 138 ancestrally matched healthy controls. None of the SNPs showed allelic or haplotypic association with alcohol dependence. All markers were in Hardy Weinberg equilibrium (HWE) in the controls. HWE for marker rs279841 in the alcohol dependent sample was p=0.0199 and combined p=0.0166. Linkage disequilibrium patterns appear to be very similar to that observed in the HapMap CEU data. A significantly higher prevalence of excess EEG fast activity was found in the patients (31 vs. 14%, p=0.018). A significant relationship was found between the presence of excess EEG fast activity and GABRA2 SNPs rs548583, rs279871 and rs279841. This allelic association study provides no evidence for an association between GABRA2 polymorphisms and alcohol dependence. However, a significant relationship was identified between GABRA2 and excess EEG fast activity. This dissociation of effect may reflect the fact that the EEG is a more direct marker of phenotypic GABRA2 expression than the more heterogeneous alcohol dependence phenotype.

Hepatic encephalopathy in a hospitalized cirrhotic patient is associated with a high mortality rate and its presence adds further to the mortality of patients with acute-on-chronic liver failure (ACLF). The exact pathophysiological mechanisms of HE in this group of patients are unclear but hyperammonemia, systemic inflammation (including sepsis, bacterial translocation, and insulin resistance) and oxidative stress, modulated by glutaminase gene alteration, remain as key factors. Moreover, alcohol misuse, hyponatremia, renal insufficiency, and microbiota are actively explored. HE diagnosis requires exclusion of other causes of neurological, metabolic and psychiatric dysfunction. Hospitalization in the ICU should be considered in every patient with overt HE, but particularly if this is associated with ACLF. Precipitating factors should be identified and treated as required. Evidence-based specific management options are limited to bowel cleansing and non-absorbable antibiotics. Ammonia lowering drugs, such as glycerol phenylbutyrate and ornithine phenylacetate show promise but are still in clinical trials. Albumin dialysis may be useful in refractory cases. Antibiotics, prebiotics, and treatment of diabetes reduce systemic inflammation. Where possible and not contraindicated, large portal-systemic shunts may be embolized but liver transplantation is the most definitive step in the management of HE in this setting. HE in patients with ACLF appears to be clinically and pathophysiologically distinct from that of acute decompensation and requires further studies and characterization. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Vitamin E is an essential micronutrient with relevant antioxidant and anti-inflammatory properties found in plant leaves, seeds, and products derived from their processing. Familial vitamin E deficiency is a rare inherited syndrome characterized by ataxia and peripheral neuropathy with a massive decrease in plasma vitamin E (

Hepatic encephalopathy (HE) is a frequent and serious complication of both chronic liver disease and acute liver failure. HE manifests as a wide spectrum of neuropsychiatric abnormalities, from subclinical changes (mild cognitive impairment) to marked disorientation, confusion and coma. The clinical and economic burden of HE is considerable, and it contributes greatly to impaired quality of life, morbidity and mortality. This review will critically discuss the latest classification of HE, as well as the pathogenesis and pathophysiological pathways underlying the neurological decline in patients with end-stage liver disease. In addition, management strategies, diagnostic approaches, currently available therapeutic options and novel treatment strategies are discussed. Crown Copyright (C) 2020 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. All rights reserved.

We currently find ourselves in the midst of a global coronavirus disease 2019 (COVID-19) pandemic, caused by the highly infectious novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we discuss aspects of SARS-CoV-2 biology and pathology and how these might interact with the circadian clock of the host. We further focus on the severe manifestation of the illness, leading to hospitalization in an intensive care unit. The most common severe complications of COVID-19 relate to clock-regulated human physiology. We speculate on how the pandemic might be used to gain insights on the circadian clock but, more importantly, on how knowledge of the circadian clock might be used to mitigate the disease expression and the clinical course of COVID-19.

Hyperammonaemia is observed after prolonged, intense exercise, or in patients with hepatic failure. In the latter, it is associated with a set of neurological and psychiatric abnormalities termed hepatic encephalopathy. 1. to measure vigilance in a condition of induced hyperammonaemia; 2. to assess whether caffeine modulates the effects of hyperammonaemia on vigilance, if any. Ten healthy volunteers (28.5 ± 5 years; 5 males) underwent three experimental sessions consisting of two-hourly measurements of capillary ammonia, subjective sleepiness (Karolinska Sleepiness Scale) and vigilance (Psychomotor Vigilance Task, PVT), in relation to the intake of breakfast (+/-coffee), an amino acid mixture which induces hyperammonaemia (amino acid challenge; AAC), and AAC+coffee (only for participants who had coffee with their standard breakfast). The AAC resulted in: 1. the expected increase in capillary ammonia levels, with highest values at approximately 4 h after the administration; 2. a significant increase in subjective sleepiness ratings; 3. a sustained increase in PVT-based reaction times. When caffeine was administered after the AAC, both subjective sleepiness and the slowing in RTs were significantly milder than in the AAC-only condition. In conclusion, acute hyperammonaemia induces an increase in subjective sleepiness and a sustained decrease in vigilance, which are attenuated by the administration of a single espresso coffee.

The assessment of diurnal preference, or the preferred timing of sleep and activity, is generally based on comprehensive questionnaires such as the Horne-Ostberg (HO). The aim of the present study was to assess the reliability of a subject's self-classification as extremely morning (Self-MM), more morning than evening (Self-M), more evening than morning (Self-E) or extremely evening (Self-EE) type, based on the last question of the HO (Self-ME). A convenience sample of 461 subjects [23.8 +/- 4.7 years; 322 females] completed a full sleep-wake assessment, including diurnal preference (HO), night sleep quality (Pittsburgh Sleep Quality Index, PSQI), daytime sleepiness (Karolinska Sleepiness Scale, KSS), and habitual sleep-wake timing (12 d sleep diaries; n = 296). Significant differences in HO total score were observed between Self-ME classes, with each class being significantly different from neighboring classes (p < 0.0001). Significant differences in sleep-wake timing (bed time, try to sleep and sleep onset, wake up, and get up time) were observed between Self-ME classes. Such differences were maintained when sleep-wake habits were analysed separately on work and free days, and also in a smaller group of 67 subjects who completed the Self-ME as a stand-alone rather than as part of the original questionnaire. Significant differences were observed in the time-course of subjective sleepiness by Self-ME class in both the large and the small group, with Self-MM and Self-M subjects being significantly more alert in the morning and sleepier in the evening hours compared with their Self-E and Self-EE counterparts. Finally, significant differences were observed in night sleep quality between Self-ME classes, with Self-EE/Self-E subjects sleeping worse than their Self-MM/Self-M counterparts, and averaging just over the abnormality PSQI threshold of 5. In conclusion, young, healthy adults can define their diurnal preference based on a single question (Self-ME) in a way that reflects their sleep-wake timing, their sleepiness levels over the daytime hours, and their night sleep quality. Validation of the Self-ME across the decades and in diseased populations seems worthy.

To evaluate the most cost-effectiveness strategy for preventing variceal growth and bleeding in patients with cirrhosis and small esophageal varices. A stochastic analysis based on decision trees was performed to compare the cost-effectiveness of beta-blockers therapy starting from a diagnosis of small varices (Strategy 1) with that of endoscopic surveillance followed by beta-blockers treatment when large varices are demonstrated (Strategy 2), for preventing variceal growth, bleeding and death in patients with cirrhosis and small esophageal varices. The basic nodes of the tree were gastrointestinal endoscopy, inpatient admission and treatment for bleeding, as required. All estimates were performed using a Monte Carlo microsimulation technique, consisting in simulating observations from known probability distributions depicted in the model. Eight-hundred-thousand simulations were performed to obtain the final estimates. All estimates were then subjected to Monte Carlo Probabilistic sensitivity analysis, to assess the impact of the variability of such estimates on the outcome distributions. The event rate (considered as progression of varices or bleeding or death) in Strategy 1 [24.09% (95%CI: 14.89%-33.29%)] was significantly lower than in Strategy 2 [60.00% (95%CI: 48.91%-71.08%)]. The mean cost (up to the first event) associated with Strategy 1 [823 £ (95%CI: 106 £-2036 £)] was not significantly different from that of Strategy 2 [799 £ (95%CI: 0 £-3498 £)]. The cost-effectiveness ratio with respect to this endpoint was equal to 50.26 £ (95%CI: -504.37 £-604.89 £) per event avoided over the four-year follow-up. When bleeding episodes/deaths in subjects whose varices had grown were included, the mean cost associated with Strategy 1 was 1028 £ (95%CI: 122 £-2581 £), while 1699 £ (95%CI: 171 £-4674 £) in Strategy 2. Beta-blocker therapy turn out to be more effective and less expensive than endoscopic surveillance for primary prophylaxis of bleeding in patients with cirrhosis and small varices.

This report provides evidence that the pattern of skin temperature fluctuations predicts survival in patients with chronic liver disease independently of standard prognostic indicators (i.e. markers of the severity of liver failure and cardiac autonomic dysfunction). This finding extends our knowledge about the potential application of physio‐markers in the clinical assessment of patients with cirrhosis for organ transplant allocation.

ObjectiveVarious imaging modalities have been used to explore pathogenic mechanisms and stratify the severity of hepatic encephalopathy (HE). The hypothesis of this meta-analysis was that there is a progressive identifiable derangement of imaging measures using magnetic resonance spectroscopy (MRS) related to the severity of the HE.MethodsStudies with more than 10 cases and HE diagnosis were identified from the electronic databases PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Literatura Latino Americana em Ciencias da Saude (LILACS), and Cochrane Central Register of Controlled Trials (CENTRAL) through July 25, 2018. Participants were stratified into healthy controls and patients with non-HE (NHE) (cirrhosis without HE), minimal HE (MHE), and overt HE (OHE). Analyses were organized by metabolite studied and brain region examined. Statistical meta-analysis was performed using the metafor package in R (v3.4.1). Pooled standardized mean differences between patient groups were calculated using a random effects model.ResultsWe identified 31 studies (1,481 patients) that included data for cirrhosis-related HE. We found the parietal region to be the most reliable in differentiating between patients with and without MHE, with standard mean differences of +0.82 (95% confidence interval [CI] +0.49 to +1.15, p < 0.0001, I-2 = 37.45%) for glutamine/glutamate, -0.36 (95% CI -0.61 to -0.10, p = 0.007, I-2 = 20.00%) for choline, and-0.77 (95% CI -1.19 to -0.34, p = 0.0004, I-2 = 67.48%) for myo-inositol. We also found that glutamine/glutamate was the metabolite that reliably correlated with HE grade in all brain regions.ConclusionsThe meta-analysis reveals that MRS changes in glutamine/glutamate, choline, and myo-inositol, particularly in the parietal lobe, correlate with the severity of HE. MRS may be of value in the assessment of HE.

Translational medicine, rather than being a unidirectional clinical utilization of basic research discoveries, should be a bidirectional process of cross-fertilization between basic science, medical knowledge and clinical utilization. While steps and processes differ across these branches of research, clear language and proper definitions are prerequisites for effective interaction of researchers to facilitate knowledge development. With respect to Hepatic Encephalopathy, at first glance the areas which require development are around prevention, both to reduce the risk of relapse following an episode of overt HE and to reduce the risk of the first episode of HE. In addition, shortening the duration of episodes of overt HE may also be relevant. Comparisons of treatments and combinations of treatments, acting by different but potentially synergistic mechanisms, are reasonable targets for both basic and applied research.

Management of hepatic encephalopathy (HE) remains challenging from a medical and psychosocial perspective. Members of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recognized 5 key unresolved questions in HE management focused on (i) driving, (ii) ammonia levels in clinical practice, (iii) testing strategies for covert or minimal HE, (iv) therapeutic options, and (v) nutrition and patient-reported outcomes. The consensus document addresses these topical issues with a succinct review of the literature and statements that critically evaluate the current science and practice, laying the groundwork for future investigations.

Background/Objectives: Hepatic encephalopathy (HE) has relevant impact on the quality of life of patients and their caregivers and causes relevant costs because of hospitalizations and work days lost. Its quantification is important to perform adequate clinical trials on this relevant complication of cirrhosis and portal-systemic shunting. Clinical neurophysiology, which detects functional alterations of the nervous system, has been applied to the study of HE for over 60 years. This review aims at summarizing and clarifying the role of neurophysiologic techniques in the study of HE. Methods: A narrative review was performed aiming at interpreting the cited papers and the techniques on the basis of their physiological and pathophysiological meaning. Results: The potential role of EEG, quantified EEG, evoked potentials-both exogenous, endogenous and motor-have been clarified to the reader that may be unfamiliar with neurophysiology. Conclusions: The EEG, reflecting the oscillatory changes of neural network is the preferable tool to detect and monitor HE, with the exception of its most severe stage, when EEG flattens. SSEP and MEP have indication to detect and monitor transmission alterations that are likely related to myelin changes and microedema.

Background: Liver cirrhosis is associated with reduced heart rate variability (HRV), which indicates impaired integrity of cardiovascular control in this patient population. There are several different indices for HRV quantification. The present study was designed to: 1) determine which of the HRV indices is best at predicting mortality in patients with cirrhosis; 2) verify if such ability to predict mortality is independent of the severity of hepatic failure. Methods: Ten minutes electrocardiogram was recorded in 74 patients with cirrhosis. Heart rate fluctuations were quantified using statistical, geometrical and non-linear analysis. The patients were followed-up for 18 months and information was collected on the occurrence of death/liver transplantation. Results: During the follow-up period, 24 patients (32%) died or were transplanted for hepatic decompensation. Cox's regression analysis showed that SDNN (total HRV), cSDNN (corrected SDNN), SD1 (short-term HRV), SD2 (long-terms HRV) and spectral indices could predict survival in these patients. However, only SD2 and cSDNN were shown to be independent of MELD in predicting survival. The prognostic value of HRV indices was independent of age, gender, use of beta blockers, and the aetiology of liver disease. Conclusion: Two HRV indices were identified that could predict mortality in patients with cirrhosis, independently of MELD. These indices are potentially useful tools for survival prediction. (C) 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Objectives: Gamma-hydroxybutyrate (GHB) is currently authorized by the European Medicines Agency (EMA) to treat narcolepsy with cataplexy in adults, and by the Food and Drug Administration (FDA) to treat cataplexy in patients with narcolepsy, with an expanded indication for the treatment of excessive daytime sleepiness. This study meta-analyses and reviews the effectiveness of GHB on the clinical features of narcolepsy and its neurophysiological correlates. Methods: A systematic review of the literature using Medline, Embase, Web of Science, Cochrane reviews, clinical-trials.gov, Scopus, Scirus, and a subsequent meta-analysis were performed. Considered outcomes were: cataplexy attacks, subjective daytime sleepiness, sleep attacks, clinical global impression change (CGI-c), quality of life (QoL), hypnagogic hallucinations, sleep paralysis, mean sleep latencies on the multiple sleep latency test (MSLT) and maintenance of wakefulness test (MWT), nocturnal polysomnographic data. Results: Nine randomized controlled trials reporting data on the effectiveness of GHB on narcolepsy were identified, for a total of 1,154 patients (771 patients in the GHB-treated group and 383 in the placebo group). The meta-analysis showed that GHB reduced cataplexy attacks both on a daily (weighted mean difference (WMD) -1.10; 95% confidence interval (CI) -1.29/-0.90, p < 0.00001) and a weekly basis (WMD -7.04; 95% CI -12.45/-1.63, p = 0.01), subjective nocturnal awakenings (WMD -1.33; 95% CI -1.78/-0.88, p < 0.00001), daytime sleep attacks on a weekly basis (WMD 9:30; 95% CI -15.92/-2.68, p = 0.006), subjective daytime sleepiness (WMD -2.81: 95% CI -4.13/-1.49, p < 0.0001) and sleep stage shifts (WMD -9.69; 95% CI -17.14/-2.24, p = 0.01). GHB increased sleep stages 3 + 4 (WMD 4.11; 95% CI 0.07/8.16, p = 0.05) and improved the CGI-c score (odds ratio (OR) 3.45: 95% CI 2.47/4.80, p < 0.00001). No significant changes were observed in night sleep latency, total sleep time, rapid-eye movement (REM) sleep and sleep stages 1 and 2. Conclusions: This meta-analysis demonstrates the effectiveness of GHB in treating major, clinically relevant narcolepsy symptoms and sleep architecture abnormalities. (c) 2011 Elsevier Ltd. All rights reserved.

A popular method to estimate proximal/distal temperature (T-PROX and T-DIST) consists in calculating a weighted average of nine wireless sensors placed on pre-defined skin locations. Specifically, T-PROX is derived from five sensors placed on the infra-clavicular and mid-thigh area (left and right) and abdomen, and T-DIST from four sensors located on the hands and feet. In clinical practice, the loss/removal of one or more sensors is a common occurrence, but limited information is available on how this affects the accuracy of temperature estimates. The aim of this study was to determine the accuracy of temperature estimates in relation to number/position of sensors removed. Thirteen healthy subjects wore all nine sensors for 24 hours and reference T-PROX and T-DIST time-courses were calculated using all sensors. Then, all possible combinations of reduced subsets of sensors were simulated and suitable weights for each sensor calculated. The accuracy of T-PROX and T-DIST estimates resulting from the reduced subsets of sensors, compared to reference values, was assessed by the mean squared error, the mean absolute error (MAE), the cross-validation error and the 25 th and 75 th percentiles of the reconstruction error. Tables of the accuracy and sensor weights for all possible combinations of sensors are provided. For instance, in relation to T-PROX, a subset of three sensors placed in any combination of three non-homologous areas (abdominal, right or left infra-clavicular, right or left mid-thigh) produced an error of 0.13 degrees C MAE, while the loss/removal of the abdominal sensor resulted in an error of 0.25 degrees C MAE, with the greater impact on the quality of the reconstruction. This information may help researchers/clinicians: i) evaluate the expected goodness of their T-PROX and T-DIST estimates based on the number of available sensors; ii) select the most appropriate subset of sensors, depending on goals and operational constraints.

Prophylaxis of the first bleeding from esophageal varices became a clinical option more than 20 years ago, and gained a large diffusion in the following years. It is based on the use of nonselective beta-blockers, which decreases portal pressure, or on the eradication of esophageal varices by endoscopic band ligation of varices. In patients with medium or large varices either of these treatments is indicated. In patients with small varices only medical treatment is feasible, and in patients with medium and large varices with contraindication or sideeffects due to beta-blockers, only endoscopic band ligation may be used. In this review the rationale and the results of the prophylaxis of bleeding from esophageal varices are discussed.

Portal hypertension is key to the natural history of cirrhosis. The standard way to assess portal hypertension is the hepatic venous pressure gradient (HVPG). HVPG has been convincingly shown to be a strong predictor of variceal bleeding and survival. In addition, it has been shown to predict other portal hypertension-related clinical events, to include fluid retention and hepatic encephalopathy. Finally, HVPG is the only suitable tool to assess the response of portal hypertension to medical treatment. Thus, although not necessarily easy to measure, HVPG provides the clinician with information which is prognostically crucial and otherwise unobtainable.

The number of effective systemic therapies for the treatment of advanced hepatocellular carcinoma (HCC) is rapidly increasing, and the advent of immunotherapy has changed the treatment paradigm for these patients, leading to significantly improved survival outcomes. However, many patients with HCC will continue to receive tyrosine kinase inhibitors, partly because of contraindications to immune checkpoint inhibitors. Currently, the best sequential first- and second-line systemic treatment remains elusive. Maintenance of optimal liver function is crucial, it is likely to impinge on temporary or permanent treatment discontinuation, and should also be considered when defining the treatment sequence. Hepatic decompensation, which does not always coincide with disease progression, is part of this complex dynamically evolving system, and must be promptly recognized and adequately managed to allow the patient to continue in the therapeutic course. The purpose of this review is to highlight and summarize the evidence on the efficacy and safety of systemic agents, with a focus on the impact of underlying cirrhosis, and to suggest new clinical outcomes for randomized controlled trials for advanced HCC to better assess the net health benefit in this specific setting. (c) 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Background: Alterations of the sleep-wake cycle are common features of neurodegenerative dementia. Objectives: To study differences in sleep-wake profiles in dementia with Lewy bodies (DLB), Alzheimer's disease (AD), and healthy controls. Methods: 30 DLB and 32 AD patients, and 33 healthy elderly participants were studied. Patients were evaluated for global cognitive impairment, extrapyramidal signs, fluctuations of attention, and behavioral disorders. A comprehensive sleep-wake profile was obtained including a set of questionnaires [Pittsburgh Sleep Quality Index (PSQI), REM Sleep Behavior Disorder Single-Question screen (RBD1Q), Epworth Sleepiness Scale (ESS)] and 12-day sleep diaries. Results: Patients were matched for age, gender, and disease severity. DLB patients showed more severe daytime somnolence/dysfunction due to somnolence, and a higher proportion of RBD-like symptoms (70%) compared to AD and controls (p < 0.001), regardless of the presence of psychoactive drug treatment. As for sleep timing, DLB patients had a greater number of daytime naps and longer night sleep, with the latter being associated with use of clonazepam. The severity of fluctuations was associated with the presence of RBD (Clinician Assessment of Fluctuation score = RBD+: 5.2 +/- 3.7; RBD-: 2.1 +/- 3.2, p = 0.04). AD patients reported the best sleep-wake profile, while healthy controls declared the poorest sleep quality, although sleep timing and the quality of wakefulness were comparable between AD and controls. Discussion: RBD and daytime fluctuations of attention may coexist in DLB and even reciprocally potentiate each other. Self-reports of sleep quality may lead to an underestimation of sleep disturbances in AD, possibly influenced by anosognosia, compared to normal elderly individuals who complain mainly of insomnia.

Hepatic encephalopathy (HE) has a major impact on health-related quality of life (HRQOL) in patients, which has clinical and psychosocial consequences. HRQOL in cirrhosis has been measured by generic and liver-specific instruments, with most studies indicating a negative impact of HE. HRQOL abnormalities span daily functioning, sleep–wake cycle changes, and the ability to work. Of these, sleep–wake cycle changes have a major effect on HRQOL, which remains challenging to treat. The personal effect of HRQOL is modulated by the presence of HE, the etiology of cirrhosis, and cognitive reserve. Patients with higher cognitive reserve are able to tolerate HE and its impact on HRQOL better than those with a poor cognitive reserve. The impact of HRQOL impairment is felt by patients (higher mortality and poor daily functioning), as well as by caregivers and families. Caregivers of patients with HE bear a major financial and psychological burden, which may affect their personal health and longevity.

Along with a growing understanding of the pathophysiology of cirrhosis and its complications, new therapies and management strategies have emerged in recent years. Many of these advances have helped inform the current EASL clinical practice guidelines1 on the management of some of the key complications of cirrhosis, such as ascites, variceal bleeding and infection. However, there are still some aspects of management where the evidence base is less clear, and/or where opinions amongst practitioners remain divided. Some of these more controversial areas are explored in this section, wherein we present evidence culminating in a suggested management approach based on expert opinion and extending beyond the current guidelines.

The letter deals with the article published in Translational Neuroscience 2011, 2 (4), 360–362. It emphasizes the importance of the authors’ findings in relation to the role of ammonaemia in diagnosing hepatic encephalopathy.

Awareness of previous hepatic encephalopathy (HE) and compliance with treatment can probably reduce HE recurrence. The aim of this study was to assess the degree of awareness of previous HE and its treatment in a group of cirrhotic patients and their caregivers. Thirty-five cirrhotic patients with a history of HE and their caregivers (n = 31) were enrolled. Patients underwent evaluation of HE (clinical, psychometry and electroencephalography), quality of life (SF36 questionnaire), and awareness of HE/treatment on an ad hoc questionnaire (QAE). Caregivers underwent the QAE plus the Caregiver Burden Inventory. On the day of study, 7 patients were unimpaired, 8 had minimal and 20 low-grade overt HE. Of the patients, 37 % were aware of previous HE, 6 % of being on treatment and 6 % understood treatment effects. Of the caregivers, 48 % were aware of previous HE, 6 % of their relative being on treatment and 6 % understood treatment effects. Significant correlations were observed between neuropsychiatric status/linear HE indices and both the patients' quality of life and the caregivers' burden. In conclusion, HE awareness was poor in both patients and caregivers, most likely in relation to insufficient/inadequate provision of information.

An unusual case of inter-haemispheric disconnection syndrome occurring in a patient who had undergone hepatic transplantation is presented. The underlying disorder, at first wrongly interpreted as encephalitis, was found to be severe, diffuse cerebral vasculitis. The hypothesis that treatment with tacrolimus might have caused, or at least favoured the vascular damage is discussed.

Cognitive Reserve (CR) modulates symptoms of brain disease. The aim of this study was: to evaluate the effect of CR on cognition in cirrhosis and on the mismatch between cognitive and neurophysiologic assessment of hepatic encephalopathy (HE). Eighty-two outpatient patients with cirrhosis without overt HE were studied [73% males; age: 62 (54-68) (median, interq. range) yrs.; education: 8 (6-13) yrs.]. The Psychometric Hepatic Encephalopathy Score (PHES) was used as cognitive measure of HE. The spectral analysis of the electroencephalogram (EEG) was used as neurophysiologic measure of HE. The CR was assessed by the CR Index (CRI), which was measured by the CRI questionnaire (CRIq) (http://cri.psy.unipd.it). The PHES was altered in 28% of patients and the EEG in 41%. Altered PHES was related to the severity of cirrhosis as assessed by Child-Pugh classification (R = 0.31, p < 0.005). Patients with maintained PHES had higher CRI than those with altered PHES (CRI = 100 +/- 20 vs. 88 +/- 12 vs., p < 0.01), but not the ones with normal EEG compared to those with abnormal EEG (CRI = 96 +/- 17 vs. 98 +/- 17 vs. p: n.s.).The PHES, but not the EEG, was found to be related to the CRI (r = 0.35, p < 0.01). The mismatch between cognitive and neurophysiologic evaluation of non-overt HE (the ratio between PHES and the mean dominant frequency -MDF- of the EEG i.e., cognitive performance normalized by EEG speed) was found to be correlated to the CRI (r = 0.36, p < 0.005). CR is a resilience factor for cognitive dysfunction in cirrhosis, and is easily measurable by CRIq.

. Neuropsychological assessment has three main applications in clinical hepatology: (i) to detect, grade and monitor liver failure-related cognitive alterations in end-stage liver disease (hepatic encephalopathy), (ii) to substantiate complaints of attention or concentration difficulties in patients with non-cirrhotic chronic hepatitis C viral infection, and (iii) to screen patients who are being considered for liver transplantation for early signs of dementia. However, there is limited agreement on how cognitive assessment should be conducted in these patients, and how results should be interpreted and used to implement clinical decisions. In this review, we summarize the available literature on neuropsychological dysfunction in patients with cirrhosis and with chronic hepatitis C viral infection and provide some guidance on how to utilize neuropsychological assessment in practice.

BACKGROUND & AIMS: Overt hepatic encephalopathy (HE) affects patients' quantity and quality of life and places a burden on families. There is evidence that overt HE might be prevented pharmacologically, but prophylaxis would be justified and cost effective only for patients at risk. We aimed to identify patients with cirrhosis at risk for overt HE. METHODS: We collected data from October 2009 through December 2012 for 216 consecutive patients with cirrhosis (based on liver biopsy, 96 patients with minimal HE), admitted to the Gastroenterology Unit at the University of Rome. Patients were followed up and evaluated for an average of 14.7 11.6 months; development of overt HE was recorded. We analyzed end-stage liver disease scores, shunt placement, previous overt or minimal HE, psychometric hepatic encephalopathy score (PHES), and levels of albumin, bilirubin, creatinine, and sodium to develop a prediction model. We validated the model in 112 patients with cirrhosis seen at the University of Padua and followed up for 12 +/- 9.5 months. RESULTS: During the follow-up period, 68 patients (32%) developed at least 1 episode of overt HE. Based on multivariate analysis, the development of overt HE was associated with previous HE, minimal HE (based on PHES), and level of albumin less than 3.5 g/dL (area under curve [AUC], 0.74). A model that excluded minimal HE but included albumin level and previous HE also identified patients who would develop overt HE (AUC, 0.71); this difference in AUC values was not statistically significant (P =.104). Both models were validated in the independent group of patients (3 variables: AUC, 0.74; 95% confidence interval, 0.66-0.83; and 2 variables: AUC, 0.71; 95% confidence interval, 0.63-0.78). CONCLUSIONS: We developed and validated a model to identify patients with cirrhosis at risk for overt HE based on previous HE, albumin levels, and PHES. If PHES was not available, previous HE and albumin levels still can identify patients at risk. Psychometric evaluation is essential for patients with no history of HE. These findings should aid in planning studies of pharmacologic prevention of overt HE.

Recent evidence reveals that inter- and intra-individual variability significantly affects cognitive performance in a number of neuropsychological pathologies. We applied a flexible family of statistical models to elucidate the contribution of inter-and intra-individual variables on cognitive functioning in healthy volunteers and patients at risk for hepatic encephalopathy (HE). Sixty-five volunteers (32 patients with cirrhosis and 33 healthy volunteers) were assessed by means of the Inhibitory Control Task (ICT). A Generalized Additive Model for Location, Scale and Shape (GAMLSS) was fitted for jointly modeling the mean and the intra-variability of Reaction Times (RTs) as a function of socio-demographic and task related covariates. Furthermore, a Generalized Linear Mixed Model (GLMM) was fitted for modeling accuracy. When controlling for the covariates, patients without minimal hepatic encephalopathy (MHE) did not differ from patients with MHE in the low-demanding condition, both in terms of RTs and accuracy. Moreover, they showed a significant decline in accuracy compared to the control group. Compared to patients with MHE, patients without MHE showed faster RTs and higher accuracy only in the high-demanding condition. The results revealed that the application of GAMLSS and GLMM models are able to capture subtle cognitive alterations, previously not detected, in patients' subclinical pathologies.

The influence of carotid stenosis and its surgical treatment on brain function is still poorly defined. We therefore performed a study to assess psychometric and quantified EEG findings after carotid endarterectomy (CEA). Sixty-nine non-demented patients (aged 72 +/- 7 years) with severe carotid stenosis (a parts per thousand yen70 %) eligible for CEA were studied. Forty patients (group A) had unilateral stenosis, and 29 patients (group B) had bilateral stenosis. Before and 5 months after CEA all the patients were evaluated by the Trail Making Test A, the Symbol Digit Test, and spectral EEG analysis. At baseline, compared to group A, group B patients performed slowly the Trail Making Test A (Z: 1.45 +/- 1.4 vs. 0.76 +/- 1.3; p < 0.05), but not the Symbol Digit Test (Z: 0.83 +/- 1.38 vs. 0.64 +/- 1.26; p = 0.59). Altogether, the patients with at least one abnormal psychometric test were 29 % (group A: 26 %; group B: 33 %, p = 0.56). The EEG did not differ significantly between patients of group A compared to group B. After CEA, psychometric tests improved (mean Z score from 0.73 +/- 1.12 to 0.45 +/- 1.15, p < 0.05). The improvement was similar in group A and B. The EEG mean dominant frequency improved only in group B patients and it was related to the improvement in psychometric tests (r = 0.43, p = 0.05). Low psychometric performance was detectable in about 1/ 3 of non-demented patients with severe carotid stenosis. CEA improved mental performance and, in patients with severe bilateral stenosis, accelerated the EEG frequency.

Systemic hypertension has been associated with impairment in cognitive performance, and both structural and functional brain abnormalities.(1) The electroencephalogram (EEG) is a cheap and noninvasive investigation, but virtually no information is available on the effects of high blood pressure, if any, on cerebral electrogenesis. Here, we show that low-amplitude EEG is considerably more common in hypertensive patients than in the general population, and associated with cognitive impairment.

Hepatitis C virus (HCV) hepatitis and other diseases related to HCV, such as cryoglobulinemia, lymphoma and renal failure, impair health-related quality of life (HRQoL). In addition, HCV per se might directly influence HRQoL via colonization of microglia in the brain or, indirectly, via the effect of systemic inflammatory cytokines which, in turn, can trigger brain interleukin production. The treatment of HCV-related disorders with interferon (IFN) has an effect on HRQoL. Initially, IFN causes a transient deterioration of HRQoL, due to the induction of depression and other side effects of treatment. Subsequently, the subjects who obtain a sustained virologic response experience an improvement in HRQoL. Only rarely does interferon treatment causes permanent detrimental effects on HRQoL, due to residual psychiatric or neurologic side effects. Liver transplantation is the only treatment for end-stage HCV-related liver disease. HRQoL generally improves massively a few months after transplantation, except in the case of serious complications of the transplant procedure. Furthermore, high levels of anxiety and neuroticism pre-transplant are associated with lower HRQoL one year after transplant. Additionally, six months after transplant, patients with HCV who experience virologic recurrence show significantly greater depression, anxiety, phobic anxiety, and paranoid ideation than anti-HCV-negative patients. In conclusion, optimal care for the overall well-being of patients with HCV infection requires adequate knowledge of their neurological and psychological status. (c) 2012 Baishideng. All rights reserved.

Patients suffering from prodromal (i.e., amnestic mild cognitive impairment, aMCI) and overt Alzheimer's disease (AD) show abnormal cortical sources of resting state electroencephalographic (EEG) rhythms. Here we tested the hypothesis that these sources show extensive abnormalities in liver cirrhosis (LC) patients with a cognitive impairment due to covert and diffuse hepatic encephalopathy (CHE). EEG activity was recorded in 64 LC (including 21 CHE), 21 aMCI, 21 AD, and 21 cognitively intact (Nold) subjects. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by LORETA. Widespread sources of theta (all but frontal), alpha 1 (all but occipital), and alpha 2 (parietal, temporal) rhythms were higher in amplitude in all LC patients than in the Nold subjects. In these LC patients, the activity of central, parietal, and temporal theta sources correlated negatively, and parietal and temporal alpha 2 sources correlated positively with an index of global cognitive status. Finally, widespread theta (all but frontal) and alpha 1 (all but occipital) sources showed higher activity in the sub-group of LC patients with CHE than in the patients with aMCI or AD. These results unveiled the larger spatial-frequency abnormalities of the resting state EEG sources in the CHE compared to the AD condition.

In a time-series, memory is a statistical feature that lasts for a period of time and distinguishes the time-series from a random, or memory-less, process. In the present study, the concept of "memory length'' was used to define the time period, or scale over which rare events within a physiological time-series do not appear randomly. The method is based on inverse statistical analysis and provides empiric evidence that rare fluctuations in cardio-respiratory time-series are 'forgotten' quickly in healthy subjects while the memory for such events is significantly prolonged in pathological conditions such as asthma (respiratory time-series) and liver cirrhosis (heart-beat time-series). The memory length was significantly higher in patients with uncontrolled asthma compared to healthy volunteers. Likewise, it was significantly higher in patients with decompensated cirrhosis compared to those with compensated cirrhosis and healthy volunteers. We also observed that the cardio-respiratory system has simple low order dynamics and short memory around its average, and high order dynamics around rare fluctuations.

Sleep and circadian rhythm disorders are common amongst medical inpatients. They are caused by a mixture of factors, including noise, loss of habitual daily routines, and abnormal exposure to light, which tends to be insufficient in the day and too high at night. The aim of the present study was to test the efficacy of morning light therapy plus night short-wavelength filter glasses on sleep quality/timing, and sleepiness/mood over the daytime hours, in a group of well-characterized medical inpatients. Thirty-three inpatients were enrolled and randomized (2:1) to either treatment (n = 22; 13 males, 48.3 +/- 13.3 years) or standard of care (n = 11; 8 males, 56.9 +/- 12.9 years). On admission, all underwent a baseline assessment of sleep quality/timing and diurnal preference. During hospitalization they underwent monitoring of sleep quality/timing (sleep diaries and actigraphy), plus hourly assessment of sleepiness/mood during the daytime hours on one, standard day of hospitalization. Patients in the treatment arm were administered bright light through glasses immediately after awakening, and wore short-wavelength filter glasses in the evening hours. Treated and untreated patients were comparable in terms of demographics, disease severity/comorbidity, diurnal preference and pre-admission sleep quality/timing. During hospitalization, sleep diaries documented a trend for a lower number of night awakenings in treated compared to untreated patients (1.6 +/- 0.8 vs. 2.4 +/- 1.3, p = 0.057). Actigraphy documented significantly earlier day mode in treated compared to untreated patients (06:39 +/- 00:35 vs. 07:44 +/- 00:40, p = 0.008). Sleepiness during a standard day of hospitalization, recorded between 09:30 and 21:30, showed physiological variation in treated compared to untreated patients, who exhibited a more blunted profile. The level of sleepiness reported by treated patients was lower over the 09:30-14:30 interval, i.e., soon after light administration (interaction effect: F = 2.661; p = 0.026). Mood levels were generally higher in treated patients, with statistically significant differences over the 09:30-14:30 time interval, i.e., soon after light administration (treatment: F = 5.692, p = 0.026). In conclusion, treatment with morning bright light and short-wavelength filter glasses in the evening, which was well tolerated, showed positive results in terms of sleepiness/mood over the morning hours and a trend for decreased night awakenings.

•Patients with MHE showed attention deficits, as revealed by the lower P3a and impaired performance.•Patients without MHE did not show a decline in performance, although they displayed a P3a reduction.•Patients without MHE showed an enhancement of the N2 and nogo-P3 amplitudes compared to controls.•The N2 and nogo-P3 increase reflects compensatory mechanisms recruited by patients without MHE. The Inhibitory Control Task (ICT) was used to detect minimal hepatic encephalopathy (MHE). ICT assesses attention, working memory and inhibition by evaluating performance in detect, go and nogo trials, respectively. The event-related potentials (ERPs) elicited by the ICT provide insight into neural mechanisms underlying the cognitive alterations associated with MHE. The performance and the ERPs elicited by ICT were measured in 31 patients with cirrhosis (13 with and 18 without MHE) and in 17 controls. The latency and amplitude of the N2, P3a, P3b and nogo-P3 were compared among the groups. Patients with MHE performed worse in all ICT trials compared to patients without MHE and controls. Cirrhotic patients, both with and without MHE, displayed a reduction in P3a amplitude, selectively in the detect trials. Patients without MHE exhibited greater N2 and nogo-P3 amplitudes compared to patients with MHE and controls. Both patients with and without MHE displayed neural alterations reflecting attentional deficits (i.e., P3a attenuation). However, patients without MHE coped with such dysfunctions by recruiting compensatory neural mechanisms, as suggested by the enhancement of the nogo-P3 and N2 amplitudes coupled with a normal ICT performance. The study suggests how initial brain dysfunction might be compensated for by recruitment of additional neurocognitive resources.

Background & Aims Learning ability may be impaired in patients with a history of overt hepatic encephalopathy (OHE). The aim of this study was to compare performance on the first/second attempt at a series of tests. Methods Two hundred and fourteen patients with cirrhosis were enrolled. On the day of study, 41% were classed as unimpaired, 38% as having minimal HE and 21% as having mild OHE; 58% had a history of OHE. Performance was compared between two versions of the trail-making test A (TMT-A), and between the first/second half of a simple/choice reaction time (sRT and cRT), and a working memory test (ScanRT). Results Both patients with and without OHE history improved in TMT-A, sRT and ScanRT. Only patients with no OHE history improved in cRT. All patients, regardless of their HE status on the day of study, improved in TMT-A and sRT. Only patients with mild OHE on the day of study improved in cRT. Only unimpaired patients improved in ScanRT. When OHE history and HE status on the day of study were tested together, only HE status had an effect. The same held true when age, the Model for End Stage Liver Disease (MELD) and educational attainment were adjusted for. Conclusions HE status on the day of study and the type of neuropsychological test had an effect on learning ability in a well-characterized group of patients with cirrhosis.

The new International Club of Ascites diagnostic criteria to diagnose acute kidney injury at hospital admission suggests the possibility of using a presumed baseline serum creatinine, defined as the last of at least two stable creatinine values during the last 3 months. Nevertheless, the possibility of the lack of such a value still remains. In these patients, the KDIGO criteria suggest to use an inverse application of MDRD equation assuming that baseline glomerular filtration rate is 75 ml/min per 1.73 m(2) (imputed baseline creatinine). We tested the accuracy of this approach to detect acute kidney injury at admission in patients with decompensated cirrhosis and creatinine

Individuals vary in how their circadian system synchronizes with the cyclic environment (zeitgeber). Assessing these differences in "phase of entrainment"-often referred to as chronotype-is an important procedure in laboratory experiments and epidemiological studies but is also increasingly applied in circadian medicine, both in diagnosis and therapy. While biochemical measurements (e.g., dim-light melatonin onset [DLMO]) of internal time are still the gold standard, they are laborious, expensive, and mostly rely on special conditions (e.g., dim light). Chronotype estimation in the form of questionnaires is useful in approximating the timing of an individual's circadian clock. They are simple, inexpensive, and location independent (e.g., administrable on- and offline) and can therefore be easily administered to many individuals. The Munich ChronoType Questionnaire (MCTQ) is an established instrument to assess chronotype by asking subjects about their sleep-wake-behavior. Here we present a shortened version of the MCTQ, the mu MCTQ, for use in situations in which instrument length is critical, such as in large cohort studies. The mu MCTQ contains only the core chronotype module of the standard MCTQ (stdMCTQ), which was shortened and adapted from 17 to 6 essential questions, allowing for a quick assessment of chronotype and other related parameters such as social jetlag and sleep duration. mu MCTQ results correspond well to the ones collected by the stdMCTQ and are externally validated by actimetry and DLMO, assessed at home (no measure of compliance). Sleep onset, midpoint of sleep, and the mu MCTQ-derived marker of chronotype showed slight deviations toward earlier times in the mu MCTQ when compared with the stdMCTQ (

Evidence is accumulating that the mammalian circadian clock system is considerably more complex than previously believed, also in terms of the cell types that actually contribute to generating the oscillation within the master clock, in the suprachiasmatic nuclei of the hypothalamus. Here we review the evidence that has lead to the identification of a bona fide astrocytic circadian clock, and that of the potential contribution of such clock to the generation of circadian and seasonal rhythmicity in health and in neurodegenerative disorders. Finally, we speculate on the role of the astrocytic clock in determining some of the clinical features of hepatic encephalopathy, a reversible neuropsychiatric syndrome associated with advanced liver disease, which is characterized by transient, profound morphological and functional astrocytic abnormalities, in the absence of significant, structural neuronal changes.

Daylight saving time (DST) is a source of circadian disruption impinging on millions of people every year. Our aim was to assess modifications, if any, in the number, type, and outcome of Accident & Emergency (A&E) visits/return visits over the DST months. The study included 366,527 visits and 84,380 return visits to the A&E of Padova hospital (Northern Italy) over 3 periods between the years 2007 and 2016: period 1 (2 weeks prior to DST to 19 weeks after), period 2 (2 weeks prior to the return to winter time to 4 weeks after), and period 3 (5 consecutive non-DST weeks). For each A&E visit/return visit, information was obtained on triage severity code, main medical complaint, and outcome. Data were aggregated by day, cumulated over the years, and analyzed by generalized Poisson models. Generalized additive models for Poisson data were then used to include photoperiod as an additional covariate. An increase in A&E visits and return visits (mostly white codes, resulting in discharges) was observed a few weeks after the enforcement of DST and was significant over most weeks of period 1 (increase of approximate to 30 [2.8%] visits and approximate to 25 [10%] return visits per week per year). After the return to winter time, a decrease in absolute number of return visits was observed (mostly white codes, resulting in discharges), which was significant at weeks 3 and 4 of period 2 (decrease of 25 [10%] return visits per week per year). When photoperiod was taken into account, changes in A&E visits (and related white codes/discharges) were no longer significant, while changes in return visits (and related white codes/discharges) were still significant. In conclusion, changes in A&E visits/return visits were observed in relation to both DST and photoperiod, which are worthy of further study and could lead to modifications in A&E organization/staffing.

The aim of the present study was to develop a Polygenic Score-based model for molecular chronotype assessment. Questionnaire-based phenotypical chronotype assessment was used as a reference. In total, 54 extremely morning/morning (MM/M; 35 females, 39.7 +/- 3.8 years) and 44 extremely evening/evening (EE/E; 20 females, 27.3 +/- 7.7 years) individuals donated a buccal DNA sample for genotyping by sequencing of the entire genetic variability of 19 target genes known to be involved in circadian rhythmicity and/or sleep duration. Targeted genotyping was performed using the single primer enrichment technology and a specifically designed panel of 5526 primers. Among 2868 high-quality polymorphisms, a cross-validation approach lead to the identification of 83 chronotype predictive variants, including previously known and also novel chronotype-associated polymorphisms. A large (35 single-nucleotide polymorphisms [SNPs]) and also a small (13 SNPs) panel were obtained, both with an estimated predictive validity of approximately 80%. Potential mechanistic hypotheses for the role of some of the newly identified variants in modulating chronotype are formulated. Once validated in independent populations encompassing the whole range of chronotypes, the identified panels might become useful within the setting of both circadian public health initiatives and precision medicine.

Portal hypertension is key to the natural history of cirrhosis and the standard way to assess it is the hepatic venous pressure gradient. Hepatic venous pressure gradient is a strong predictor of variceal bleeding/survival and is the only suitable tool to assess the response of portal hypertension to medical treatment. The clinical applications, indications and timing for hepatic venous pressure gradient measurement, together with measurement principles and costs, are reviewed.

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 HE‐related 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.

Spontaneous portosystemic shunts (SPSS) are common in cirrhosis. Their characterization and clinical implications remain unclear. To devise a system of assessment of these shunts, and assess their clinical implications We retrospectively studied patients with cirrhosis who underwent imaging in a liver transplant program. A novel index was computed to assess total SPSS -the diameter of a circle having an area equivalent to the sum of the areas of all the existing shunts. This ‘SPSS equivalent diameter’ was compared with the clinical variables. Among 127 patients, 70% (CI95% 62–77) had SPSS, and 57% (CI95% 62–77) had multiple SPSS. The risk for SPSS was related to the severity of cirrhosis (Child-Pugh B/C vs. A: OR 2.4 CI95% 1.1–5.4) and alcoholic aetiology (OR 2.9 CI95% 1.2–7.1). The SPSS equivalent diameter was related to a history of HE, cognitive impairment (EEG/PHES) and ammonia(p19.5 mm was a predictor of large SPSS (AUC 0.77, CI95%:0.68–0.87, p ≤ 0.001). The SPSS equivalent diameter, a comprehensive assessment of portosystemic shunting, was associated with severity of liver disease, hyperammonemia, and cognitive dysfunction. The diameter of the inferior vena cava was a good predictor of SPSS.

Electroencephalography has not been completely quantified in patients with cirrhosis. We investigated the electroencephalogram (EEG) dynamics in patients with cirrhosis. We performed closed-eye EEGs on 175 patients with cirrhosis (age, 55 ± 11 years; 24% Child–Pugh class A, 48% class B, and 285 class C), conducted clinical and psychometric assessments for hepatic encephalopathy (HE), and followed the patients for 1 year. EEG characteristics were assessed in the frequency domain, in the frontal (F3–F4) and parietal (P3–P4) derivations. Intrahemispheric (frontoparietal, right, and left) and interhemispheric (F3–F4 and P3–P4) coherence were computed. The EEGs of 50 healthy volunteers (age, 56 ± 17 years) served as controls. Compared with controls, the EEGs of patients with cirrhosis had a reduced frequency in the posterior derivations (P3/P4 mean dominant frequency, 9.1 ± 1.8 and 8.9 ± 1.7 Hz vs 10.4 ± 1.3 and 10.2 ± 1.3 Hz, respectively; P < .01) and an increase in interhemispheric parietal relative coherence within the theta band (22.3% ± 5.5% vs 18.9% ± 3.5%; P < .01). These features were more prominent in patients with Child class C and in patients with a history of overt HE; they correlated with hyperammonemia and hyponatremia. The decrease in EEG frequency, along with the increase in interhemispheric theta coherence in the posterior derivations, was inversely associated with survival and the occurrence of overt HE during the follow-up period. In patients with cirrhosis, alterations in the EEG were significantly associated with the severity of liver disease and HE; the EEG might be used in determining prognosis.

To investigate the agreement and prognostic value of different measures of covert hepatic encephalopathy (CHE). One-hundred-and-thirty-two cirrhotic outpatients underwent electroencephalography (EEG), paper-and-pencil psychometry (PHES) and critical flicker frequency, scored on the original/modified (CFFo/CFFm) thresholds. Eighty-four patients underwent Doppler-ultrasound to diagnose/exclude portal-systemic shunt. Seventy-nine were followed-up for 11 ± 7 mo in relation to the occurrence of hepatic encephalopathy (HE)-related hospitalisations. On the day of study, 36% had grade I HE, 42% abnormal EEG, 33% abnormal PHES and 31/21% abnormal CFFo/CFFm. Significant associations were observed between combinations of test abnormalities; however, agreement was poor (Cohen's κ < 0.4). The prevalence of EEG, PHES and CFFo/CFFm abnormalities was significantly higher in patients with grade I overt HE. The prevalence of EEG and CFFm abnormalities was higher in patients with shunt. The prevalence of EEG abnormalities was significantly higher in patients with a history of HE. During follow-up, 10 patients died, 10 were transplanted and 29 had HE-related hospitalisations. Grade I HE (P = 0.004), abnormal EEG (P = 0.008) and abnormal PHES (P = 0.04) at baseline all predicted the subsequent occurrence of HE; CFF did not. CHE diagnosis probably requires a combination of clinical, neurophysiological and neuropsychological indices.

The burden of hepatic encephalopathy on health services is increasing, and some degree of consensus in relation to drug therapy and prophylaxis has been reached. This review focuses on the role of nutritional interventions in the management of hepatic encephalopathy. A number of relatively new pieces of evidence are emerging in relation to nutrition and hepatic encephalopathy as follows: first, reduction of protein intake is not useful for hepatic encephalopathy, but protein selection should be considered; second, oral supplementation with branched chain amino acids has a role not only for its nutritional effect in cirrhosis per se, but also for its effect in reducing the risk of recurrence of hepatic encephalopathy; third, alterations in gut microbiota develop in parallel with decompensation of cirrhosis, and modulation of gut microbiota may be effective for treating and preventing hepatic encephalopathy; fourth, prebiotics and probiotics are potentially useful in this aim, thus further research or trials on prebiotics and probiotics are required; fifth, micronutrient deficiency, which is common in end-stage liver disease, has adverse effects on the brain and may either directly cause encephalopathy per se, or interact with the mechanisms leading to hepatic encephalopathy. Properly performed nutritional interventions are likely to be useful for patients with hepatic encephalopathy, but well conducted clinical trials are required. http://links.lww.com/COCN/A7.

•Obese individuals discount food reward more steeply than secondary rewards.•Impulsivity toward food reward is linearly related to BMI.•Personality, psychopathology, and executive functioning did not affect these findings. Obesity is a medical condition frequently associated with psychopathological symptoms and neurocognitive and/or personality traits related to impulsivity. Impulsivity during intertemporal choices seems to be typical of obese individuals. However, so far, the specific relationship between different types of reward and neuropsychological and psychopathological profile are yet to be unravelled. Here, we investigated impulsive choice for primary and secondary reward in obese individuals and normal-weight controls with comparable neuropsychological and psychopathological status. Participants performed three intertemporal choice tasks involving food, money, and discount voucher, respectively. Moreover, they completed a battery of neuropsychological tests and psychometric questionnaires assessing psychopathological state, impulsivity, and personality traits. Obese individuals showed increased preference for immediate food reward compared with controls, whereas no group difference emerged concerning money and discount voucher. Moreover, the higher the body mass index (BMI), the steeper the food discounting. These findings emerged in light of comparable neuropsychological and psychopathological profile between groups. Steeper food discounting in obese individuals appears to be related to BMI but not to psychopathological and neuropsychological profile. We suggest using intertemporal choice in the clinical practice as measure of the effectiveness of different types of intervention (e.g., educational, psychological, pharmacological or surgical) aimed at reducing impulsivity toward food and increasing cognitive control during food intake in obese individuals.

Screening for hepatic encephalopathy (HE) that does not cause obvious disorientation or asterixis (minimal HE [MHE]/grade 1 HE) is important. We examined if the animal naming test (ANT ) (maximum number of animals listed in 1 minute) is useful in this context. In total, 208 healthy controls, 40 controls with inflammatory bowel disease, and 327 consecutive patients with cirrhosis underwent the ANT . Patients were tested for MHE by the psychometric HE score, and 146 were assessed by electroencephalography; 202 patients were followed up regarding the occurrence of overt HE and death. In the healthy controls, ANT was influenced by limited education (80 years, P < 0.001). Using an age and education adjusting procedure, the simplified ANT (S-ANT ) was obtained. An S-ANT of

To date urinary metabolic profiling has been applied to define a specific metabolic fingerprint of hepatocellular carcinoma on a background of cirrhosis. Its utility for the stratification of other complications of cirrhosis, such as hepatic encephalopathy (HE), remains to be established. Urinary proton nuclear magnetic resonance (H-1-NMR) spectra were acquired and NMR data from 52 patients with cirrhosis (35 male; 17 female, median (range) age [60 (18-81) years]) and 17 controls were compared. A sub-set of 45 patients (33 male; 12 female, [60 (18-90) years, median model for end stage liver disease (MELD) score 11 (7-27)]) were fully characterised by West-Haven criteria, Psychometric Hepatic Encephalopathy Score (PHES) and electroencephalogram (EEG), and defined as overt HE (OHE, n = 21), covert HE (cHE, n = 7) or no HE (n = 17). Urinary proton nuclear magnetic resonance (H-1-NMR) spectra were analysed by partial-least-squares discriminant analysis (PLS-DA). The results showed good discrimination between patients with cirrhosis (n = 52) and healthy controls (n = 17) (R2X = 0.66, R2Y = 0.47, Q2Y = 0.31, sensitivity-60 %, specificity-100 %) as the cirrhosis group had higher 1-methylnicotinamide with lower hippurate, acetate, phenylacetylglycine and N-methyl nicotinic acid levels. While patients with OHE could be discriminated from those with no HE, with higher histidine, citrate and creatinine levels, the best models lack robust validity (R2X = 0.65, R2Y = 0.48, Q2Y = 0.12, sensitivity-100 %, specificity-64 %) with the sample size used. Urinary H-1-NMR metabolic profiling did not discriminate patients with cHE from those without HE, nor discriminate subjects on the basis of PHES/EEG result or MELD score. In conclusion, patients with cirrhosis showed different urinary H-1-NMR metabolic profiles compared to healthy controls and those with OHE may be distinguished from those with no HE although larger studies are required. However, urinary H-1-NMR metabolic profiling did not discriminate patients with differing grades of HE or according to severity of underlying liver disease.

Electroencephalography (EEG) is useful to objectively diagnose/grade hepatic encephalopathy (HE) across its spectrum of severity. However, it requires expensive equipment, and hepatogastroenterologists are generally unfamiliar with its acquisition/interpretation. Recent technological advances have led to the development of low-cost, user-friendly EEG systems, allowing EEG acquisition also in settings with limited neurophysiological experience. The aim of this study was to assess the relationship between EEG parameters obtained from a standard-EEG system and from a commercial, low-cost wireless headset (light-EEG) in patients with cirrhosis and varying degrees of HE. Seventy-two patients (58 males, 61 +/- 9 years) underwent clinical evaluation, the Psychometric Hepatic Encephalopathy Score (PHES), and EEG recording with both systems. Automated EEG parameters were calculated on two derivations. Strong correlations were observed between automated parameters obtained from the two EEG systems. Bland and Altman analysis indicated that the two systems provided comparable automated parameters, and agreement between classifications (normal versus abnormal EEG) based on standard-EEG and light-EEG was good (0.6 < < 0.8). Automated parameters such as the mean dominant frequency obtained from the light-EEG correlated significantly with the Model for End-Stage Liver Disease score (r = -0.39, P < 0.05), fasting venous ammonia levels (r = -0.41, P < 0.01), and PHES (r = -0.49, P < 0.001). Finally, significant differences in light-EEG parameters were observed in patients with varying degrees of HE. Conclusion: Reliable EEG parameters for HE diagnosing/grading can be obtained from a cheap, commercial, wireless headset; this may lead to more widespread use of this patient-independent tool both in routine liver practice and in the research setting. (Hepatology 2016;63:1651-1659)

In patients with cirrhosis a normal neuropsychiatric performance has been traditionally defined by the absence of any degree of hepatic encephalopathy and/or the absence of psychometric or neurophysiological abnormalities, compared with data from the healthy population. As the understanding and management of end-stage liver disease continues to change, it is our impression that the concept of normal neuropsychiatric performance also needs updating. This review explores novel and more pragmatic interpretations of neuropsychiatric "normality" compared with top personal performance, in terms of risk of overt hepatic encephalopathy or brain failure and in relation with events such as liver transplantation, decompensation, acute-on-chronic liver failure and transjugular intrahepatic portosystemic shunt placement.

Details of two patients with alcohol-related and mixed aetiology cirrhosis who developed acute-on-chronic liver failure/hepatic decompensation with no obvious precipitants are reported. Cytomegalovirus (CMV) infection or reactivation was diagnosed in both, and required treatment with ganciclovir in one. Both returned to baseline hepatic function and remain well. Physicians should be alert to the possibility that CMV might cause or contribute to hepatic decompensation in patients with cirrhosis, even if they are not severely immunocompromised, and especially if they are alcohol misusers.

Impaired sleep quality and daytime sleepiness have been described in patients with primary biliary cirrhosis (PBC). However, no information is available on their sleep timing/diurnal preference. To evaluate such variables and determine their relationship with sleep quality, fatigue, pruritus and quality of life. Seventy-four patients with PBC (58 ± 12 years), 79 healthy volunteers (56 ± 8 years) and 60 patients with cirrhosis (58 ± 12 years) underwent formal assessment of sleep quality/timing, diurnal preference and daytime sleepiness. Patients with PBC also underwent assessment of fatigue, quality of life and the daytime course of sleepiness/pruritus. Sleep timing was significantly delayed in both patients with PBC and with cirrhosis, compared to healthy volunteers (sleep onset time: 23:18 ± 01:00 vs. 23:30 ± 01:00 vs. 22:54 ± 00:54 hours, respectively; P < 0.05). In patients with PBC, delayed sleep timing was associated with impaired sleep quality (P < 0.05). Sleepiness showed a physiological daily rhythm, with early afternoon/evening peaks. Pruritus was absent in the morning and increased over the afternoon/evening hours. Both the daytime course of pruritus and sleepiness changed in relation to diurnal preference. Patients with PBC and significant pruritus (upper quartile) had prolonged sleep latency (39 ± 37 vs. 21 ± 23 min, P = 0.05) and earlier wake-up times (5.9 ± 0.8 vs. 6.7 ± 0.9 min, P < 0.05). Significant correlations were observed between sleep timing and quality of life. Patients with PBC exhibited a delay in sleep timing that was associated with impaired sleep quality/quality of life. In addition, an interplay was observed between diurnal preference and the daytime course of pruritus/sleepiness.

Background & AimsA slowed electroencephalogram (EEG) is indicative of the presence of hepatic encephalopathy (HE). Since HE is not reflected in the MELD score and is an important prognostic parameter, we assess the prognostic benefit of the addition of an EEG-based HE index to the MELD. MethodsThree hundred and ninety-two patients with cirrhosis underwent EEG and automated determination of its mean dominant frequency (MDF). MELD was calculated at the time of EEG recording. Patients were monitored for up to 18months in relation to the occurrence of death/transplantation. The prognostic value of the stand-alone/combined MELD and MDF was calculated using standard survival analysis techniques. Patients transplanted for hepatic decompensation were considered dead on the day of transplantation, those transplanted for hepatocellular carcinoma were censored. The findings were validated using a split-sample technique (reference group: n=256; test group: n=136). During the follow-up period, 107 patients died/were transplanted for hepatic decompensation. ResultsBoth MELD and MDF predicted mortality on Kaplan-Meier analysis, and both were independent predictors of mortality on a Cox model. Based on Cox regression parameters, a novel prognostic index was devised, as follows: MELD-EEG=0.087*MELD-0.306*MDF. On ROC curve analysis, MELD-EEG had higher prognostic accuracy in predicting 12- and 18-month mortality compared to MELD (P=0.016 and P=0.018, respectively). In addition, it had better sensitivity and reduced the misclassification rate for given levels of specificity. On validation, no significant differences were observed between the reference/test groups. ConclusionsThe addition of an automatically obtained EEG-based index improves the prognostic accuracy of the MELD score.

Nitrogen metabolism plays a major role in the development of hepatic encephalopathy (HE) in patients with cirrhosis. Modulation of this relationship is key to the management of HE, but is not the only nutritional issue that needs to be addressed. The assessment of nutritional status in patients with cirrhosis is problematic. In addition, there are significant sex-related differences in body composition and in the characteristics of tissue loss, which limit the usefulness of techniques based on measures of muscle mass and function in women. Techniques that combine subjective and objective variables provide reasonably accurate information and are recommended. Energy and nitrogen requirements in patients with HE are unlikely to differ substantially from those recommended in patients with cirrhosis per se viz. 35-45 kcal/g and 1.2-1.5g/kg protein daily. Small meals evenly distributed throughout the day and a late-night snack of complex carbohydrates will help minimize protein utilization. Compliance is, however, likely to be a problem. Diets rich in vegetables and dairy protein may be beneficial and are therefore recommended, but tolerance varies considerably in relation to the nature of the staple diet. Branched chain amino acid supplements may be of value in the occasional patient intolerant of dietary protein. Increasing dietary fiber may be of value, but the utility of probiotics is, as yet, unclear. Short-term multivitamin supplementation should be considered in patients admitted with decompensated cirrhosis. Hyponatremia may worsen HE; it should be prevented as far as possible and should always be corrected slowly. Conclusion: Effective management of these patients requires an integrated multidimensional approach. However, further research is needed to fill the gaps in the current evidence base to optimize the nutritional management of patients with cirrhosis and HE.

Sleep-wake abnormalities in patients with cirrhosis have been traditionally associated with hepatic encephalopathy (HE). In recent years, a certain amount of work has been devoted to the study of this relationship. This has lead to a modified picture, with weakening of the association between HE and poor night sleep, and the emergence of stronger links between HE and excessive daytime sleepiness. This brief review focuses on the evidence in favor of the interpretation of HE as a sleepiness syndrome, and on the diagnostic, therapeutic and social implications of such an interpretation.

The psychometric hepatic encephalopathy score (PHES), which includes 5 psychometric tests, is a standard for the diagnosis of minimal hepatic encephalopathy (HE). We investigated whether a simplified PHES (SPHES) is as useful as the whole PHES. The PHES was determined for 79 cirrhotic patients (the training group), who were followed up for the development of overt HE. Backward logistic regression was performed by eliminating stepwise variables—removal did not impair regression. A separate series of 65 patients was used as a validation group. The PHES was abnormal in 45 patients. The SPHES, determined from the digit symbol, serial dotting, and line tracing tests, did not differ significantly from the full PHES; 24 of the 79 patients developed overt HE. The likelihood of developing overt HE was higher among patients with an abnormal PHES (log-rank P = .003) or SPHES ( P = .004). By using Cox regression and model for end-stage liver disease scores to analyze data from patients with previous HE and transjugular intrahepatic portosystemic shunts, PHES (relative risk, 4.16; P = .003) and SPHES (relative risk, 3.70; P = .004) were the only variables associated with the development of overt HE. The accuracy of the SPHES was confirmed in the validation group. A simplified PHES is as good as the PHES in diagnosing minimal HE and in predicting the occurrence of overt HE.

About 50% of patients with hepatitis C virus (HCV) infection complain of neuropsychiatric symptoms, "brain fog", weakness, fatigue, and exhibit some degree of quality of life impairment, irrespective of the severity of liver disease. Since the first observation of HCV-related cognitive deficits, 10 studies have been published that have evaluated neuropsychiatric performance in patients with HCV infection and different degrees of hepatic impairment. Unfortunately, these have often included patients with cirrhosis, patients who had acquired the infection through previous intravenous drug misuse, who had a history of relatively recent treatment with interferon, or were on psychoactive medication. In addition, different neuropsychological batteries and tests that explored different cognitive domains were used, which makes the results of the studies difficult to compare. Finally, limited information is available on the pathogenesis of HCV-related cognitive impairment. Cerebral and/or systemic inflammation may be important players but their potential role has not been substantiated by experimental data. The present review outlines the available evidence of the presence of cognitive impairment in patients with HCV infection, with a focus on the potential relationship with cerebral and/or systemic inflammation. (C) 2011 Baishideng. All rights reserved.

The vaccination campaign against Sars-CoV-2 commenced in Italy at the end of December 2020. The first ones to receive the immunization against the virus were the health workers and the residents of nursing homes, following which the vaccine would be available for the entire population, beginning with the most vulnerable individuals. SARS-CoV2 vaccines have been demonstrated to be safe for the general population, although no data for patients with liver diseases or those having undergone liver transplantation are available so far. The present position statement AISF is an attempt to suggest, based on the published data on the impact of Sars-Cov-2 infection in patients with chronic liver disease, a possible priority for vaccination for this category of patients. (c) 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

[Display omitted] •The Psychomotor Vigilance Task (PVT) is a test of vigilance and provides a series of parameters which are stable in the healthy population, regardless of sex, age and level of education.•PVT parameters correlate well with standard measures of hepatic encephalopathy (HE).•PVT parameters may be useful to quantify mild overt HE and identify dangerous drivers among patients with cirrhosis. Hepatic encephalopathy (HE) is a syndrome of decreased vigilance and has been associated with impaired driving ability. The aim of this study was to evaluate the psychomotor vigilance task (PVT), which is used to assess both vigilance and driving ability, in a group of patients with cirrhosis and varying degrees of HE. A total of 145 patients (120 males, 59 ± 10 years, model for end-stage liver disease [MELD] score 13 ± 5) underwent the PVT; a subgroup of 117 completed a driving questionnaire and a subgroup of 106 underwent the psychometric hepatic encephalopathy score (PHES) and an electroencephalogram (EEG), based on which, plus a clinical evaluation, they were classed as being unimpaired (n = 51), or as having minimal (n = 35), or mild overt HE (n = 20). All patients were followed up for an average of 13 ± 5 months in relation to the occurrence of accidents and/or traffic offences, HE-related hospitalisations and death. Sixty-six healthy volunteers evenly distributed by sex, age and education served as a reference cohort for the PVT. Patients showed worse PVT performance compared with healthy volunteers, and PVT indices significantly correlated with MELD, ammonia levels, PHES and the EEG results. Significant associations were observed between neuropsychiatric performance/PVT indices and licence/driving status. PVT, PHES and EEG results all predicted HE-related hospitalisations and/or death over the follow-up period; none predicted accidents or traffic offences. However, individuals with the slowest reaction times and most lapses on the PVT were often not driving despite having a licence. When patients who had stopped driving for HE-related reasons (n = 6) were modelled as having an accident or fine over the subsequent 6 and 12 months, PVT was a predictor of accidents and traffic offences, even after correction for MELD and age. The PVT is worthy of further study for the purposes of both HE and driving ability assessment. Hepatic encephalopathy (HE) is a complication of advanced liver disease that can manifest as excessive sleepiness. Some patients with HE have been shown to have difficulty driving. Herein, we used a test called the Psychomotor Vigilance Task (PVT), which measures sleepiness and can also be used to assess driving competence. We showed that PVT performance is fairly stable in healthy individuals. We also showed that PVT performance parallels performance in tests which are commonly used in cirrhotic patients to measure HE. We suggest that this test is helpful in quantifying HE and identifying dangerous drivers among patients with cirrhosis.

Hepatic encephalopathy (HE) occurs in 20-50% of patients after transjugular intrahepatic portosystemic shunt (TIPS) placement. Older age, HE history and severe liver failure have all been associated with post-TIPS HE but it remains difficult to identify patients at risk. The aim of the present pathophysiological, pilot study was to assess the role of induced hyperammonaemia and associated neuropsychological and neurophysiological changes as predictors of post-TIPS HE. Eighteen TIPS candidates with no overt HE history (56 +/- 8 yrs., MELD 11 +/- 3) underwent neurophysiological [Electroencephalography (EEG)], neuropsychological [Psychometric Hepatic Encephalopathy Score (PHES) and Scan tests], ammonia and sleepiness assessment at baseline and after the induction of hyperammonaemia by an oral amino acid challenge (AAC). Pre-AAC, 17% of patients had abnormal EEG, 5% abnormal PHES, and 33% abnormal Scan performance. Post-AAC, 17% had abnormal EEG, 0% abnormal PHES, and 17% abnormal Scan performance. Pre-AAC, ammonia concentrations were 201 +/- 73 mu g/dL and subjective sleepiness 2.5 +/- 1.2 (1-9 scale). Post-AAC, patients exhibited the expected increase in ammonia/sleepiness. Six months post-TIPS, 3 patients developed an episode of HE requiring hospitalization; these showed significantly lower pre-AAC fasting ammonia concentrations compared to patients who did not develop HE (117 +/- 63 vs. 227 +/- 57 mu g/dL p = 0.015). They also showed worse PHES/Scan performance pre-AAC, and worse Scan performance post-AAC. Findings at 12 months follow-up (n = 5 HE episodes) were comparable. In conclusion, baseline ammonia levels and both pre- and post-AAC neuropsychiatric indices hold promise in defining HE risk in TIPS candidates with no HE history.

Hepatic encephalopathy (HE) is a common, worrisome and sometimes difficult to manage complication of end-stage liver disease. HE is often recurrent, requiring multiple hospital admissions. It can have serious implications in terms of a patient’s ability to perform complex tasks (for example driving), their earning capacity, their social and family roles. This guideline reviews current knowledge on HE definition, pathophysiology, diagnosis and treatment, both by general principles and by way of a summary of available drugs and treatment strategies. The quality of the published, pertinent evidence is graded, and practical recommendations are made. Where possible, these are placed within the Italian health service context, with reference to local diagnosis and management experience.

Sleep preparation/onset are associated with peripheral vasodilatation and a decrease in body temperature. The hyperdynamic syndrome exhibited by patients with cirrhosis may impinge on sleep preparation, thus contributing to their difficulties falling asleep. The aim of this study was the assessment of skin temperature, in relation to sleep-wake patterns, in patients with cirrhosis. Fifty-three subjects were initially recruited, and 46 completed the study. Of the final 46, 12 were outpatients with cirrhosis, 13 inpatients with cirrhosis, 11 inpatients without cirrhosis and 10 healthy volunteers. All underwent baseline sleep-wake evaluation and blood sampling for inflammatory markers and morning melatonin levels. Distal/proximal skin temperature and their gradient (DPG) were recorded for 24 hours by a wireless device. Over this period subjects kept a sleep-wake diary. Inpatients with cirrhosis slept significantly less well than the other groups. Inpatients and outpatients with cirrhosis had higher proximal temperature and blunted rhythmicity compared to the other groups. Inpatients with/without cirrhosis had higher distal temperature values and blunted rhythmicity compared to the other groups. Inpatients and outpatients with cirrhosis had significantly lower DPG values compared to the other groups, and DPG reached near-zero values several hours later. Significant correlations were observed between temperature and sleep-wake variables and inflammatory markers. Alterations of distal/proximal skin temperature, their gradient and their time-course were observed in patients with cirrhosis, which may contribute to their sleep disturbances.

The Poincaré plot is a geometrical technique used to visualize and quantify the correlation between two consecutive data points in a time-series. Since the dynamics of fluctuations in physiological rhythms exhibit long-term correlation and memory, this study aimed to extend the Poincaré plot by calculating the correlation between sequential data points in a time-series, rather than between two consecutive points. By incorporating this so-called lag, we hope to integrate a temporal aspect into quantifying the correlation, to depict whether a physiological system holds prolonged association between events separated by time. In doing so, it attempts to instantaneously characterize the intrinsic behavior of a complex system. We tested this hypothesis on three different physiological time-series: heart rate variability in patients with liver cirrhosis, respiratory rhythm in asthma and body temperature fluctuation in patients with cirrhosis, to evaluate the potential application of the extended Poincaré method in clinical practice. When studying the cardiac inter-beat intervals, the extended Poincaré plot revealed a stronger autocorrelation for patients with decompensated liver cirrhosis compared to less severe cases using Pearson’s correlation coefficient. In addition, long-term variability (known as SD2 in the extended Poincaré plot) appeared as an independent prognostic variable. This holds significance by acting as a non-invasive tool to evaluate patients with chronic liver disease and potentially facilitate transplant selection as an adjuvant to traditional criteria. For asthmatics, employing the extended Poincaré plot allowed for a non-invasive tool to differentially diagnose various classifications of respiratory disease. In the respiratory inter-breath interval analysis, the receiver operating characteristic (ROC) curve provided evidence that the extension of the Poincaré plot holds a greater advantage in the classification of asthmatic patients, over the traditional Poincaré plot. Lastly, the analysis of body temperature from patients using the extended Poincaré plot helped identify inpatients from outpatients with cirrhosis. Through these analyses, the extended Poincaré plot provided unique and additional information which could potentially make a difference in clinical practice. Conclusively, the potential use of our work lies in its possible application of predicting mortality for the organ allocation procedure in patients with cirrhosis and non-invasively distinguish between atopic and non-atopic asthma.

Background Providing structured information for the understanding of hepatic encephalopathy (HE) might be relevant to the prevention and management of the syndrome. The aim of our study was to design a brief, structured educational intervention and evaluate its usefulness in preventing HE-related hospitalisation over time. Methods Thirty-nine cirrhotic outpatients with a history of HE were enrolled and randomly assigned to an intervention (group A; n=20) or control group (group B; n=19). All of them underwent evaluation of HE (clinical and quantitative neuropsychiatric assessment) and completed the Questionnaire on the Awareness of Encephalopathy. A 15 min educational session was then provided to patients in group A, including basic information on the pathophysiology, hygienic and medical management of HE. Results No demographic/clinical differences were observed at baseline between the two groups. Similarly, there were no significant differences in HE-related information available at baseline between the two groups; knowledge of HE was limited in both. The intervention was highly effective in increasing patients' understanding of treatment of the condition (from 5% to 80%). The educational intervention also reduced the risk of developing an episode of HE over a period of 12 months. Conclusion The educational intervention confirmed the poor knowledge of patients with previous HE about their condition, served as a tool to increase patients' awareness, and minimised HE-related readmission rates over a period of 1 year.

Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.

The influence of liver transplantation (LT) on mental performance is debated, as is the role of pretransplant overt hepatic encephalopathy (OHE). The aim of this study was to evaluate the time course of the neuropsychological and electroencephalogram (EEG) features of patients with cirrhosis before and after LT with respect to prior OHE. The study population included 65 patients with cirrhosis on the transplant waiting list; 23 had a history of OHE. Each patient underwent an extensive psychometric assessment (10 tests, including paper and pencil tests and a computerized test) and an EEG before and 9 to 12 months after LT. For a subgroup of 11 patients, the assessment was also performed 3 and 6 months after LT. EEGs were analyzed spectrally, and the mean dominant frequencies were obtained. Both psychometric tests and EEGs improved 9 to 12 months after LT. Patients with a history of OHE before LT had worse cognitive performances (P < 0.001) and EEG performances in comparison with their counterparts with a negative history. They also showed greater cognitive improvement after LT (P < 0.01); however, their global cognitive performance remained slightly impaired (P < 0.01). After LT, EEGs normalized for 98% of the patients (P < 0.01), regardless of any history of OHE. In the subgroup of patients evaluated every 3 months, psychometric and EEG findings showed deterioration at 3 months and subsequently steady improvements from 6 months onward. In conclusion, both neuropsychological and EEG performances had significantly improved 1 year after LT. Patients with a history of OHE showed greater improvements after LT than patients with a negative history, but their global cognitive function remained slightly worse; in contrast, EEGs normalized in both groups. (C) 2014 AASLD.

The diagnosis of hepatic encephalopathy (HE) relies on clinical, neurophysiological, psychometric and laboratory variables. The relationships between such tests remain debated. The aim of this study was to determine the laboratory correlates/prognostic value of neurophysiological/psychometric abnormalities in patients with cirrhosis. Seventy-two patients and 14 healthy volunteers underwent EEG and paper-and-pencil psychometry (PHES). Blood was obtained for C reactive protein (CRP), interleukin 6 (IL6), tumor necrosis factor (TNF)alpha, ammonia and indole/oxindole. Patients were followed prospectively for a median of 22 months in relation to the occurrence of death, transplantation and HE-related hospitalizations. Thirty-three patients had normal PHES and EEG, 6 had abnormal PHES, 18 abnormal EEG and 13 abnormal PHES and EEG. Patients with abnormal PHES had higher CRP (17 +/- 22 vs 7 +/- 6, P < 0.01), IL6 (32 +/- 54 vs 12 +/- 13, P < 0.05) and TNF alpha (17 +/- 8 vs 11 +/- 7, P < 0.001) levels than those with normal PHES. Patients with abnormal EEG had higher indole (430 270 vs 258 255, P < 0.01) and ammonia (66 35 vs 45 27, P < 0.05) levels than those with normal EEG. Psychometric test scores showed significant correlations with CRP, TNFa and IL6; EEG indices with ammonia and IL6. CRP and TNF alpha concentrations were independent predictors of abnormal PHES, ammonia and indole of abnormal EEG on multivariate analysis. Seven patients were lost to follow-up; of the remaining 65, 20 died and 14 underwent transplantation; 15 developed HE requiring hospitalization. PHES and EEG performance were independent predictors of HE and death (P < 0.05). Conclusion: PHES and EEG abnormalities in patients with cirrhosis have partially different biochemical correlates and independently predict outcome. (HEPATOLOGY 2011;53:558-566)

Background & Aims Chronic alcohol misuse, HCV infection and cirrhosis may cause cognitive alterations. The aim of the present study was to assess the influence of alcohol misuse, HCV infection and cirrhosis per se on the neuropsychological and electroencephalogram (EEG) profile and to evaluate the role of alcohol misuse and HCV infections as potential confounding factors in the detection of minimal hepatic encephalopathy. Methods A comprehensive neuropsychological profile and EEG spectral parameters were obtained in six age-matched groups of 30 subjects each: (i) HCV-related hepatitis without cirrhosis, (ii) chronic alcohol abusers, (iii) patients with HCV-related cirrhosis, (iv) alcohol-related cirrhosis, (v) cirrhosis not related to alcohol or HCV and (vi) healthy subjects. Cirrhotic patients were matched for MELD score. Results The factor cirrhosis' was associated with low Phonemic Verbal Fluency (PVF) and Difference between Trail Making Test B and A (TMT) (B-A) (P

Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. NCT03056612. Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death – termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD – patients in this group rarely require hospital admission and have a much lower 1-year mortality risk. [Display omitted] •Patients with acutely decompensated cirrhosis without ACLF develop 3 different clinical courses.•Patients with pre-ACLF develop ACLF within 90 days and have high systemic inflammation and mortality.•Patients with unstable decompensated cirrhosis suffer from complications of severe portal hypertension.•Patients with stable decompensated cirrhosis have less frequent complications and lower 1-year mortality risk.

Details of 2 patients with cirrhosis and hepatic encephalopathy whose hobby or job were possibly responsible for a selectively enhanced performance in 1 neuropsychiatric test are reported. Clinicians should be alert to the fact that personal inclinations and habits may impinge on both neuropsychological and psychophysic performance, thus producing a mismatch between the results of different mental status tests. A prospective study with accurate history taking, use of comprehensive assessment protocols, and modeling/critical interpretation of the test results is required to confirm this hypothesis.

In patients with cirrhosis, hyperammonemia and hepatic encephalopathy are common after gastrointestinal bleeding and can be simulated by an amino acid challenge (AAC), or the administration of a mixture of amino acids mimicking the composition of hemoglobin. The aim of this study was to investigate the clinical, psychometric, and wake-/sleep-electroencephalogram (EEG) correlates of induced hyperammonemia. Ten patients with cirrhosis and 10 matched healthy volunteers underwent: (1) 8-day sleep quality/timing monitoring; (2) neuropsychiatric assessment at baseline/after AAC; (3) hourly ammonia/subjective sleepiness assessment for 8 hours after AAC; (4) sleep EEG recordings (nap opportunity: 17:00-19:00) at baseline/after AAC. Neuropsychiatric performance was scored according to age-/education-adjusted Italian norms. Sleep stages were scored visually for 20-second epochs; power density spectra were calculated for consecutive 20-second epochs and average spectra determined for consolidated episodes of non-rapid eye movement (non-REM) sleep of minimal common length. The AAC resulted in: (i) an increase in ammonia concentrations/subjective sleepiness in both patients and healthy volunteers; (ii) a worsening of neuropsychiatric performance (wake EEG slowing) in two (20%) patients and none of the healthy volunteers; (iii) an increase in the length of non-REM sleep in healthy volunteers [49.3 (26.6) versus 30.4 (15.6) min; P = 0.08]; (iv) a decrease in the sleep EEG beta power (fast activity) in the healthy volunteers; (v) a decrease in the sleep EEG delta power in patients. Conclusion: AAC led to a significant increase in daytime subjective sleepiness and changes in the EEG architecture of a subsequent sleep episode in patients with cirrhosis, pointing to a reduced ability to produce restorative sleep. (HEPATOLOGY 2012)

Background: Despite the impact of hepatic encephalopathy on quality of life and prognosis, easily administered tests for its diagnosis are still lacking. Aim: To assess the usefulness of the Scan package, a three-level-difficulty computerised reaction time test, to diagnose varying degrees of hepatic encephalopathy. Methods: Sixty-one cirrhotic patients underwent clinical evaluation, paper-and-pencil psychometry and the Scan package; 32 healthy controls served as reference. Results: Twenty-nine patients were classified as unimpaired, 15 as having minimal and 17 as having overt hepatic encephalopathy. All healthy controls were able to complete the Scan package; in contrast, the number of patients who were able to complete three/two/one part decreased in parallel with the degree of encephalopathy (chi(2) = 17, p=0.01). Reaction times in all three parts increased significantly with the severity of encephalopathy. However, the profile of increase was different [group: F(3,77) = 26, p

The influence of sociobiological variables and aging on the variability of the Trail Making Tests (TMT), the Symbol Digit Substituting Test (SDT), and the Line Trait Test (LTT) in the general healthy populations are not well known. Even less is known about the reliability at re-testing. This study aimed at determining the reference range of these tests, taking into account sociobiological variables and age, and the re-testing effect. We studied 300 healthy subjects from 20 to 80 years of age. The sample was derived by the pooling of two samples stratified by age and sex: a randomized sample of 161 subjects collected from the city registers of Padova, and a convenience sample of 139 subjects collected in 20 towns (mainly rural) of Northern Italy. After normalization, data were assayed for the influence of age, education, job, and gender. Age was found to be a significant independent predictor for all the tests, education for all but the LTT, job only for the TMT-B and a geometrical version of the same test (TMT-G) which was proved to be highly correlated with the TMT-B (r=0.80, p

Introduction: Sleep–wake disturbances are common in hospitalized patients but few studies have assessed them systematically. The aim of the present study was to assess sleep quality in a group of medical inpatients, in relation to environmental factors, and the switch to daylight-saving time. Methods: Between March and April 2013, 118 consecutive inpatients were screened and 99 (76 ± 11 years; hospitalization: 8 ± 7 days) enrolled. They slept in double or quadruple rooms, facing South/South-East, and were qualified as sleeping near/far from the window. They underwent daily sleep assessment by standard questionnaires/diaries. Illuminance was measured by a luxmeter at each patient’s eye-level, four times per day. Noise was measured at the same times by a phonometer. Information was recorded on room lighting, position of the rolling shutters and number/type of extra people in the room. Results: Compliance with sleep-wake assessment was poor, with a range of completion of 2–59%, depending on the questionnaires. Reported sleep quality was sufficient and sleep timing dictated by hospital routine; 33% of the patients reported one/more sleepless nights. Illuminance was generally low, and rolling shutters half-way down for most of the 24 h. Patients who slept near the window were exposed to more light in the morning (i.e., 222 ± 72 vs. 174 ± 85 lux, p  

Quantification of the number of noninhibited responses (lures) in the inhibitory control task (ICT) has been proposed for the diagnosis of minimal hepatic encephalopathy (MHE). We assessed the efficacy of ICT compared with recommended diagnostic standards. We studied patients with cirrhosis and healthy individuals (controls) who underwent the ICT at 2 centers (center A: n = 51 patients and 41 controls, center B: n = 24 patients and 14 controls). Subjects were evaluated for MHE by psychometric hepatic encephalopathy score (PHES). Patients from center B also were assessed for MHE by critical flicker frequency and spectral electroencephalogram analyses. Patients with cirrhosis had higher ICT lures (23.2 ± 12.8 vs 12.9 ± 5.8, respectively, P < .01) and lower ICT target accuracy (0.88 ± 0.17 vs 0.96 ± 0.03, respectively, P < .01) compared with controls. However, lures were comparable (25.2 ± 12.5 vs 21.4 ± 13.9, respectively, P = .32) among patients with/without altered PHES (center A). There was a reverse, U-shaped relationship between ICT lure and target accuracy; a variable adjusting lures was devised based on target accuracy (weighted lures at center B). This variable differed between patients with and without MHE. The variable weighted lures was then validated from data collected at center A by receiver operator characteristic curve analysis; it discriminated between patients with and without PHES alterations (area under the curve = 0.71 ± 0.07). However, target accuracy alone was as effective as a stand-alone variable (area under the curve = 0.81 ± 0.06). The ICT is not useful for the diagnosis of MHE, unless adjusted by target accuracy. Testing inhibition (lures) does not seem to be superior to testing attention (target accuracy) for the detection of MHE.

Background/objectives: The Mini-Mental State Examination (MMSE) has been utilized for the diagnosis of hepatic encephalopathy (HE). However, its threshold of abnormality has not been formally tested in patients with cirrhosis and its diagnostic/prognostic validity remains unknown. The aim of this study was to assess it in a large group of well-characterized outpatients with cirrhosis and no overt HE. Methods: One-hundred-and-ninety-one patients underwent clinical assessment, MMSE, electroencephalography (EEG) and paper-and-pencil psychometry (PHES); 117 were followed up for 8 +/- 5 months in relation to the occurrence of HE-related hospitalizations. Results: On the day of study, 81 patients (42%) had abnormal EEG and 67 (35%) abnormal PHES; 103 (60%) had a history of HE. Average MMSE was 26.6 +/- 3.5; 22 (19%) patients had abnormal MMSE based on the standard threshold of 24. Patients with abnormal EEG/PHES/history of HE had worse MMSE performance than their counterparts with normal tests/negative history (25.7 +/- 4.2 vs. 27.3 +/- 2.7; P < 0.01; 25.5 +/- 3.2 vs. 27.9 +/- 1.8, P < 0.0001; 26.3 +/- 3.7 vs. 27.4 +/- 2.6, P < 0.05, respectively). Based on the above results, MMSE thresholds of 26 and 27 were tested against abnormalities in clinical/EEG/PHES indices and significant associations were observed. An MMSE threshold of 26 was also a predictor of HE-related hospitalization (Cox-Mantel: P = 0.001); patients with MMSE< 26 were significantly older than those with MMSE$ 26 but comparable in terms of liver dysfunction and ammonia levels. When MMSE items were considered separately, those which correlated most significantly with standard HE indices where spatial orientation and writing. Conclusion: In conclusion, an MMSE < 26 identifies older patients with cirrhosis who are more prone to manifest HE signs.

BackgroundSince direct-acting antivirals (DAAs) have been approved for the treatment of hepatitis C virus (HCV) infection, a small series of patients with new-onset neuropsychiatric alterations have been referred to us. We therefore set out to study neuropsychiatric function in relation to DAAs prospectively.MethodsTen patients with cirrhosis and 12 post-liver transplant (post-LT) patients were enrolled. All underwent wake electroencephalography (EEG) and a neuropsychological evaluation (paper and pencil battery, simple/choice reaction times, working memory task) at baseline, at the end of treatment with DAAs and after 6 months. At the same time points, full blood count, liver/kidney function tests, quantitative HCV RNA, ammonia and immunosuppressant drug levels were obtained, as appropriate.ResultsPatients with cirrhosis were significantly older than post-LT patients (65±12 vs 55±7 years; P

Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze the blood metabolome in patients with cirrhosis, with and without ACLF. We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy individuals. Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid β-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabotoxins. In ACLF, intense systemic inflammation is associated with blood metabolite accumulation and profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures. Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. We identified a 38-metabolite blood fingerprint specific for ACLF that revealed mitochondrial dysfunction in peripheral organs. This may contribute to organ failures. [Display omitted] •Metabolomics performed in sera of a large series of patients with acute decompensation (AD) of cirrhosis, with/without ACLF.•Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF relative to those with AD.•38 metabolites comprised a distinctive ACLF fingerprint, whose intensity correlated with systemic inflammation.•The ACLF fingerprint represented increases in glycolysis and related pathways.•Fingerprint indicated reduced mitochondrial ATP-producing fatty acid β-oxidation which may contribute to organ failure(s).

The term minimal hepatic encephalopathy refers to the subtle changes in cognitive function, electrophysiological parameters, cerebral neurochemical/neurotransmitter homeostasis, cerebral blood flow, metabolism, and fluid homeostasis that can be observed in patients with cirrhosis who have no clinical evidence of hepatic encephalopathy. Use of this term emphasizes the fact that the entity of hepatic encephalopathy is a single syndrome with quantitatively distinct features relating to severity. The absence of clinical evidence of hepatic encephalopathy is key to the diagnosis and can only be determined by a detailed assessment of the patients' history and a comprehensive neurological assessment of consciousness, cognitive, and motor function. The neuropsychological features of minimal hepatic encephalopathy point to a disorder of executive functioning, particularly selective attention and psychomotor speed, but other abnormalities may be observed. Alterations in electrophysiological variables have been described; endogenous evoked potentials are, in principle, more likely to reflect the presence of minimal hepatic encephalopathy, since they reflect cognitive phenomena rather than mere stimulus conduction but the specificity of the changes observed is unclear at present. Changes have also been described in the execution of diadochokinetic movements and in the capacity to discriminate flickering light, both of which may have diagnostic potential. The changes observed in cerebral blood flow and metabolism in SPET, PET, and 1H and 31P MRS studies reflect the pathogenic process that underlies the condition rather than providing diagnostic information. Similarly, the morphological brain abnormalities identified in this population, including mild brain oedema, hyperintensity of the globus pallidus and other subcortical nuclei observed in cerebral MR studies, and the central and cortical atrophy observed in neural imaging studies, are unlikely to have diagnostic utility. The presence of minimal hepatic encephalopathy is not without clinical consequence; it has a detrimental effect on health-related quality of life, the ability to perform complex tasks such as driving, and on outcome.

Slowing of the electroencephalogram (EEG) is a recognised feature of hepatic encephalopathy but its diagnostic sensitivity is indeterminate. Recent advances in EEG analysis should provide better quantifiable/more informative data. The aim of this study was to isolate and determine the scalp distribution of the posterior basic rhythm, in patients with cirrhosis, using a technique for spatio-temporal decomposition (SEDACA) of the EEG. One hundred and ten patients with cirrhosis, classified, using clinical and psychometric criteria, as neuropsychiatrically unimpaired or as having minimal/overt hepatic encephalopathy were studied. Eyes-closed, awake EEGs were obtained and subjected to standard spectral analysis and spatio-temporal decomposition. Control data were obtained from 26 reference EEGs. The error in the estimate of the SEDACA-derived mean dominant frequency was lower than for the standard EEG derivation ( P< 0.00001). The SEDACA-derived spectral estimates correlated better with neuropsychiatric status and allowed differentiation of the patients with minimal hepatic encephalopathy from the reference population. The SEDACA-derived spatial information showed an anteriorization of the posterior basic rhythm, which became more prominent as the degree of neuropsychiatric impairment increased ( P = 0.00052). Analysis of the EEG utilising SEDACA provides significantly more diagnostic information on the neuropsychiatric status of patients with cirrhosis than obtained conventionally.

There is no "gold standard" for diagnosing hepatic encephalopathy in patients with cirrhosis. In consequence, the presence of this condition, unless floridly overt, is often missed. As a result, the majority of patients are denied the benefits of treatment. There are a number of individual techniques, which access different aspects of cerebral function that can be used, singly or in combination, to provide diagnostic information in this condition, including mental state assessment, psychometric testing, electroencephalography, sensory and cognitive evoked potentials, and neuroimaging. These have been variously applied to the study of hepatic encephalopathy but fundamental differences in the essential aims of the studies, as well as differences in the patient populations and the acquisition and analysis of the data, have made comparisons difficult. Thus, there is no clear consensus as to the sensitivity, specificity, or validity of these tests when used alone or in combination. There are, however, a number of additional methods that could be used to analyze the electrophysiological data, and a number of alternative evoked potentials that could be measured to provide better diagnostic information. In addition, there are a number of techniques, such as critical flicker frequency and smooth pursuit eye movements, which have not yet been applied systematically in this condition and which may provide useful diagnostic information. Clearly the methods for assessing hepatic encephalopathy need to be reviewed, newer methods for analyzing the electrophysiological data and newer techniques for assessing alternative aspects of cerebral function need to be explored for their diagnostic utility. This process should aim at developing a multidimensional diagnostic tool.

Smooth pursuit eye movements (SPEM) are the conjugate movements used to track the smooth trajectory of small dots. Jerky or ‘saccadic’ ocular pursuit has been reported in patients with cirrhosis, but no formal assessment of SPEM has ever been undertaken. The aim of this study was to evaluate SPEM in patients with cirrhosis and varying degrees of hepatic encephalopathy. The patient population comprised 56 individuals (31 men, 25 women) of mean age 51.1 (range, 25–70) years, with biopsy-proven cirrhosis, classified, using clinical, electroencephalographic, and psychometric variables, as either neuropsychiatrically unimpaired or as having minimal or overt hepatic encephalopathy; patients were further categorized in relation to their treatment status. The reference population comprised 28 healthy volunteers (12 men, 16 women) of mean age 47.3 (range, 26–65) years. SPEM was assessed using an electro-oculographic technique. Visual inspection of the SPEM recordings showed clear disruption of smooth pursuit in the patients with minimal hepatic encephalopathy, and more pronounced disruption, if not complete loss, of smooth pursuit in patients with overt hepatic encephalopathy. The differences observed in quantifiable SPEM indices between the healthy volunteers/unimpaired patients and those with overt hepatic encephalopathy were significant (P < .05). In conclusion, SPEM performance is impaired in patients with hepatic encephalopathy in parallel with the degree of neuropsychiatric disturbance: the pathophysiology of these changes is unknown, but retinal, extrapyramidal, and attentional abnormalities are likely to play a role. Treatment status confounds the classification of neuropsychiatric status and should be taken into account when categorizing these patients. (HEPATOLOGY 2005;42:772–781.)

Minimal hepatic encephalopathy is the term applied to the neuropsychiatric status of patients with cirrhosis who are unimpaired on clinical examination but show alterations in neuropsychological tests exploring psychomotor speed/executive function and/or in neurophysiological variables. There is no gold standard for the diagnosis of this syndrome. As these patients have, by definition, no recognizable clinical features of brain dysfunction, the primary prerequisite for the diagnosis is careful exclusion of clinical symptoms and signs. A large number of psychometric tests/test systems have been evaluated in this patient group. Of these the best known and validated is the Portal Systemic Hepatic Encephalopathy Score (PHES) derived from a test battery of five paper and pencil tests; normative reference data are available in several countries. The electroencephalogram (EEG) has been used to diagnose hepatic encephalopathy since the 1950s but, once popular, the technology is not as accessible now as it once was. The performance characteristics of the EEG are critically dependent on the type of analysis undertaken; spectral analysis has better performance characteristics than visual analysis; evolving analytical techniques may provide better diagnostic information while the advent of portable wireless headsets may facilitate more widespread use. A large number of other diagnostic tools have been validated for the diagnosis of minimal hepatic encephalopathy including Critical Flicker Frequency, the Inhibitory Control Test, the Stroop test, the Scan package and the Continuous Reaction Time; each has its pros and cons; strengths and weaknesses; protagonists and detractors. Recent AASLD/EASL Practice Guidelines suggest that the diagnosis of minimal hepatic encephalopathy should be based on the PHES test together with one of the validated alternative techniques or the EEG. Minimal hepatic encephalopathy has a detrimental effect on the well-being of patients and their care-givers. It responds well to treatment with resolution of test abnormalities and the associated detrimental effects on quality of life, liver-related mortality and morbidity. Patients will only benefit in this way if they can be effectively diagnosed. Corporate efforts and consensus agreements are needed to develop effective diagnostic algorithms.

Heart rate variability (HRV) is reduced in several clinical settings associated with either systemic inflammation or neuropsychiatric impairment. The possibility that the changes in HRV observed in patients with neuropsychiatric impairment might relate to the overproduction of inflammatory cytokines does not seem to have been considered in the studies undertaken to date. HRV is decreased in patients with liver cirrhosis but its relationship to the impairment of neuropsychiatric performance, commonly observed in these patients, is unknown. The aim of this study was to investigate the relationship between HRV, hepatic encephalopathy, and production of inflammatory cytokines in patients with cirrhosis. Eighty patients with cirrhosis [53 men, 27 women; mean (±1SD) age 54 ± 10 yr], classified as neuropsychiatrically unimpaired or as having minimal or overt hepatic encephalopathy, and 11 healthy subjects were studied. HRV was assessed by applying Poincaré plot analysis to the R-R interval series on a 5-min ECG. Inflammatory cytokines (TNF-α, IL-6, IL-10, and IL-12) were measured in a subgroup of patients. Long-term R-R variability was significantly decreased in the patients with cirrhosis, in parallel with the degree of neuropsychiatric impairment ( P< 0.01) and independently of the degree of hepatic dysfunction ( P = 0.011). The relative risk of death increased by 7.7% for every 1-ms drop in this variable. Plasma levels of IL-6 significantly correlated with indexes of both HRV and neuropsychiatric performance. The changes observed in HRV and in neuropsychiatric status in patients with cirrhosis are significantly correlated, most likely reflecting a common pathogenic mechanism mediated by inflammatory cytokines.

Psychometric performance has been reported to be related to brain atrophy in cirrhotics, but the relationship between brain atrophy and EEG findings is still unknown. The aim of this study was to ascertain the relationship among brain atrophy, EEG, and cognitive performance in cirrhotics. Sixty-eight cirrhotics (age = 55 ± 10 years; males-66%) underwent psychometric evaluation (Symbol Digit Test, Trail Making Test—Part A, Scan test), EEG recording and spectral analysis (S-EEG), and brain CT scan. Central brain atrophy was ascertained by the following indexes of brain atrophy: the Evans' index, the bicaudate index, the cella media index, the bifrontal index, and the ventricular index; cortical brain atrophy by the sulci index. The severity of liver failure was assessed by the Child–Pugh score: 18% of patients were Child–Pugh Class A, 50% Class B, and 32% Class C. Central and cortical atrophies were found to be correlated with age, but not with the Child–Pugh score. Psychometric performance and the EEG mean dominant frequency (MDF) were found to be correlated with brain atrophy. Multivariate analysis showed that a poor psychometric performance was independently predicted by EEG slowing (MDF: p < 0.01) and by central brain atrophy (cella media index: p < 0.01). In conclusion, brain atrophy was associated with a poor psychometric performance and EEG alterations in cirrhosis. Both brain atrophy and EEG alterations independently predicted cognitive dysfunction in cirrhotic patients.