Publications by authors named "Sara Montagnese"

120 Publications

Italian association for the study of the liver position statement on SARS-CoV2 vaccination.

Dig Liver Dis 2021 Apr 5. Epub 2021 Apr 5.

Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; Humanitas Research Hospital IRCCS, Rozzano, Italy.

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.
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http://dx.doi.org/10.1016/j.dld.2021.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086184PMC
April 2021

A pilot study of Golexanolone, a new GABA-A receptor modulating steroid antagonist, in patients with covert hepatic encephalopathy.

J Hepatol 2021 Mar 24. Epub 2021 Mar 24.

Umecrine Cognition AB, Stockholm, Sweden. Electronic address:

Background: Golexanolone is a novel small molecule GABA-A receptor modulating steroid antagonist under development for treatment of cognitive and vigilance disorders due to 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. Here we report golexanolone safety, pharmacokinetics (PK) and effects on the electroencephalogram (EEG), subjective sleepiness and cognitive performance 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 80mg bid) or placebo. CRT, Psychometric Hepatic Encephalopathy Score (PHES), Animal Naming Test (ANT), Epworth Sleepiness Scale (ESS) and EEG (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 subjects 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 subjects 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. The results implicate GABA-A receptor modulating neurosteroids in the pathogenesis of HE and suggest that golexanolone deserves further study as a potential therapeutic.

Lay Summary: Many patients with liver 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 the study suggest that golexanolone is well tolerated and may improve cognition as reflected by measures of sleepiness, attention span and brain wave activity and they pave the way for future larger studies of this promising experimental drug.

Clinical Trial Registration Number: EudraCT 2016-003651-30.
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http://dx.doi.org/10.1016/j.jhep.2021.03.012DOI Listing
March 2021

A Timely Call to Arms: COVID-19, the Circadian Clock, and Critical Care.

J Biol Rhythms 2021 02 11;36(1):55-70. Epub 2021 Feb 11.

Institute of Medical Psychology, Faculty of Medicine, LMU Munich, Munich, Germany.

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.
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http://dx.doi.org/10.1177/0748730421992587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882674PMC
February 2021

Sleep, Circadian Rhythmicity and Response to Chronotherapy in University Students: Tips from Chronobiology Practicals.

J Circadian Rhythms 2021 Jan 21;19. Epub 2021 Jan 21.

Department of Biology, University of Padova, Padova, Italy.

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.
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http://dx.doi.org/10.5334/jcr.202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824979PMC
January 2021

The role of astrocytes in generating circadian rhythmicity in health and disease.

J Neurochem 2021 Apr 3;157(1):42-52. Epub 2021 Mar 3.

Department of Medicine, University of Padova, Padova, Italy.

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.
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http://dx.doi.org/10.1111/jnc.15312DOI Listing
April 2021

Lights and Shadows in Hepatic Encephalopathy Diagnosis.

J Clin Med 2021 Jan 18;10(2). Epub 2021 Jan 18.

Department of Internal Medicine, DIMED, University of Padova, I-35100 Padova, Italy.

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.
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http://dx.doi.org/10.3390/jcm10020341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831133PMC
January 2021

Clinical, neuropsychological and neurophysiological indices and predictors of hepatic encephalopathy (HE).

Liver Int 2021 May 25;41(5):1070-1082. Epub 2021 Jan 25.

Department of Medicine, and Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy.

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.
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http://dx.doi.org/10.1111/liv.14785DOI Listing
May 2021

Heart Rate Turbulence Predicts Survival Independently From Severity of Liver Dysfunction in Patients With Cirrhosis.

Front Physiol 2020 9;11:602456. Epub 2020 Dec 9.

Institute for Liver and Digestive Health, Division of Medicine, UCL, London, United Kingdom.

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, < 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.
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http://dx.doi.org/10.3389/fphys.2020.602456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755978PMC
December 2020

Spontaneous portosystemic shunts in cirrhosis: Detection, implications, and clinical associations.

Dig Liver Dis 2020 Dec 16. Epub 2020 Dec 16.

Department of Medicine-DIMED(,) University of Padova, Padova, Italy. Electronic address:

Background: Spontaneous portosystemic shunts (SPSS) are common in cirrhosis. Their characterization and clinical implications remain unclear.

Aims: To devise a system of assessment of these shunts, and assess their clinical implications METHODS: 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.

Results: Among 127 patients, 70% (CI 62-77) had SPSS, and 57% (CI 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 CI 1.1-5.4) and alcoholic aetiology (OR 2.9 CI 1.2-7.1). The SPSS equivalent diameter was related to a history of HE, cognitive impairment (EEG/PHES) and ammonia(p<0.05). The diameter of the inferior cava vein >19.5 mm was a predictor of large SPSS (AUC 0.77, CI:0.68-0.87, p ≤ 0.001).

Conclusions: 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.
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http://dx.doi.org/10.1016/j.dld.2020.11.020DOI Listing
December 2020

Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy.

J Hepatol 2020 12 21;73(6):1526-1547. Epub 2020 Oct 21.

Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jhep.2020.07.013DOI Listing
December 2020

Endpoints and design of clinical trials in patients with decompensated cirrhosis: Position paper of the LiverHope Consortium.

J Hepatol 2021 Jan 5;74(1):200-219. Epub 2020 Sep 5.

Liver Unit, Hospital Clínic De Barcelona, Barcelona, School of Medicine and Health Sciences University of Barcelona, Spain; Institut d´Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jhep.2020.08.009DOI Listing
January 2021

Organ System Network Disruption Is Associated With Poor Prognosis in Patients With Chronic Liver Failure.

Front Physiol 2020 5;11:983. Epub 2020 Aug 5.

Network Physiology Laboratory, UCL Division of Medicine, University College London, London, United Kingdom.

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.
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http://dx.doi.org/10.3389/fphys.2020.00983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422730PMC
August 2020

Assessing the impact of COVID-19 on the management of patients with liver diseases: A national survey by the Italian association for the study of the Liver.

Dig Liver Dis 2020 09 10;52(9):937-941. Epub 2020 Jul 10.

Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital Padua, Italy.

Background: 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.

Aims: 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.

Methods: 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).

Results: 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 CONCLUSION: 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.
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http://dx.doi.org/10.1016/j.dld.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351426PMC
September 2020

The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.

J Hepatol 2020 10 13;73(4):842-854. Epub 2020 Jul 13.

CHTMAD Vila Real, Vila Real, Portugal.

Background & Aims: 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.

Methods: 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.

Results: 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).

Conclusions: 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. CLINICALTRIALS.

Gov Number: NCT03056612.

Lay Summary: 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.
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http://dx.doi.org/10.1016/j.jhep.2020.06.013DOI Listing
October 2020

Important Unresolved Questions in the Management of Hepatic Encephalopathy: An ISHEN Consensus.

Am J Gastroenterol 2020 07;115(7):989-1002

Department of Medicine, University of Padova, Padova, Italy.

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.
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http://dx.doi.org/10.14309/ajg.0000000000000603DOI Listing
July 2020

Skin temperature variability is an independent predictor of survival in patients with cirrhosis.

Physiol Rep 2020 06;8(12):e14452

Network Physiology Lab, Division of Medicine, UCL, London, UK.

Background: Cirrhosis is a disease with multisystem involvement. It has been documented that patients with cirrhosis exhibit abnormal patterns of fluctuation in their body temperature. However, the clinical significance of this phenomenon is not well understood. The aim of this study was to determine if temperature variability analysis can predict survival in patients with cirrhosis.

Methods: Thirty eight inpatients with cirrhosis were enrolled in the study. Wireless temperature sensors were used to record patients' proximal skin temperature for 24 hr. The pattern of proximal temperature fluctuation was assessed using the extended Poincaré plot to measure short-term and long-term proximal temperature variability (PTV). Patients were followed up for 12 months, and information was collected on the occurrence of death/liver transplantation.

Results: During the follow-up period, 15 patients (39%) died or underwent transplantation for hepatic decompensation. Basal proximal skin temperature absolute values were comparable in survivors and nonsurvivors. However, nonsurvivors showed a significant reduction in both short-term and long-term HRV indices. Cox regression analysis showed that both short-term and long-term PTV indices could predict survival in these patients. However, only measures of short-term PTV were shown to be independent of the severity of hepatic failure in predicting survival. Finally, the prognostic value of short-term PTV was also independent of heart rate variability, that is, a measure of autonomic dysfunction.

Conclusion: Changes in the pattern of patients' temperature fluctuations, rather than their absolute values, hold key prognostic information, suggesting that impaired thermoregulation may play an important role in the pathophysiology of cirrhosis.
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http://dx.doi.org/10.14814/phy2.14452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305245PMC
June 2020

Effect of Morning Light Glasses and Night Short-Wavelength Filter Glasses on Sleep-Wake Rhythmicity in Medical Inpatients.

Front Physiol 2020 28;11. Epub 2020 Jan 28.

Department of Medicine, University of Padua, Padua, Italy.

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 ( = 22; 13 males, 48.3 ± 13.3 years) or standard of care ( = 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, = 0.057). Actigraphy documented significantly earlier day mode in treated compared to untreated patients (06:39 ± 00:35 vs. 07:44 ± 00:40, = 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: = 2.661; = 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: = 5.692, = 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.
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http://dx.doi.org/10.3389/fphys.2020.00005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997239PMC
January 2020

Meta-analysis of magnetic resonance spectroscopy in the diagnosis of hepatic encephalopathy.

Neurology 2020 03 9;94(11):e1147-e1156. Epub 2020 Jan 9.

From the Faculty of Medicine (G.Z., B.B., M.D.), St Vincent's Clinical School, UNSW; Departments of Gastroenterology (G.Z., M.D.), Medical Imaging (J.C.), and Neurology and Immunology (B.B.), St Vincent's Hospital; Faculty of Medicine (R.P.), South Western Sydney Clinical School, UNSW, Sydney, Australia; and Department of Medicine (S.M.), University of Padua, Italy.

Objective: Various 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.

Methods: Studies 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 Ciências da Saúde (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.

Results: We 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, < 0.0001, = 37.45%) for glutamine/glutamate, -0.36 (95% CI -0.61 to -0.10, = 0.007, = 20.00%) for choline, and-0.77 (95% CI -1.19 to -0.34, = 0.0004, = 67.48%) for myo-inositol. We also found that glutamine/glutamate was the metabolite that reliably correlated with HE grade in all brain regions.

Conclusions: The 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.
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http://dx.doi.org/10.1212/WNL.0000000000008899DOI Listing
March 2020

The µMCTQ: An Ultra-Short Version of the Munich ChronoType Questionnaire.

J Biol Rhythms 2020 02 3;35(1):98-110. Epub 2019 Dec 3.

Institute of Medical Psychology, LMU Munich, Munich, Germany.

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 µMCTQ, for use in situations in which instrument length is critical, such as in large cohort studies. The µMCTQ 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. µMCTQ 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 µMCTQ-derived marker of chronotype showed slight deviations toward earlier times in the µMCTQ when compared with the stdMCTQ (<35 min). The µMCTQ assessment of chronotype showed good test-retest reliability and correlated significantly with phase markers from actimetry and melatonin (DLMO), especially with measurements taken on work-free days. Because of its brevity, the µMCTQ represents an ideal tool to estimate individual internal time in time-critical contexts, from large cohort studies to individualized medicine.
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http://dx.doi.org/10.1177/0748730419886986DOI Listing
February 2020

Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF.

J Hepatol 2020 04 25;72(4):688-701. Epub 2019 Nov 25.

Service de Pharmacologie et Immuno-Analyse (SPI), Laboratoire d'Etude du Métabolisme des Médicaments, CEA, INRA, Université Paris Saclay, MetaboHUB, F-91191 Gif-sur-Yvette, France.

Background & Aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Lay Summary: 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.
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http://dx.doi.org/10.1016/j.jhep.2019.11.009DOI Listing
April 2020

Clinical value of asterixis in 374 well-characterised patients with cirrhosis and varying degree of hepatic encephalopathy.

Dig Liver Dis 2020 02 30;52(2):235-236. Epub 2019 Sep 30.

Department of Medicine, University of Padova, Padova, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.dld.2019.09.003DOI Listing
February 2020

Predictive value of induced hyperammonaemia and neuropsychiatric profiling in relation to the occurrence of post-TIPS hepatic encephalopathy.

Metab Brain Dis 2019 12 10;34(6):1803-1812. Epub 2019 Sep 10.

Department of Medicine, University of Padova, Padova, Italy.

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 μg/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 μg/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.
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http://dx.doi.org/10.1007/s11011-019-00490-5DOI Listing
December 2019

Agreement and compliance with process measures proposed by the AASLD Practice Metrics Committee: An Italian perspective.

Dig Liver Dis 2019 11 29;51(11):1619-1620. Epub 2019 Aug 29.

Department of Medicine, University of Padua, Padua, Italy.

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http://dx.doi.org/10.1016/j.dld.2019.07.019DOI Listing
November 2019

Corrigendum: The Application of the Extended Poincaré Plot in the Analysis of Physiological Variabilities.

Front Physiol 2019 28;10:669. Epub 2019 May 28.

UCL Division of Medicine, University College London, London, United Kingdom.

[This corrects the article DOI: 10.3389/fphys.2019.00116.].
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http://dx.doi.org/10.3389/fphys.2019.00669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547061PMC
May 2019

Familial vitamin E deficiency: Multiorgan complications support the adverse role of oxidative stress.

Nutrition 2019 Jul - Aug;63-64:57-60. Epub 2018 Dec 1.

Department of Medicine, University of Padova, Padova, Italy. Electronic address:

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 (<0.5 mg/dL). This report describes the history of two siblings suffering from ataxia with vitamin E deficiency who developed premature systemic disorders (atherosclerotic vascular disease, ischemic heart disease, and liver steatosis) in absence of relevant risk factors. The association of neuromuscular symptoms and multiorgan involvement in patients with ataxia with vitamin E deficiency has not been reported to our knowledge. The lack of an effective vitamin E activity seems to be implicated in the pathogenesis of cardiovascular, gastrointestinal, and other diseases in which oxidative stress is a risk factor.
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http://dx.doi.org/10.1016/j.nut.2018.11.012DOI Listing
September 2020

The Application of the Extended Poincaré Plot in the Analysis of Physiological Variabilities.

Front Physiol 2019 19;10:116. Epub 2019 Feb 19.

UCL Division of Medicine, University College London, London, United Kingdom.

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.
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http://dx.doi.org/10.3389/fphys.2019.00116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390508PMC
February 2019

Impact of Hepatic Encephalopathy in Cirrhosis on Quality-of-Life Issues.

Drugs 2019 Feb;79(Suppl 1):11-16

Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, VA, 23249, USA.

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.
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http://dx.doi.org/10.1007/s40265-018-1019-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416233PMC
February 2019

The influence of HE history, HE status and neuropsychological test type on learning ability in patients with cirrhosis.

Liver Int 2019 05 17;39(5):861-870. Epub 2019 Feb 17.

Department of Medicine, University of Padova, Padova, Italy.

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.
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http://dx.doi.org/10.1111/liv.14046DOI Listing
May 2019