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Zeng G, Krishnamurthy S, Staats Pires A, Guller A, Chaganti J, Tun N, Lockart I, Montagnese S, Brew B, Guillemin GJ, Danta M, Heng B. Activation of the kynurenine pathway identified in individuals with covert hepatic encephalopathy. Hepatol Commun 2024; 8:e0559. [PMID: 39774873 PMCID: PMC11567712 DOI: 10.1097/hc9.0000000000000559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 07/24/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND HE is a neuropsychiatric complication of liver disease characterized by systemic elevation in ammonia and proinflammatory cytokines. These neurotoxins cross the blood-brain barrier and cause neuroinflammation, which can activate the kynurenine pathway (KP). This results in dysregulated production of neuroactive KP metabolites, such as quinolinic acid, which is known to cause astrocyte and neuronal death. Our aim was to compare KP activity between patients with covert HE (CHE), patients without encephalopathic cirrhosis (NHE), and healthy controls (HCs). METHODS This was a single-center prospective cohort study conducted between 2018 and 2021 at St Vincent's Hospital, Sydney. Overall, 13 patients with CHE, 10 patients with NHE, and 12 with HC were recruited. Patients with cirrhosis were diagnosed with CHE if they scored ≤-4 on the Psychometric Hepatic Encephalopathy Score. KP metabolite levels were quantified on plasma samples via HPLC and gas chromatography/mass spectrometry. One-way Kruskal-Wallis test was used to compare the expression levels of KP enzymes. RESULTS KP was highly activated in patients with cirrhosis, demonstrated by higher levels of activity in the rate-limiting enzymes, indoleamine 2,3-dioxygenase, and tryptophan-2,3-dioxygenase in both CHE (65.04±20.72, p=0.003) and patients with NHE (64.85±22.10, p=0.015) compared to HC (40.95±7.301). Higher quinolinic acid concentrations were demonstrated in CHE (3726 nM±3385, p<0.001) and patients with NHE (1788 nM±632.3, p=0.032) compared to HC (624 nM±457). KP activation was positively correlated with inflammatory marker C-reactive protein in patients with CHE (Rs=0.721, p≤0.01). CONCLUSIONS KP is highly activated in patients with CHE, resulting in heightened production of neurotoxic metabolites. Dysregulation of the pathway is demonstrable in patients who do not yet show clinical signs of neurocognitive impairment. Therapeutic agents that modulate KP activity may be able to alleviate symptoms of patients with CHE.
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Affiliation(s)
- Georgia Zeng
- Department of Gastroenterology and Hepatology, St Vincent’s Hospital, Sydney, Australia
- School of Clinical Medicine, St Vincent’s Healthcare Campus, Faculty of Medicine, UNSW Sydney, Sydney, Australia
| | - Shivani Krishnamurthy
- Macquarie Medicine School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia
| | - Ananda Staats Pires
- Macquarie Medicine School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia
| | - Anna Guller
- Macquarie Medicine School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia
- Computational Neurosurgery (CNS) Laboratory, Macquarie Medicine School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia
| | - Joga Chaganti
- Department of Medical Imaging, St Vincent’s Hospital, Sydney, Australia
| | - Nway Tun
- Department of Gastroenterology and Hepatology, St Vincent’s Hospital, Sydney, Australia
- School of Clinical Medicine, St Vincent’s Healthcare Campus, Faculty of Medicine, UNSW Sydney, Sydney, Australia
| | - Ian Lockart
- Department of Gastroenterology and Hepatology, St Vincent’s Hospital, Sydney, Australia
- School of Clinical Medicine, St Vincent’s Healthcare Campus, Faculty of Medicine, UNSW Sydney, Sydney, Australia
| | - Sara Montagnese
- Department of Medicine, Padova University Hospital, Padova, Italy
- Department of Chronobiology, Institute for Sustainability, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Bruce Brew
- Department of Neurology, St Vincent’s Hospital, Sydney, Australia
| | | | - Mark Danta
- Department of Gastroenterology and Hepatology, St Vincent’s Hospital, Sydney, Australia
- School of Clinical Medicine, St Vincent’s Healthcare Campus, Faculty of Medicine, UNSW Sydney, Sydney, Australia
| | - Benjamin Heng
- Macquarie Medicine School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia
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Lv XH, Lu Q, Deng K, Yang JL, Yang L. Prevalence and Characteristics of Covert/Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis: A Systematic Review and Meta-Analysis. Am J Gastroenterol 2024; 119:690-699. [PMID: 37856206 DOI: 10.14309/ajg.0000000000002563] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/09/2023] [Indexed: 10/20/2023]
Abstract
INTRODUCTION Covert/minimal hepatic encephalopathy (C/MHE) is the mildest form of hepatic encephalopathy (HE), but it is closely related to the quality of life and prognosis of patients with cirrhosis. Currently, the epidemiological data of C/MHE have not been well described. METHODS We searched the PubMed, Embase, and Cochrane Library databases for relevant articles. We performed a random-effects meta-analysis of proportions to estimate the pooled prevalence of C/MHE in patients with cirrhosis. We also examined potential risk factors for C/MHE by comparing characteristics of patients with and without C/MHE. RESULTS Finally, a total of 101 studies were included. The prevalence of C/MHE was 40.9% (95% confidence interval, 38.3%-43.5%) among patients with cirrhosis worldwide. The pooled C/MHE prevalence was 39.9% (95% confidence interval 36.7%-43.1%) based on studies using the psychometric HE score as a diagnostic tool. Meta-regression models showed that geographic region, sample size, mean age, sex ratio, and Child-Pugh classification were influencing factors for the heterogeneity of C/MHE prevalence. The presence of C/MHE was found to be associated with various factors including age, level of education, alcoholic etiology, Child-Pugh classification, MELD score, history of overt HE, presence of other complications, and laboratory tests related to impaired liver function. DISCUSSION This study reports detailed data on the prevalence of C/MHE as well as clinical features associated with C/MHE, suggesting that C/MHE is one of the most common complications of liver cirrhosis.
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Affiliation(s)
- Xiu-He Lv
- Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Qing Lu
- Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Kai Deng
- Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jin-Lin Yang
- Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Li Yang
- Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, Department of Gastroenterology and Hepatology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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Juanola A, Ma AT, de Wit K, Gananandan K, Roux O, Zaccherini G, Jiménez C, Tonon M, Solé C, Villaseca C, Uschner FE, Graupera I, Pose E, Moreta MJ, Campion D, Beuers U, Mookerjee RP, Francoz C, Durand F, Vargas V, Piano S, Alonso S, Trebicka J, Laleman W, Asrani SK, Soriano G, Alessandria C, Serra-Burriel M, Morales-Ruiz M, Torres F, Allegretti AS, Krag A, Caraceni P, Watson H, Abraldes JG, Solà E, Kamath PS, Hernaez R, Ginès P. Novel prognostic biomarkers in decompensated cirrhosis: a systematic review and meta-analysis. Gut 2023; 73:156-165. [PMID: 37884354 DOI: 10.1136/gutjnl-2023-329923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 09/18/2023] [Indexed: 10/28/2023]
Abstract
BACKGROUND Patients with decompensated cirrhosis experience high mortality rates. Current prognostic scores, including the model for end-stage liver disease (MELD), may underperform in settings other than in those they were initially developed. Novel biomarkers have been proposed to improve prognostication accuracy and even to predict development of complications. METHODS We performed a systematic review and meta-analysis on novel urine and blood biomarkers and their ability to predict 90-day mortality in patients with decompensated cirrhosis. Secondary outcomes included 28-day and 1-year mortality, and development of acute-on-chronic liver failure, acute kidney injury and other complications. To overcome differences in units, temporal changes in assays and reporting heterogeneity, we used the ratio of means (RoM) as measure of association for assessing strength in predicting outcomes. An RoM>1 implies that the mean biomarker level is higher in those that develop the outcome than in those that do not. RESULTS Of 6629 unique references, 103 were included, reporting on 29 different biomarkers, with a total of 31 362 biomarker patients. Most studies were prospective cohorts of hospitalised patients (median Child-Pugh-Turcotte score of 9 and MELD score of 18). The pooled 90-day mortality rate was 0.27 (95% CI 0.24 to 0.29). The RoM for predicting 90-day mortality was highest for interleukin 6 (IL-6) (2.56, 95% CI 2.39 to 2.74), followed by urinary neutrophil gelatinase-associated lipocalin (uNGAL) (2.42, 95% CI 2.20 to 2.66) and copeptin (2.33, 95% CI 2.17 to 2.50). These RoMs were all higher than for MELD (1.44, 95% CI 1.42 to 1.46). CONCLUSION Novel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.
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Affiliation(s)
- Adrià Juanola
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Barcelona, Spain
| | - Ann Thu Ma
- Toronto Centre for Liver Disease Francis Family Liver Clinic, Toronto General Hospital, Toronto, Ontario, Canada
| | - Koos de Wit
- Gastroenterology and Hepatology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands
| | - Kohilan Gananandan
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Olivier Roux
- Department of Hepatology, Beaujon Hospital, Clichy, France
| | - Giacomo Zaccherini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-related Diseases, University of Bologna Hospital of Bologna Sant'Orsola-Malpighi Polyclinic, Bologna, Italy
| | - César Jiménez
- Liver Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain
| | - Marta Tonon
- Department of Medicine (DIMED), University of Padova, Padova, Italy
| | - Cristina Solé
- Department of Gastroenterology and Hepatology, Consorci Corporació Sanitària Parc Taulí, Sabadell, Spain
| | - Clara Villaseca
- Digestive Disease Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Frank E Uschner
- Department of Internal Medicine B, University of Münster, Munster, Germany
| | - Isabel Graupera
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Barcelona, Spain
| | - Elisa Pose
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Barcelona, Spain
| | - Maria José Moreta
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
| | - Daniela Campion
- Division of Gastroenterology and Hepatology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Ulrich Beuers
- Gastroenterology & Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Rajeshawar P Mookerjee
- Institute of Liver and Digestive Health, University College London Medical School, London, UK
| | - Claire Francoz
- Department of Hepatology, Beaujon Hospital, Clichy, France
| | - Francois Durand
- DHU Unity, Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, Hôpital Beaujon, AP-HP, Clichy, France
- Université Denis Diderot-Paris 7, Paris, France
| | - Victor Vargas
- Liver Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain
| | - Salvatore Piano
- Department of Medicine (DIMED), University of Padova, Padova, Italy
| | - Sonia Alonso
- Digestive Disease Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Munster, Germany
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Wim Laleman
- Division of Liver and Biliopanreatic Disorders, KU Leuven, University of Leuven, Leuven, Belgium
| | - Sumeet K Asrani
- Division of Hepatology, Department of Medicine, Baylor University Medical Center at Dallas, Dallas, Texas, USA
| | - German Soriano
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Carlo Alessandria
- Division of Gastroenterology and Hepatology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Miquel Serra-Burriel
- University of Zurich Institute of Epidemiology Biostatistics and Prevention, Zurich, Switzerland
| | - Manuel Morales-Ruiz
- Biochemistry and Molecular Genetics Department-CDB, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Ferran Torres
- Biostatistics and Data Management Core Facility, IDIBAPS, Hospital Clinic Barcelona, Barcelona, Spain
- Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Andrew S Allegretti
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Aleksander Krag
- Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Juan G Abraldes
- Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Alberta, Canada
| | - Elsa Solà
- Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, California, USA
| | - Patrick S Kamath
- Gastroenterology and Hepatology, Mayo Medical School, Rochester, Minnesota, USA
| | - Ruben Hernaez
- Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
- Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Pere Ginès
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Barcelona, Spain
- Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain
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4
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Gairing SJ, Mangini C, Zarantonello L, Gioia S, Nielsen EJ, Danneberg S, Gabriel M, Ehrenbauer AF, Bloom PP, Ripoll C, Sultanik P, Galle PR, Labenz J, Thabut D, Zipprich A, Lok AS, Weissenborn K, Marquardt JU, Lauridsen MM, Nardelli S, Montagnese S, Labenz C. Prevalence of Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis: A Multicenter Study. Am J Gastroenterol 2023; 118:2191-2200. [PMID: 36940426 DOI: 10.14309/ajg.0000000000002251] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 03/01/2023] [Indexed: 03/22/2023]
Abstract
INTRODUCTION The prevalence of minimal hepatic encephalopathy (MHE), in particular in different subgroups, remains unknown. This study aimed to analyze the prevalence of MHE in different subgroups to identify patients at high risk and to pave the way for personalized screening approaches. METHODS In this study, data of patients recruited at 10 centers across Europe and the United States were analyzed. Only patients without clinical signs of hepatic encephalopathy were included. MHE was detected using the Psychometric Hepatic Encephalopathy Score (PHES, cut-off < or ≤-4 depending on local norms). Clinical and demographic characteristics of the patients were assessed and analyzed. RESULTS In total, 1,868 patients with cirrhosis with a median model for end-stage liver disease (MELD) of 11 were analyzed (Child-Pugh [CP] stages: A 46%, B 42%, and C 12%). In the total cohort, MHE was detected by PHES in 650 patients (35%). After excluding patients with a history of overt hepatic encephalopathy, the prevalence of MHE was 29%. In subgroup analyses, the prevalence of MHE in patients with CP A was low (25%), whereas it was high in CP B or C (42% and 52%). In patients with a MELD score <10, the prevalence of MHE was only 25%, but it was 48% in patients with a MELD score ≥20. Standardized ammonia levels (ammonia level/upper limit of normal of each center) correlated significantly, albeit weakly with PHES (Spearman ρ = -0.16, P < 0.001). DISCUSSION The prevalence of MHE in patients with cirrhosis was high but varied substantially between diseases stages. These data may pave the way for more individualized MHE screening approaches.
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Affiliation(s)
- Simon Johannes Gairing
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Chiara Mangini
- Department of Medicine, University of Padova, Padova, Italy
| | | | - Stefania Gioia
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Elise Jonasson Nielsen
- Department of Gastroenterology and Hepatology, Hospital of South West Jutland, Esbjerg, Denmark
| | - Sven Danneberg
- Department of Medicine I, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Maria Gabriel
- Clinic for Neurology, Hannover Medical School, Hannover, Germany
| | | | - Patricia P Bloom
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Cristina Ripoll
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
- First Department of Internal Medicine, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Philippe Sultanik
- Service d'hépato-gastroentérologie, Sorbonne Université, Hôpital Pitié-Salpêtrière Assistance Publique Hôpitaux de Paris, Paris, France
| | - Peter Robert Galle
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Joachim Labenz
- Department of Medicine, Diakonie Hospital Jung-Stilling, Siegen, Germany
| | - Dominique Thabut
- Service d'hépato-gastroentérologie, Sorbonne Université, Hôpital Pitié-Salpêtrière Assistance Publique Hôpitaux de Paris, Paris, France
| | - Alexander Zipprich
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
- First Department of Internal Medicine, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Anna S Lok
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Jens Uwe Marquardt
- Department of Medicine I, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Mette Munk Lauridsen
- Department of Gastroenterology and Hepatology, Hospital of South West Jutland, Esbjerg, Denmark
| | - Silvia Nardelli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Sara Montagnese
- Department of Medicine, University of Padova, Padova, Italy
- Chronobiology Section, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Christian Labenz
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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Testino G, Bottaro LC, Andorno E, Bandini F, Balbinot P, Beltramini S, Bottino S, Caltabellotta M, Caputo F, Caviglia E, Curone P, DI Biagio A, Gagliano C, Gandolfo N, Pestarino L, Rollero A, Romairone E, Sampietro L, Torre E, Zuccarelli S, Pellicano R. Hepatic encephalophathy: management and diagnostic therapeutic assistance path of Ligurian Local Health Company 3 (ASL3). Minerva Med 2023; 114:698-718. [PMID: 36952221 DOI: 10.23736/s0026-4806.22.08408-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/24/2023]
Abstract
Hepatic encephalophathy (HE) is a neuropsychiatric syndrome with a prevalence in the cirrhotic population ranging from 20 to 80%. HE is a cause of inappropriate hospitalization, caregiver burdening and increased social costs. There is need to create dedicated care pathways to better manage patients and support family caregivers. The data used for the preparation of this diagnostic therapeutic assistance path (DTAP) are based on a detailed analysis of the scientific literature published before June 30, 2022 (PubMed, Web of Science, Scopus, Google Scholar). Furthermore, in the process of developing this work, we consulted in particular the guidelines/ position papers of International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN), Italian Association for the Study of the Liver (AISF), European Association for the Study of the Liver (EASL), American Association for the Study of Liver Diseases (AASLD), Italian Society on Alcohol (Società Italiana di Alcologia [SIA]) and other relevant papers. DTAP was created based on the most recent recommendations of the international scientific literature. The present DTAP highlight the need for a multidisciplinary activity integrated with territorial medicine in close connection with caregivers. This guarantees improved therapeutic adherence, hospital readmission reduction, improved quality of life for patients and caregivers and a significant reduction in costs.
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Affiliation(s)
- Gianni Testino
- Addiction and Hepatology Unit/Alcohological Regional Centre and Study Centre "Self Help, Community Program and Caregiver Training" ASL3, Genoa, Italy -
| | | | - Enzo Andorno
- Liver Transplantation Unit, San Martino Polyclinic Hospital, Genoa, Italy
| | | | - Patrizia Balbinot
- Addiction and Hepatology Unit/Alcohological Regional Centre and Study Centre "Self Help, Community Program and Caregiver Training" ASL3, Genoa, Italy
| | | | | | | | - Fabio Caputo
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Center for the Study and Treatment of Chronic Inflammatory Intestinal Diseases (IBD) and Gastroenterological Manifestations of Rare Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Center for the Study and Treatment of Alcohol-Related Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Department of Internal Medicine, Santissima Annunziata Hospital, University of Ferrara, Ferrara, Italy
| | | | | | - Antonio DI Biagio
- Department of Health Sciences, Infectious Diseases Clinic, IRCCS San Martino Polyclinic Hospital, University of Genoa, Genoa, Italy
| | | | | | | | | | | | | | - Enrico Torre
- Unit of Endocrinology, Metabolic Diseases and Diabetology, ASL3 Liguria, Genoa, Italy
| | | | - Rinaldo Pellicano
- Unit of Gastroenterology, Molinette Hospital, Città della Salute e della Scienza, Turin, Italy
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Ripoll C, Greinert R, Reuken P, Reichert MC, Weber SN, Hupfer Y, Staltner R, Meier Clinien M, Lammert F, Bruns T, Zipprich A. Influence of NOD2 risk variants on hepatic encephalopathy and association with inflammation, bacterial translocation and immune activation. Liver Int 2023; 43:1793-1802. [PMID: 37249050 DOI: 10.1111/liv.15627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/21/2023] [Accepted: 05/18/2023] [Indexed: 05/31/2023]
Abstract
BACKGROUND Nucleotide-binding oligomerization domain containing 2 (NOD2) risk variants lead to impaired mucosal barrier function, increased bacterial translocation (BT), and systemic inflammation. AIM To evaluate the association between the presence of NOD2 risk variants, BT, inflammation, and hepatic encephalopathy (HE). PATIENTS AND METHODS This prospective multicenter study included patients with cirrhosis and testing for NOD2 risk variants (p.R702W, p.G908R, c.3020insC, N289S, and c.-958T>C). Patients were evaluated for covert (C) and overt (O) HE. Markers of systemic inflammation (leukocytes, CRP, IL-6, LBP) and immune activation (soluble CD14) as well as bacterial endotoxin (hTRL4 activation) were determined in serum. RESULTS Overall, 172 patients (70% men; median age 60 [IQR 54-66] years; MELD 12 [IQR 9-16]; 72% ascites) were included, of whom 53 (31%) carried a NOD2 risk variant. In this cohort, 11% presented with OHE and 27% and CHE. Presence and severity of HE and surrogates of inflammation, BT, and immune activation did not differ between patients with and without a NOD2 risk variant, also not after adjustment for MELD. HE was associated with increased ammonia and systemic inflammation, as indicated by elevated CRP (w/o HE: 7.2 [2.7-16.7]; with HE 12.6 [4.5-29.7] mg/dL; p < 0.001) and elevated soluble CD14 (w/o HE 2592 [2275-3033]; with HE 2755 [2410-3456] ng/mL; p = 0.025). CONCLUSIONS The presence of NOD2 risk variants in patients with cirrhosis is not associated with HE and has no marked impact on inflammation, BT, or immune activation. In contrast, the presence of HE was linked to ammonia, the acute phase response, and myeloid cell activation.
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Affiliation(s)
- Cristina Ripoll
- Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Robin Greinert
- Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Philipp Reuken
- Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | | | - Susanne N Weber
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Yvonne Hupfer
- Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Raphaela Staltner
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Magdalena Meier Clinien
- Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | | | - Tony Bruns
- Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
- Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Alexander Zipprich
- Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
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Granados-Fuentes D, Cho K, Patti GJ, Costa R, Herzog ED, Montagnese S. Hyperammonaemia disrupts daily rhythms reversibly by elevating glutamate in the central circadian pacemaker. Liver Int 2023; 43:673-683. [PMID: 36367321 PMCID: PMC9974605 DOI: 10.1111/liv.15476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/21/2022] [Accepted: 11/09/2022] [Indexed: 11/13/2022]
Abstract
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 ~35 days in a 12:12 light-dark (LD) cycle followed by ~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 ~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.
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Affiliation(s)
| | - Kevin Cho
- Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, USA
| | - Gary J. Patti
- Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, USA
| | - Rodolfo Costa
- Department of Biology, University of Padova, Padova, Italy
- Institute of Neuroscience, National Research Council of Italy (CNR), Padova, Italy
- Chronobiology Section, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Erik D. Herzog
- Biology Department, Washington University in St. Louis, USA
| | - Sara Montagnese
- Chronobiology Section, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
- Department of Medicine, University of Padova, Italy
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8
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Fagan A, Gavis EA, Gallagher ML, Mousel T, Davis B, Puri P, Sterling RK, Luketic VA, Lee H, Matherly SC, Sanyal AJ, Stravitz RT, Patel V, Siddiqui MS, Asgharpour A, Fuchs M, Thacker L, Bajaj JS. A double-blind randomized placebo-controlled trial of albumin in outpatients with hepatic encephalopathy: HEAL study. J Hepatol 2023; 78:312-321. [PMID: 36152764 DOI: 10.1016/j.jhep.2022.09.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/26/2022] [Accepted: 09/13/2022] [Indexed: 01/24/2023]
Abstract
BACKGROUND & AIMS Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life (QoL), can persist. A double-blind, placebo-controlled randomized clinical trial was performed to determine the impact of albumin vs. saline on MHE and QoL in individuals with prior HE already on standard of care. METHODS Outpatients with cirrhosis and prior HE, MHE and hypoalbuminemia already on treatment for HE were included. Patients on regular IV albumin infusions were excluded. Participants were randomized 1:1 to receive either weekly infusions of 25% IV albumin 1.5 g/kg or saline over 5 weeks. MHE was defined using either psychometric hepatic encephalopathy score (PHES), Stroop or critical clicker frequency. MHE, QoL (based on sickness impact profile [SIP] total, physical, psychosocial domain) and serum markers (inflammation, endothelial dysfunction, and ischemia-modified albumin) were compared between baseline, the final infusion visit (end-of-drug [EOD]) and 1-week post final infusion (end-of-study [EOS]). RESULTS Forty-eight (24/group) participants were randomized and balanced (including by HE medication use) at baseline. Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and ischemia-modified albumin decreased only in the albumin group at EOD and EOS vs. baseline. PHES and Stroop MHE reversal and improvement were greater in the albumin group at EOD and persisted at EOS. SIP total and psychosocial, but not physical, domain improved only in the albumin group at EOD and EOS vs. baseline. A significant reduction in IL-1β and endothelial dysfunction markers was also observed in the albumin group. CONCLUSION In a double-blind, placebo-controlled trial of outpatients with cirrhosis, prior HE and current MHE, albumin infusions were associated with improved cognitive function and psychosocial QoL, likely due to amelioration of endothelial dysfunction. CLINICAL TRIALS REGISTRATION www. CLINICALTRIALS gov NCT03585257. IMPACT AND IMPLICATIONS Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life, can persist. We found that intravenous albumin infusions were associated with improved cognitive function and psychosocial quality of life, likely owing to amelioration of endothelial dysfunction, compared to placebo in outpatients with prior HE and current MHE. In patients who continue to demonstrate cognitive dysfunction and impaired quality of life despite standard of care therapy for HE, albumin infusions could be considered if these results are validated.
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Affiliation(s)
- Andrew Fagan
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Edith A Gavis
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | | | - Travis Mousel
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Brian Davis
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Puneet Puri
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Richard K Sterling
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Velimir A Luketic
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Hannah Lee
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Scott C Matherly
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - R Todd Stravitz
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Vaishali Patel
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Mohammad S Siddiqui
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Amon Asgharpour
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Michael Fuchs
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA
| | - Leroy Thacker
- Department of Biostatistics, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Richmond, Virginia, USA.
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9
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Gairing SJ, Anders J, Kaps L, Nagel M, Michel M, Kremer WM, Hilscher M, Galle PR, Schattenberg JM, Wörns MA, Labenz C. Evaluation of IL-6 for Stepwise Diagnosis of Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis. Hepatol Commun 2022; 6:1113-1122. [PMID: 35032100 PMCID: PMC9035565 DOI: 10.1002/hep4.1883] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 11/28/2021] [Accepted: 12/06/2021] [Indexed: 11/10/2022] Open
Abstract
Diagnosis of minimal hepatic encephalopathy (MHE) requires psychometric testing, which is time-consuming and often neglected in clinical practice. Elevated Interleukin-6 (IL-6) serum levels have been linked to MHE. The aim of this study was to investigate the usefulness of IL-6 as a biomarker in a stepwise diagnostic algorithm to detect MHE in patients with liver cirrhosis. A total of 197 prospectively recruited patients without clinical signs of hepatic encephalopathy (HE) served as the development cohort. Another independent cohort consisting of 52 patients served for validation purposes. Psychometric Hepatic Encephalopathy Score (PHES) was applied for the diagnosis of MHE. Fifty (25.4%) patients of the development cohort presented with MHE. Median IL-6 levels were more than twice as high in patients with MHE than in patients without HE (16 vs. 7 pg/mL; P < 0.001). On multivariable logistic regression analysis, higher IL-6 levels (odds ratio 1.036; 95% confidence interval [CI] 1.009-1.064; P = 0.008) remained independently associated with the presence of MHE. IL-6 levels ≥ 8pg/mL discriminated best between patients with and without MHE in receiver operating characteristic (ROC) analysis (area under the ROC 0.751). With a cutoff value of ≥7 pg/mL, further elaborate testing with PHES could be avoided in 38% of all patients with a sensitivity of 90% (95% CI 77%-96%) and a negative predictive value (NPV) of 93% (95% CI 84%-98%). This diagnostic accuracy was confirmed in the validation cohort (sensitivity 94%; NPV 93%). Conclusion: Using IL-6 serum levels as a biomarker in a stepwise diagnostic algorithm to detect MHE could substantially reduce the number of patients requiring testing with PHES and in turn the workload. IL-6 may have especially helped in patients who are unable to perform other screening tests.
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Affiliation(s)
- Simon Johannes Gairing
- Department of Internal Medicine IUniversity Medical Center of the Johannes Gutenberg-UniversityMainzGermany.,Cirrhosis Center MainzUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany
| | - Julian Anders
- Department of Internal Medicine IUniversity Medical Center of the Johannes Gutenberg-UniversityMainzGermany
| | - Leonard Kaps
- Department of Internal Medicine IUniversity Medical Center of the Johannes Gutenberg-UniversityMainzGermany.,Cirrhosis Center MainzUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany
| | - Michael Nagel
- Department of Internal Medicine IUniversity Medical Center of the Johannes Gutenberg-UniversityMainzGermany.,Cirrhosis Center MainzUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany
| | - Maurice Michel
- Department of Internal Medicine IUniversity Medical Center of the Johannes Gutenberg-UniversityMainzGermany.,Cirrhosis Center MainzUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany
| | - Wolfgang Maximilian Kremer
- Department of Internal Medicine IUniversity Medical Center of the Johannes Gutenberg-UniversityMainzGermany.,Cirrhosis Center MainzUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany
| | - Max Hilscher
- Department of Internal Medicine IUniversity Medical Center of the Johannes Gutenberg-UniversityMainzGermany.,Cirrhosis Center MainzUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany
| | - Peter Robert Galle
- Department of Internal Medicine IUniversity Medical Center of the Johannes Gutenberg-UniversityMainzGermany.,Cirrhosis Center MainzUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany
| | - Jörn M Schattenberg
- Department of Internal Medicine IUniversity Medical Center of the Johannes Gutenberg-UniversityMainzGermany.,Metabolic Liver Research ProgramUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany
| | - Marcus-Alexander Wörns
- Department of Internal Medicine IUniversity Medical Center of the Johannes Gutenberg-UniversityMainzGermany.,Cirrhosis Center MainzUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany.,Department of Gastroenterology, Hematology, Oncology and EndocrinologyKlinikum Dortmund GmbHDortmundGermany
| | - Christian Labenz
- Department of Internal Medicine IUniversity Medical Center of the Johannes Gutenberg-UniversityMainzGermany.,Cirrhosis Center MainzUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany
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10
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Hansen MKG, Kjærgaard K, Eriksen LL, Grønkjær LL, Mikkelsen ACD, Sandahl TD, Vilstrup H, Thomsen KL, Lauridsen MME. Psychometric methods for diagnosing and monitoring minimal hepatic encephalopathy -current validation level and practical use. Metab Brain Dis 2022; 37:589-605. [PMID: 35102491 DOI: 10.1007/s11011-022-00913-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 01/14/2022] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE) is cerebral dysfunction caused by liver failure and inflicts 30-40% of patients with liver cirrhosis during their disease course. Clinically manifest HE is often preceded by minimal HE (MHE) - a clinically undetectable cognitive disturbance closely associated with loss of quality of life. Accordingly, detecting and treating MHE improve the patients' daily functioning and prevent HE-related hospital admissions. The scope of this review article is to create an overview of the validation level and usage of psychometric tests used to detect MHE: Portosystemic hepatic encephalopathy test, continuous reaction time test, Stroop EncephalApp, animal naming test, critical flicker frequency test, and inhibitory control test. Our work is aimed at the clinician or scientist who is about to decide on which psychometric test would fit best in their clinic, cohort, or study. First, we outline psychometric test validation obstacles and requirements. Then, we systematically approach the literature on each test and select well-conducted studies to answer the following questions:• Which percentage of patients with cirrhosis does the test deem as having MHE?• Is the test able to predict clinically manifest HE?• Is there a well-known test-retest variation and inter-observer variation?• Is the test able to detect a treatment response?• Is the test result affected by age, educational level, gender, or comorbidities?
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Affiliation(s)
- Mads Kingo Guldberg Hansen
- Department of Gastroenterology and Hepatology, University Hospital South Denmark, Finsensgade 35, 6700, Esbjerg, Denmark.
| | - Kristoffer Kjærgaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Lotte Lindgreen Eriksen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Lea Ladegaard Grønkjær
- Department of Gastroenterology and Hepatology, University Hospital South Denmark, Finsensgade 35, 6700, Esbjerg, Denmark
| | - Anne Catrine Daugaard Mikkelsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Thomas Damgaard Sandahl
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Karen Louise Thomsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Mette Munk Enok Lauridsen
- Department of Gastroenterology and Hepatology, University Hospital South Denmark, Finsensgade 35, 6700, Esbjerg, Denmark
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11
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Labenz C, Nagel M, Kämper P, Engel S, Bittner S, Kaps L, Galle PR, Schattenberg JM, Wörns MA, Lüssi F. Association Between Serum Levels of Neurofilament Light Chains and Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis. Clin Transl Gastroenterol 2021; 12:e00419. [PMID: 34665788 PMCID: PMC8528231 DOI: 10.14309/ctg.0000000000000419] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/22/2021] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Serum biomarkers for the diagnosis of minimal hepatic encephalopathy (MHE) in patients with liver cirrhosis would be desirable. In this proof-of-concept study, we investigated the association between MHE and serum levels of neurofilament light chains (sNfL) in patients with liver cirrhosis. METHODS sNfL were studied in patients with liver cirrhosis (with or without MHE) and controls (patients with ischemic stroke, transitory ischemic attack, and healthy individuals). MHE was diagnosed using the Psychometric Hepatic Encephalopathy Score. RESULTS Patients with MHE showed higher sNfL than patients without MHE and controls. In multivariable analyses, higher sNfL were independently associated with the presence of MHE. sNfL had a reliable discriminative power for the detection of MHE with an area under the curve of 0.872. DISCUSSION MHE is associated with higher sNfL.
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Affiliation(s)
- Christian Labenz
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Michael Nagel
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Paula Kämper
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Sinah Engel
- Department of Neurology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Stefan Bittner
- Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Leonard Kaps
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Peter R. Galle
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Jörn M. Schattenberg
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Metabolic Liver Research Program, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Marcus-Alexander Wörns
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Department of Gastroenterology, Hematology, Oncology, and Endocrinology, Klinikum Dortmund, Germany
| | - Felix Lüssi
- Department of Neurology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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12
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Tamai Y, Iwasa M, Eguchi A, Shigefuku R, Kamada Y, Miyoshi E, Takei Y. Rifaximin ameliorates intestinal inflammation in cirrhotic patients with hepatic encephalopathy. JGH Open 2021; 5:827-830. [PMID: 34263080 PMCID: PMC8264230 DOI: 10.1002/jgh3.12596] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/05/2021] [Accepted: 06/08/2021] [Indexed: 01/07/2023]
Abstract
Rifaximin (RFX) treatment can attenuate not only hyperammonemia but also Enterococcus faecalis translocation and 10-7G values, suggesting that RFX treatment may improve intestinal inflammation and result in better overall survival.
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Affiliation(s)
- Yasuyuki Tamai
- Department of Gastroenterology and HepatologyMie University Graduate School of MedicineTsuJapan
| | - Motoh Iwasa
- Department of Gastroenterology and HepatologyMie University Graduate School of MedicineTsuJapan
| | - Akiko Eguchi
- Department of Gastroenterology and HepatologyMie University Graduate School of MedicineTsuJapan
| | - Ryuta Shigefuku
- Department of Gastroenterology and HepatologyMie University Graduate School of MedicineTsuJapan
| | - Yoshihiro Kamada
- Department of Molecular Biochemistry and Clinical InvestigationOsaka University Graduate School of MedicineOsakaJapan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical InvestigationOsaka University Graduate School of MedicineOsakaJapan
| | - Yoshiyuki Takei
- Department of Gastroenterology and HepatologyMie University Graduate School of MedicineTsuJapan
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13
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Minimal Hepatic Encephalopathy and Biejia-Ruangan Are Associated with First Hospital Readmission in Nonalcoholic Cirrhosis Patients. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6652858. [PMID: 34055016 PMCID: PMC8123979 DOI: 10.1155/2021/6652858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 04/06/2021] [Accepted: 04/19/2021] [Indexed: 11/17/2022]
Abstract
Introductionand Aim. Patients with cirrhosis are often hospitalized repeatedly for a variety of complications. This retrospective study aimed to assess the effects of minimal hepatic encephalopathy (MHE) and Biejia-Ruangan (BR) on first hospital readmission in nonalcoholic cirrhosis patients without previous overt hepatic encephalopathy (OHE) or hepatocellular carcinoma (HCC). Materials and Methods. A total of 176 hospitalized patients with nonalcoholic cirrhosis were included in this retrospective study. Patients who were first admitted to Beijing Ditan Hospital of Capital Medical University from January 2017 to September 2019 were enrolled. The primary endpoint was their first liver-related hospital readmission. The risk factors for readmission were analyzed by Cox proportional hazard regression analysis. Results. A total of 176 nonalcoholic cirrhosis patients without previous OHE or HCC were included; 57 patients (32.4%) were diagnosed with MHE, and 63 patients (35.8%) were administered BR (2 g, three times a day). Multivariate analysis revealed that nonalcoholic cirrhosis patients with MHE (HR, 5.805; 95% CI, 3.007-11.206; x, P < 0.001) and a higher Model for End-Stage Liver Disease (MELD) score (HR, 1.145; 95% CI, 1.068-1.227; P < 0.001) had an increased risk of first hospital readmission, and patients treated with BR (HR, 0.318; 95% CI, 0.151-0.670; P=0.003) had a decreased risk of first hospital readmission. Conclusion. MHE increased the risk of hospital readmission in nonalcoholic cirrhosis patients without previous OHE or HCC, and this risk was decreased by BR administration.
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14
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Kimer N, Gluud LL, Pedersen JS, Tavenier J, Møller S, Bendtsen F. The Psychometric Hepatic Encephalopathy Syndrome score does not correlate with blood ammonia, endotoxins or markers of inflammation in patients with cirrhosis. Transl Gastroenterol Hepatol 2021; 6:8. [PMID: 33409402 DOI: 10.21037/tgh.2020.02.14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 02/10/2020] [Indexed: 12/18/2022] Open
Abstract
Background The pathogenesis of hepatic encephalopathy (HE) remains unclear but impaired clearance of gut-derived neurotoxins and increased systemic inflammation are thought to play key roles. The diagnosis is based on detection of neurophysiological and neuropsychometric abnormalities. The Psychometric Hepatic Encephalopathy Score (PHES) have been found to correlate with markers of systematic inflammation including interleukin 6, C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α). This study explores the associations between the PHES score and systemic inflammation, endotoxins and disease severity using baseline data from a trial involving patients with cirrhosis and minimal or no HE (NCT01769040). Methods Arterial blood was obtained during hepatic vein catheterization, from 54 patients [median age 55 (range, 33-70) years; 83% men] with decompensated but stable cirrhosis. None had clinical evidence of HE but 34 (55.6%) had an abnormal PHES score indicating the presence of minimal HE. Relationships were sought between the PHES score and markers of systemic inflammation, high sensitivity-CRP, cytokines (SDF-1α, TGF-b1, IP-10, IL-6, 10 and 18, and TNF-α; lipopolysaccharide (LPS), the lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14); and the blood ammonia. Results No significant relationships were found between the PHES score and any of the variables tested with the single exception of the correlation with serum IL-6 (r=-0.29, 95% confidence interval, -0.53 to -0.02, P=0.031). No independent predictors of the PHES score were identified in regression analyses. Conclusions No predictive associations were identified between the PHES scores and circulating blood ammonia, endotoxins, or markers of systemic inflammation in this patient population.
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Affiliation(s)
- Nina Kimer
- Gastrounit, Medical Division, University Hospital Hvidovre, Hvidovre, Denmark.,Centre of Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, University Hospital Hvidovre, Hvidovre, Denmark
| | - Lise Lotte Gluud
- Gastrounit, Medical Division, University Hospital Hvidovre, Hvidovre, Denmark
| | | | - Juliette Tavenier
- Clinical Research Centre, University Hospital Hvidovre, Hvidovre, Denmark
| | - Søren Møller
- Centre of Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, University Hospital Hvidovre, Hvidovre, Denmark
| | - Flemming Bendtsen
- Gastrounit, Medical Division, University Hospital Hvidovre, Hvidovre, Denmark
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15
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Bajaj JS, Lauridsen M, Tapper EB, Duarte-Rojo A, Rahimi RS, Tandon P, Shawcross DL, Thabut D, Dhiman RK, Romero-Gomez M, Sharma BC, Montagnese S. Important Unresolved Questions in the Management of Hepatic Encephalopathy: An ISHEN Consensus. Am J Gastroenterol 2020; 115:989-1002. [PMID: 32618647 DOI: 10.14309/ajg.0000000000000603] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
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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Affiliation(s)
- Jasmohan S Bajaj
- Virginia Commonwealth University, McGuire VA Medical Center, Richmond, Virginia, USA
| | | | | | | | | | | | | | - Dominique Thabut
- Paris Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France
| | - Radha K Dhiman
- Postgraduate Institute of Medical Education & Research, Chandigarh, India
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16
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Arłukowicz-Grabowska M, Wójcicki M, Raszeja-Wyszomirska J, Szydłowska-Jakimiuk M, Piotuch B, Milkiewicz P. Acute liver injury, acute liver failure and acute on chronic liver failure: A clinical spectrum of poisoning due to Gyromitra esculenta. Ann Hepatol 2020; 18:514-516. [PMID: 31014949 DOI: 10.1016/j.aohep.2018.11.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 11/28/2018] [Accepted: 11/28/2018] [Indexed: 02/04/2023]
Abstract
Gyromitra esculenta, also known as "false morel" is one of the most poisonous mushrooms. This species is found all over the world, growing in coniferous forest in early spring time. Common manifestation of poisoning includes gastrointestinal symptoms which include varied degrees of liver impairment. We describe three cases: acute liver injury, acute liver failure and acute-on-chronic liver failure due to G. esculenta poisoning. At admission patients presented with encephalopathy and features of liver failure. Two of them recovered completely following supportive management while the remaining patient who also had preexisting liver disease developed multiorgan failure and subsequently died. Although a rare occurrence, G. esculenta poisoning should be considered in the differential diagnosis of acute liver failure.
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Affiliation(s)
- Magdalena Arłukowicz-Grabowska
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland.
| | - Maciej Wójcicki
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Joanna Raszeja-Wyszomirska
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Monika Szydłowska-Jakimiuk
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Bernard Piotuch
- Department of Surgery, Ministry of the Interior and Administration Hospital, Szczecin, Poland
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland; Translation Medicine Group, Pomeranian Medical University, Szczecin, Poland
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Cassard AM, Houron C, Ciocan D. Microbiote intestinal et stéatopathie métabolique. NUTR CLIN METAB 2020. [DOI: 10.1016/j.nupar.2019.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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KASL clinical practice guidelines for liver cirrhosis: Varices, hepatic encephalopathy, and related complications. Clin Mol Hepatol 2020; 26:83-127. [PMID: 31918536 PMCID: PMC7160350 DOI: 10.3350/cmh.2019.0010n] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 02/06/2023] Open
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Luo M, Ma P, Li L, Cao WK. Advances in psychometric tests for screening minimal hepatic encephalopathy: From paper-and-pencil to computer-aided assessment. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 30:398-407. [PMID: 31060994 DOI: 10.5152/tjg.2019.18226] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Minimal hepatic encephalopathy (MHE) is a major neuropsychiatric complication of liver cirrhosis and portosystemic shunting. Although MHE produces a spectrum of cognitive impairments in the domains of short-term attention, working memory, and executive function, it generally does not present with obvious clinical manifestation on conventional assessments. Paper-and-pencil psychometric tests, such as the psychometric hepatic encephalopathy score and the repeatable battery for the assessment of neuropsychological status, are recommended to diagnose MHE. However, these tests are neither rapid nor convenient to use in practice. To facilitate repeated testing in clinic and follow-up, computer-aided psychometric tests, such as the scan test, Cognitive Drug Research assessment battery, inhibitory control test, EncephalApp Stroop App, and critical flicker frequency, have been used to screen for MHE among patients with liver cirrhosis. The aim of this review was to describe the progression from the utility of paper-and-pencil to computer-aided psychometric tests for MHE screening in clinical practice.
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Affiliation(s)
- Ming Luo
- Department of Gastroenterology, Ningxia People's Hospital, Ningxia, China
| | - Ping Ma
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Lei Li
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Wu-Kui Cao
- Tianjin Liver Disease Institute, Tianjin Second People's Hospital, Tianjin, China
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20
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Senzolo M, Zarantonello L, Formentin C, Orlando C, Beltrame R, Vuerich A, Angeli P, Burra P, Montagnese S. Predictive value of induced hyperammonaemia and neuropsychiatric profiling in relation to the occurrence of post-TIPS hepatic encephalopathy. Metab Brain Dis 2019; 34:1803-1812. [PMID: 31506797 DOI: 10.1007/s11011-019-00490-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 09/03/2019] [Indexed: 01/16/2023]
Abstract
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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Affiliation(s)
- Marco Senzolo
- Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
| | | | | | - Costanza Orlando
- Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Raffaello Beltrame
- Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Anna Vuerich
- Department of Medicine, University of Padova, Padova, Italy
| | - Paolo Angeli
- Department of Medicine, University of Padova, Padova, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Sara Montagnese
- Department of Medicine, University of Padova, Padova, Italy.
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Specific Gut and Salivary Microbiota Patterns Are Linked With Different Cognitive Testing Strategies in Minimal Hepatic Encephalopathy. Am J Gastroenterol 2019; 114:1080-1090. [PMID: 30816877 PMCID: PMC6610654 DOI: 10.14309/ajg.0000000000000102] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Minimal hepatic encephalopathy (MHE) is epidemic in cirrhosis, but testing strategies often have poor concordance. Altered gut/salivary microbiota occur in cirrhosis and could be related to MHE. Our aim was to determine microbial signatures of individual cognitive tests and define the role of microbiota in the diagnosis of MHE. METHODS Outpatients with cirrhosis underwent stool collection and MHE testing with psychometric hepatic encephalopathy score (PHES), inhibitory control test, and EncephalApp Stroop. A subset provided saliva samples. Minimal hepatic encephalopathy diagnosis/concordance between tests was compared. Stool/salivary microbiota were analyzed using 16srRNA sequencing. Microbial profiles were compared between patients with/without MHE on individual tests. Logistic regression was used to evaluate clinical and microbial predictors of MHE diagnosis. RESULTS Two hundred forty-seven patients with cirrhosis (123 prior overt HE, MELD 13) underwent stool collection and PHES testing; 175 underwent inhibitory control test and 125 underwent Stroop testing. One hundred twelve patients also provided saliva samples. Depending on the modality, 59%-82% of patients had MHE. Intertest Kappa for MHE was 0.15-0.35. Stool and salivary microbiota profiles with MHE were different from those without MHE. Individual microbiota signatures were associated with MHE in specific modalities. However, the relative abundance of Lactobacillaceae in the stool and saliva samples was higher in MHE, regardless of the modality used, whereas autochthonous Lachnospiraceae were higher in those without MHE, especially on PHES. On logistic regression, stool and salivary Lachnospiraceae genera (Ruminococcus and Clostridium XIVb) were associated with good cognition independent of clinical variables. DISCUSSION Specific stool and salivary microbial signatures exist for individual cognitive testing strategies in MHE. The presence of specific taxa associated with good cognitive function regardless of modality could potentially be used to circumvent MHE testing.
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Yoon EL, Jun DW, Jeong JY, Kim TY, Song DS, Ahn SB, Kim HY, Jung YK, Song MJ, Kim SE, Kim HS, Jeong SW, Kim SG, Lee TH, Cho YK, Kim JK, Ryu H. Validation of the Korean Stroop Test in Diagnosis of Minimal Hepatic Encephalopathy. Sci Rep 2019; 9:8027. [PMID: 31142824 PMCID: PMC6541633 DOI: 10.1038/s41598-019-44503-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 05/15/2019] [Indexed: 12/13/2022] Open
Abstract
The burden of minimal hepatic encephalopathy (MHE) is significant, but no universal criteria for diagnosis have been established. We aimed to validate the Korean Stroop Test for MHE screening. Chronic hepatitis B-related liver cirrhosis patients were recruited prospectively from 13 centers. The Korean Stroop Test consisted of two Stroop-off states (color and word) and two Stroop-on states (inhibition and switching). Accuracy adjusted psychomotor speed (rate correct score) of these tests were analyzed. Sex- and age- adjusted rate correct scores of these tests were rated as the Korean Stroop Score (K-Stroop score). MHE was diagnosed when Portosystemic Encephalopathy Syndrome Test (PHES) scores were below -4. A total of 220 liver cirrhosis patients and 376 healthy controls were enrolled. Prevalence of MHE was 20.6% in cirrhosis patients. Rate correct scores and the K-Stroop score showed significant differences between healthy controls, cirrhosis patients without MHE, and cirrhosis patients with MHE. The rate correct score of the K-Stroop score was 0.74 (95% Confidence Interval: 0.66-0.83, P < 0.001). Female gender and the K-Stroop score were significant for MHE diagnosis. The Korean Stroop Test is simple and valid for screening of MHE.
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Affiliation(s)
- Eileen L Yoon
- Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, 01757, Republic of Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, 04763, Republic of Korea.
| | - Jae Yoon Jeong
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri-si, 11923, Republic of Korea
| | - Tae Yeob Kim
- Department of Internal Medicine, New Hope Internal Medicine Clinic, Seoul, 03113, Republic of Korea
| | - Do Seon Song
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, 16247, Republic of Korea
| | - Sang Bong Ahn
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University College of Medicine, Seoul, 01830, Republic of Korea
| | - Hee Yeon Kim
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu-si, 11765, Republic of Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University Medical Center, Ansan-si, 02841, Republic of Korea
| | - Myeong Jun Song
- Department of Internal Medicine, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, 34943, Republic of Korea
| | - Sung Eun Kim
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang-si, 14068, Republic of Korea
| | - Hyoung Su Kim
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, 05355, Republic of Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Soonchunhyang University Seoul Hospital, Seoul, 04401, Republic of Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon-si, 14584, Republic of Korea
| | - Tae Hee Lee
- Department of Internal Medicine, Konyang University College of Medicine, Daejeon, 35365, Republic of Korea
| | - Yong Kyun Cho
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 03181, Republic of Korea
| | - Jae-Kwan Kim
- Department of Arts & Technology, Hanyang University, Seoul, 04763, Republic of Korea
| | - Hokyoung Ryu
- Department of Arts & Technology, Hanyang University, Seoul, 04763, Republic of Korea
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Zarantonello L, Turco M, Formentin C, Izquierdo-Altarejos P, Vuerich A, Barcenas Jimenez MJ, Montoliu C, Felipo V, Angeli P, Amodio P, Montagnese S. The influence of HE history, HE status and neuropsychological test type on learning ability in patients with cirrhosis. Liver Int 2019; 39:861-870. [PMID: 30658006 DOI: 10.1111/liv.14046] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 12/06/2018] [Accepted: 01/11/2019] [Indexed: 12/25/2022]
Abstract
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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Affiliation(s)
| | - Matteo Turco
- Department of Medicine, University of Padova, Padova, Italy
| | | | - Paula Izquierdo-Altarejos
- Department of Medicine, University of Padova, Padova, Italy.,Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Valencia, Spain
| | - Anna Vuerich
- Department of Medicine, University of Padova, Padova, Italy
| | | | - Carmina Montoliu
- Fundación Investigación Hospital Clínico, Instituto Investigación Sanitaria-INCLIVA, Valencia, Spain
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro Investigación Príncipe Felipe, Valencia, Spain
| | - Paolo Angeli
- Department of Medicine, University of Padova, Padova, Italy
| | - Piero Amodio
- Department of Medicine, University of Padova, Padova, Italy
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Montagnese S, Russo FP, Amodio P, Burra P, Gasbarrini A, Loguercio C, Marchesini G, Merli M, Ponziani FR, Riggio O, Scarpignato C. Hepatic encephalopathy 2018: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF). Dig Liver Dis 2019; 51:190-205. [PMID: 30606696 DOI: 10.1016/j.dld.2018.11.035] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 11/27/2018] [Accepted: 11/28/2018] [Indexed: 12/11/2022]
Abstract
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.
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Affiliation(s)
| | | | - Piero Amodio
- Department of Medicine, University of Padova, Italy
| | - Patrizia Burra
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy
| | - Antonio Gasbarrini
- Division of Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - Carmela Loguercio
- Department of Clinical and Experimental Medicine, University of Campania "L. Vanvitelli", Naples, Italy
| | - Giulio Marchesini
- Unit of Metabolic Diseases & Clinical Dietetics, Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Manuela Merli
- Division of Gastroenterology, Department of Clinical Medicine, La Sapienza University of Rome, Italy
| | - Francesca Romana Ponziani
- Division of Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - Oliviero Riggio
- Division of Gastroenterology, Department of Clinical Medicine, La Sapienza University of Rome, Italy
| | - Carmelo Scarpignato
- Clinical Pharmacology & Digestive Pathophysiology Unit, Department of Clinical & Experimental Medicine, University of Parma, Italy
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Montrief T, Koyfman A, Long B. Acute liver failure: A review for emergency physicians. Am J Emerg Med 2018; 37:329-337. [PMID: 30414744 DOI: 10.1016/j.ajem.2018.10.032] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/15/2018] [Accepted: 10/17/2018] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Acute liver failure (ALF) remains a high-risk clinical presentation, and many patients require emergency department (ED) management for complications and stabilization. OBJECTIVE This narrative review provides an evidence-based summary of the current data for the emergency medicine evaluation and management of ALF. DISCUSSION While ALF remains a rare clinical presentation, surveillance data suggest an overall incidence between 1 and 6 cases per million people every year, accounting for 6% of liver-related deaths and 7% of orthotopic liver transplants (OLT) in the U.S. The definition of ALF includes neurologic dysfunction, an international normalized ratio ≥ 1.5, no prior evidence of liver disease, and a disease course of ≤26 weeks, and can be further divided into hyperacute, acute, and subacute presentations. There are many underlying etiologies, including acetaminophen toxicity, drug induced liver injury, and hepatitis. Emergency physicians will be faced with several complications, including encephalopathy, coagulopathy, infectious processes, renal injury, and hemodynamic instability. Critical patients should be evaluated in the resuscitation bay, and consultation with the transplant team for appropriate patients improves patient outcomes. This review provides several guiding principles for management of acute complications. Using a pathophysiological-guided approach to the management of ALF associated complications is essential to optimizing patient care. CONCLUSIONS ALF remains a rare clinical presentation, but has significant morbidity and mortality. Physicians must rapidly diagnose these patients while evaluating for other diseases and complications. Early consultation with a transplantation center is imperative, as is identifying the underlying etiology and initiating symptomatic care.
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Affiliation(s)
- Tim Montrief
- University of Miami, Jackson Memorial Hospital/Miller School of Medicine, Department of Emergency Medicine, 1611 N.W. 12th Avenue, Miami, FL 33136, United States
| | - Alex Koyfman
- The University of Texas Southwestern Medical Center, Department of Emergency Medicine, 5323 Harry Hines Boulevard, Dallas, TX 75390, United States
| | - Brit Long
- Brooke Army Medical Center, Department of Emergency Medicine, 3841 Roger Brooke Dr, Fort Sam Houston, TX 78234, United States.
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Nguyen HH, Swain MG, Wong P, Congly SE. Canadian regulations and legal ramifications for hepatic encephalopathy: a descriptive analysis. CMAJ Open 2018; 6:E575-E579. [PMID: 30510040 PMCID: PMC6277253 DOI: 10.9778/cmajo.20180024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Hepatic encephalopathy, a form of brain dysfunction seen in the setting of liver insufficiency, negatively affects driving performance and so is both a patient and public safety issue. We aimed to review the motor vehicle codes in each Canadian province and territory relating to the reporting of patients with hepatic encephalopathy and to search a Canadian legal database for cases of motor vehicle collisions involving patients with hepatic encephalopathy. METHODS In this descriptive analysis, the transportation agencies of each Canadian province and territory were contacted via telephone and/or email between April and August 2017. Requirements of physicians to report medical conditions (including liver disease and hepatic encephalopathy) affecting a patient's fitness to drive were assessed. WestlawNext Canada was searched for any Canadian cases on hepatic encephalopathy and driving-related lawsuits from inception to Dec. 31, 2017. RESULTS Reporting of medically unfit drivers is a requirement in all Canadian provinces and territories except Alberta, Quebec and Nova Scotia. Hepatic encephalopathy, cirrhosis and advanced liver disease were not specifically identified as reportable medical conditions in any province or territory. Our search did not identify any lawsuits involving a motor vehicle collision in Canada that were made either against physicians caring for patients with hepatic encephalopathy or against such patients themselves. INTERPRETATION Although hepatic encephalopathy has a substantial impact on driving performance, it is not specifically identified as a reportable medical condition in Canada. Increasing awareness of the potential impact of hepatic encephalopathy on safe driving for health care providers and the public is critical.
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Affiliation(s)
- Henry H Nguyen
- University of Calgary Liver Unit, Department of Medicine (Nguyen, Swain, Congly), Division of Gastroenterology and Hepatology, Calgary, Alta.; McGill University Health Centre (Wong), Royal Victoria Hospital, Montréal, Que
| | - Mark G Swain
- University of Calgary Liver Unit, Department of Medicine (Nguyen, Swain, Congly), Division of Gastroenterology and Hepatology, Calgary, Alta.; McGill University Health Centre (Wong), Royal Victoria Hospital, Montréal, Que
| | - Philip Wong
- University of Calgary Liver Unit, Department of Medicine (Nguyen, Swain, Congly), Division of Gastroenterology and Hepatology, Calgary, Alta.; McGill University Health Centre (Wong), Royal Victoria Hospital, Montréal, Que
| | - Stephen E Congly
- University of Calgary Liver Unit, Department of Medicine (Nguyen, Swain, Congly), Division of Gastroenterology and Hepatology, Calgary, Alta.; McGill University Health Centre (Wong), Royal Victoria Hospital, Montréal, Que.
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Amodio P. Hepatic encephalopathy: Diagnosis and management. Liver Int 2018; 38:966-975. [PMID: 29624860 DOI: 10.1111/liv.13752] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 03/28/2018] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE) is a peculiar kind of brain dysfunction caused by liver insufficiency and/or portal-systemic shunting. It is related to gut-derived substances. It is a relevant cause of morbidity and hospitalisation for patients with cirrhosis. The prognosis of HE is important in terms of survival and re-hospitalisation. It is related to impaired quality of life, falls and poor driving; presents a relevant burden for caregivers and health services; and may negatively impact on patient's job and income. Proper diagnosis and classification are expected to improve HE management. Once diagnosed, the management and therapeutic options for HE are generally clear. The improvement of knowledge in recent years has also clarified which are the further aims of research in this field of medicine. Prophylaxis of overt HE should always be performed, and this is generally secondary prophylaxis. Primary prophylaxis should be done immediately after upper gastrointestinal bleeding. Great advances in the detection and treatment of mild forms of HE are expected to lead to further improvement in patient management.
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Affiliation(s)
- Piero Amodio
- Department of Medicine -DIMED- and CIRMANMEC, University of Padova, Padova, Italy
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28
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Ridola L, Cardinale V, Riggio O. The burden of minimal hepatic encephalopathy: from diagnosis to therapeutic strategies. Ann Gastroenterol 2018; 31:151-164. [PMID: 29507462 PMCID: PMC5825945 DOI: 10.20524/aog.2018.0232] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 11/29/2017] [Indexed: 12/12/2022] Open
Abstract
Minimal hepatic encephalopathy (MHE) is the mildest form of hepatic encephalopathy (HE). It affects the performance of psychometric tests focused on attention, working memory, psychomotor speed, and visuospatial ability, as well as electrophysiological and other functional brain measures. MHE is a frequent complication of liver disease, affecting up to 80% of tested patients. By being related to falls, an impairment in fitness to drive and the development of overt HE, MHE severely affects the lives of patients and caregivers by altering their quality of life and their socioeconomic status. MHE is detected in clinically asymptomatic patients using appropriate psychometric tests and neurophysiological methods that highlight neuropsychological alterations, such as video-spatial orientation deficits, attention disorders, memory, reaction times, electroencephalogram slowing, prolongation of latency-evoked cognitive potentials, and reduction in the critical flicker frequency. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics such as rifaximin, probiotics and branched-chain amino acids. However, because of the multiple diagnosis methods, the various endpoints of treatment trials and the variety of agents used in trials, the treatment of MHE is not currently recommended as routine, but only on a case-by-case basis.
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Affiliation(s)
- Lorenzo Ridola
- Department of Medico-Surgical Sciences and Biotechnologies (Lorenzo Ridola, Vincenzo Cardinale), Sapienza University of Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies (Lorenzo Ridola, Vincenzo Cardinale), Sapienza University of Rome, Italy
| | - Oliviero Riggio
- Department of Clinical Medicine (Oliviero Riggio), Sapienza University of Rome, Italy
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Felipo V, Montagnese S. A rare and revealing glimpse of the cerebrospinal fluid of patients with hepatic encephalopathy. J Hepatol 2016; 65:1077-1078. [PMID: 27677713 DOI: 10.1016/j.jhep.2016.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 09/17/2016] [Accepted: 09/19/2016] [Indexed: 12/04/2022]
Affiliation(s)
- Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
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30
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Tilg H, Cani PD, Mayer EA. Gut microbiome and liver diseases. Gut 2016; 65:2035-2044. [PMID: 27802157 DOI: 10.1136/gutjnl-2016-312729] [Citation(s) in RCA: 341] [Impact Index Per Article: 37.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 09/13/2016] [Accepted: 09/16/2016] [Indexed: 12/20/2022]
Abstract
The gut microbiota has recently evolved as a new important player in the pathophysiology of many intestinal and extraintestinal diseases. The liver is the organ which is in closest contact with the intestinal tract, and is exposed to a substantial amount of bacterial components and metabolites. Various liver disorders such as alcoholic liver disease, non-alcoholic liver disease and primary sclerosing cholangitis have been associated with an altered microbiome. This dysbiosis may influence the degree of hepatic steatosis, inflammation and fibrosis through multiple interactions with the host's immune system and other cell types. Whereas few results from clinical metagenomic studies in liver disease are available, evidence is accumulating that in liver cirrhosis an oral microbiome is overrepresented in the lower intestinal tract, potentially contributing to disease process and severity. A major role for the gut microbiota in liver disorders is also supported by the accumulating evidence that several complications of severe liver disease such as hepatic encephalopathy are efficiently treated by various prebiotics, probiotics and antibiotics. A better understanding of the gut microbiota and its components in liver diseases might provide a more complete picture of these complex disorders and also form the basis for novel therapies.
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Affiliation(s)
- Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology & Endocrinology, Medical University Innsbruck, Innsbruck, Austria
| | - Patrice D Cani
- WELBIO-Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Metabolism and Nutrition Research Group, Université catholique de Louvain, Brussels, Belgium
| | - Emeran A Mayer
- Division of Digestive Diseases, G. Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Iwasa M, Sugimoto R, Mifuji-Moroka R, Hara N, Yoshikawa K, Tanaka H, Eguchi A, Yamamoto N, Sugimoto K, Kobayashi Y, Hasegawa H, Takei Y. Factors contributing to the development of overt encephalopathy in liver cirrhosis patients. Metab Brain Dis 2016; 31:1151-6. [PMID: 27353278 DOI: 10.1007/s11011-016-9862-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 06/19/2016] [Indexed: 12/17/2022]
Abstract
The aim of this study was to clarify the relationships among psychometric testing results, blood ammonia (NH3) levels, electrolyte abnormalities, and degree of inflammation, and their associations with the development of overt hepatic encephalopathy (HE) in liver cirrhosis (LC) patients. The relationships between covert HE and blood NH3, sodium (Na), and C-reactive protein (CRP) were examined in 40 LC patients. The effects of elevated NH3, hyponatremia, and elevated CRP on the development of overt HE were also investigated. The covert HE group had significantly lower serum Na levels and significantly higher serum CRP levels. During the median observation period of 11 months, 10 patients developed overt HE, and the results of multivariate analysis showed that covert HE and elevated blood NH3 were factors contributing to the development of overt HE. Electrolyte abnormalities and mild inflammation are involved in the pathogenesis of HE. Abnormal psychometric testing results and hyperammonemia are linked to subsequent development of overt HE.
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Affiliation(s)
- Motoh Iwasa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu, Mie, 514-8507, Japan.
| | - Ryosuke Sugimoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu, Mie, 514-8507, Japan
| | - Rumi Mifuji-Moroka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu, Mie, 514-8507, Japan
| | - Nagisa Hara
- Nutrition Unit, Mie University Hospital, Tsu, Japan
| | - Kyoko Yoshikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu, Mie, 514-8507, Japan
| | - Hideaki Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu, Mie, 514-8507, Japan
| | - Akiko Eguchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu, Mie, 514-8507, Japan
| | - Norihiko Yamamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu, Mie, 514-8507, Japan
| | - Kazushi Sugimoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu, Mie, 514-8507, Japan
| | - Yoshinao Kobayashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu, Mie, 514-8507, Japan
| | - Hiroshi Hasegawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu, Mie, 514-8507, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu, Mie, 514-8507, Japan
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Garrido M, Skorucak J, Raduazzo D, Turco M, Spinelli G, Angeli P, Amodio P, Achermann P, Montagnese S. Vigilance and wake EEG architecture in simulated hyperammonaemia: a pilot study on the effects of L-Ornithine-L-Aspartate (LOLA) and caffeine. Metab Brain Dis 2016; 31:965-74. [PMID: 27193025 DOI: 10.1007/s11011-016-9835-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 05/10/2016] [Indexed: 12/21/2022]
Abstract
UNLABELLED 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 < 0.05; paired t-test). Changes in ammonia levels, subjective sleepiness and the EEG in the three conditions were less obvious in patients. In conclusion, both LOLA and caffeine contained the AAC-induced increase in capillary ammonia, especially in healthy volunteers. Caffeine also counteracted the AAC effects on sleepiness/EEG amplitude. The association of ammonia-lowering and vigilance-enhancing medication in the management of HE is worthy of further study.
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Affiliation(s)
- Maria Garrido
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy
| | - Jelena Skorucak
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland
- Center for Interdisciplinary Sleep Research, University of Zurich, Zurich, Switzerland
| | - Daniela Raduazzo
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy
- USO Dipartimentale di Servizio Urgenza ed Emergenza Medica, ULSS 13, Dolo, Regione Veneto, Italy
| | - Matteo Turco
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy
| | - Giuseppe Spinelli
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy
- Department of Psychology, Sapienza University of Rome, Rome, Italy
| | - Paolo Angeli
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy
| | - Piero Amodio
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy
| | - Peter Achermann
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland
- Center for Interdisciplinary Sleep Research, University of Zurich, Zurich, Switzerland
- Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Sara Montagnese
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy.
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Lauridsen MM, Poulsen L, Rasmussen CK, Høgild M, Nielsen MK, de Muckadell OBS, Vilstrup H. Effects of common chronic medical conditions on psychometric tests used to diagnose minimal hepatic encephalopathy. Metab Brain Dis 2016; 31:267-72. [PMID: 26435407 DOI: 10.1007/s11011-015-9741-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Accepted: 09/24/2015] [Indexed: 02/03/2023]
Abstract
Many chronic medical conditions are accompanied by cognitive disturbances but these have only to a very limited extent been psychometrically quantified. An exception is liver cirrhosis where hepatic encephalopathy is an inherent risk and mild forms are diagnosed by psychometric tests. The preferred diagnostic test battery in cirrhosis is often the Continuous Reaction Time (CRT) and the Portosystemic Encephalopathy (PSE) tests but the effect on these of other medical conditions is not known. We aimed to examine the effects of common chronic (non-cirrhosis) medical conditions on the CRT and PSE tests. We studied 15 patients with heart failure (HF), 15 with end stage renal failure (ESRF), 15 with dysregulated type II diabetes (DMII), 15 with chronic obstructive pulmonary disease (COPD), and 15 healthy persons. We applied the CRT test, which is a 10-min computerized test measuring sustained attention and reaction time stability and the PSE test, which is a paper-pencil test battery consisting of 5 subtests. We found that a high fraction of the patients with HF (8/15, 0.002) or COPD (7/15, p = 0.006) had pathological CRT test results; and COPD patients also frequently had an abnormal PSE test result (6/15, p < 0.0001). Both tests were unaffected by ESRF and DMII. Half of the patients with HF or COPD had psychometrically measurable cognitive deficits, whereas those with ESRF or DMII had not. This adds to the understanding of the clinical consequences of chronic heart- and lung disease, and implies that the psychometric tests should be interpreted with great caution in cirrhosis patients with heart- or lung comorbidity.
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Affiliation(s)
- M M Lauridsen
- Department of Gastroenterology, Hospital of South West Jutland, Finsensgade 35, 6700, Esbjerg, Denmark.
| | - L Poulsen
- Department of Gastroenterology, Hospital of South West Jutland, Finsensgade 35, 6700, Esbjerg, Denmark
| | - C K Rasmussen
- Department of Gastroenterology, Hospital of South West Jutland, Finsensgade 35, 6700, Esbjerg, Denmark
| | - M Høgild
- Department of Gastroenterology, Hospital of South West Jutland, Finsensgade 35, 6700, Esbjerg, Denmark
| | - M K Nielsen
- Department of Gastroenterology, Hospital of South West Jutland, Finsensgade 35, 6700, Esbjerg, Denmark
| | | | - H Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Nørrebrogade 44, 8200, Aarhus, Denmark
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Thomsen KL, Macnaughtan J, Tritto G, Mookerjee RP, Jalan R. Clinical and Pathophysiological Characteristics of Cirrhotic Patients with Grade 1 and Minimal Hepatic Encephalopathy. PLoS One 2016; 11:e0146076. [PMID: 26745876 PMCID: PMC4706303 DOI: 10.1371/journal.pone.0146076] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023] Open
Abstract
Background and Aims EASL/AASLD hepatic encephalopathy (HE) guidelines proposed the alternative use of the term ‘Covert HE’ combining minimal HE (mHE) and Grade 1 HE into a single entity. However, longitudinal data to indicate that these are indeed a single entity are lacking. The aims of this study were to determine whether the occurrence of complications of cirrhosis requiring hospital admission and mortality were similar in these sub-groups of patients. Methods Clinically-stable cirrhotic patients (n = 106) with no previous history of ‘Overt HE’ were included over a 2-year period and classified as having no HE (n = 23), mHE (n = 39) or Grade 1 HE (n = 44). Standard biochemistry, venous ammonia, bacterial DNA and neutrophil function were measured at inclusion and the patients were followed for a mean of 230±95 days. Results Patients with Grade 1 HE had significantly more complications requiring hospitalisation (infection 9/18/34%; HE 4/8/18%; other 13/10/11%; P = 0.02) and significantly greater mortality (4/5/20%; P = 0.04) compared to patients with no HE or mHE respectively. Patients with mHE and grade 1 HE had similar ammonia levels, but higher than the no HE group (P<0.001). MELD score was similar between groups but Grade 1 HE patients had increased frequency of bacterial translocation (P = 0.06) and neutrophil spontaneous respiratory burst (P = 0.02) compared to patients with mHE. Conclusions The results of this study show for the first time that ‘Covert HE’ is a heterogeneous entity with significantly greater hospitalisations and mortality in the Grade 1 HE patients compared with mHE. Further prospective longer-term studies are required before EASL/AASLD guidance is fully implemented.
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Affiliation(s)
- Karen Louise Thomsen
- Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom
| | - Jane Macnaughtan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom
| | - Giovanni Tritto
- Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom
| | - Rajeshwar P. Mookerjee
- Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, University College London Medical School, London, United Kingdom
- * E-mail:
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Lauridsen MM, Schaffalitzky de Muckadell OB, Vilstrup H. Minimal hepatic encephalopathy characterized by parallel use of the continuous reaction time and portosystemic encephalopathy tests. Metab Brain Dis 2015; 30:1187-92. [PMID: 26016624 DOI: 10.1007/s11011-015-9688-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 05/22/2015] [Indexed: 12/11/2022]
Abstract
Minimal hepatic encephalopathy (MHE) is a frequent complication to liver cirrhosis that causes poor quality of life, a great burden to caregivers, and can be treated. For diagnosis and grading the international guidelines recommend the use of psychometric tests of different modalities (computer based vs. paper and pencil). To compare results of the Continuous Reaction time (CRT) and the Portosystemic Encephalopathy (PSE) tests in a large unselected cohort of cirrhosis patients without clinically detectable brain impairment and to clinically characterize the patients according to their test results. The CRT method is a 10-minute computerized test of a patient's motor reaction time stability (CRTindex) to 150 auditory stimuli. The PSE test is a 20-minute paper-pencil test evaluating psychomotor speed. Both tests were performed at the same occasion in 129 patients. Both tests were normal in only 36% (n = 46) of the patients and this group had the best quality of life, a normal CRP, a low risk of subsequent overt HE, and a low short term mortality. Either the CRT or the PSE test was abnormal in a total of 64% of the patients (n = 83), the CRT in 53% (n = 69) and the PSE in 34% (n = 44). All these patients had a poorer quality of life, low-grade CRP elevation, moderate risk for subsequent overt HE, and a higher than 20% short term mortality. Both tests were abnormal in 23% (n = 30) of the patients and this group had more advanced cirrhosis and a 40 % short-term mortality. One of the tests was abnormal in the majority of the patients but concordant in only 60%. Most cirrhosis patients seem to have impairments of different cognitive domains and more domains with advancing disease. Two abnormal tests identified patients with an increased risk of overt HE and death.
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Affiliation(s)
- M M Lauridsen
- Department of Gastroenterology, Hospital of South West Jutland, Finsensgade 35, 6700, Esbjerg, Denmark,
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Activation of NMDA receptor by elevated homocysteine in chronic liver disease contributes to encephalopathy. Med Hypotheses 2015; 85:64-7. [DOI: 10.1016/j.mehy.2015.03.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Revised: 03/23/2015] [Accepted: 03/28/2015] [Indexed: 11/18/2022]
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Weissenborn K. Diagnosis of minimal hepatic encephalopathy. J Clin Exp Hepatol 2015; 5:S54-9. [PMID: 26041959 PMCID: PMC4442856 DOI: 10.1016/j.jceh.2014.06.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Accepted: 06/05/2014] [Indexed: 12/12/2022] Open
Abstract
Minimal hepatic encephalopathy (mHE) has significant impact upon a liver patient's daily living and health related quality of life. Therefore a majority of clinicians agree that mHE should be diagnosed and treated. The optimal means for diagnosing mHE, however, is controversial. This paper describes the currently most frequently used methods-EEG, critical flicker frequency, Continuous Reaction time Test, Inhibitory Control Test, computerized test batteries such as the Cognitive Drug Research test battery, the psychometric hepatic encephalopathy score (PHES) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)-and their pros and cons.
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Key Words
- CDR, cognitive drug research
- CFF, critical flicker frequency
- CRT, continuous reaction time test
- EEG, electroencephalography
- ICT, inhibitory control test
- PHES, psychometric hepatic encephalopathy score
- PSE, portosystemic encephalopathy
- RBANS, repeatable battery for the assessment of neuropsychological status
- TA, target accuracy
- WL, weighted lures
- diagnostic means
- diagnostic use
- mHE, minimal hepatic encephalopathy
- minimal hepatic encephalopathy
- sensitivity
- specificity
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Affiliation(s)
- Karin Weissenborn
- Address for correspondence: Karin Weissenborn, Department of Neurology, Hannover Medical School, 30623 Hannover, Germany. Tel.: +49 511 532 2339; fax: +49 511 532 3115.
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Montagnese S, De Rui M, Schiff S, Ceranto E, Valenti P, Angeli P, Cillo U, Zanus G, Gatta A, Amodio P, Merkel C. Prognostic benefit of the addition of a quantitative index of hepatic encephalopathy to the MELD score: the MELD-EEG. Liver Int 2015; 35:58-64. [PMID: 24517387 DOI: 10.1111/liv.12490] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 02/03/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS A 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. METHODS Three 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 18 months 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. RESULTS Both 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. CONCLUSIONS The addition of an automatically obtained EEG-based index improves the prognostic accuracy of the MELD score.
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Montagnese S, Balistreri E, Schiff S, De Rui M, Angeli P, Zanus G, Cillo U, Bombonato G, Bolognesi M, Sacerdoti D, Gatta A, Merkel C, Amodio P. Covert hepatic encephalopathy: Agreement and predictive validity of different indices. World J Gastroenterol 2014; 20:15756-15762. [PMID: 25400460 PMCID: PMC4229541 DOI: 10.3748/wjg.v20.i42.15756] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Revised: 05/06/2014] [Accepted: 06/17/2014] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the agreement and prognostic value of different measures of covert hepatic encephalopathy (CHE).
METHODS: 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.
RESULTS: 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.
CONCLUSION: CHE diagnosis probably requires a combination of clinical, neurophysiological and neuropsychological indices.
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Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol 2014; 61:642-659. [PMID: 25015420 DOI: 10.1016/j.jhep.2014.05.042] [Citation(s) in RCA: 320] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 05/28/2014] [Indexed: 02/07/2023]
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Abstract
The interleukin-6 (IL-6) is a pleiotropic cytokine that plays a key role in interaction between immune and nervous system. Although IL-6 has neurotrophic properties and beneficial effects in the CNS, its overexpression is generally detrimental, adding to the pathophysiology associated with CNS disorders. The source of the increase in peripheral IL-6 remains to be established and varies among different pathologies, but has been found to be associated with cognitive dysfunction in several pathologies. This comprehensive review provides an update summary of the studies performed in humans concerning the role of central and peripheral IL-6 in cognitive dysfunction in dementias and in other systemic diseases accompained by cognitive dysfuction such as cardiovascular, liver disease, Behçet's disease and systemic lupus erythematosus. Further research is needed to correlate specific deficits in IL-6 and its receptors in pathologies characterized by cognitive dysfunction and to understand how systemic IL-6 affects high cerebral function in order to open new directions in pharmacological treatments that modulate IL-6 signalling.
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Affiliation(s)
- Isabel Trapero
- Department of Nursing, University of Valencia, 46010, Valencia, Spain
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Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology 2014; 60:715-735. [PMID: 25042402 DOI: 10.1002/hep.27210] [Citation(s) in RCA: 1385] [Impact Index Per Article: 125.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 04/28/2014] [Indexed: 12/13/2022]
Affiliation(s)
- Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Campagna F, Montagnese S, Schiff S, Biancardi A, Mapelli D, Angeli P, Poci C, Cillo U, Merkel C, Gatta A, Amodio P. Cognitive impairment and electroencephalographic alterations before and after liver transplantation: what is reversible? Liver Transpl 2014; 20:977-86. [PMID: 24809329 DOI: 10.1002/lt.23909] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 04/26/2014] [Indexed: 12/11/2022]
Abstract
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.
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Nabi E, Thacker LR, Wade JB, Sterling RK, Stravitz RT, Fuchs M, Heuman DM, Bouneva I, Sanyal AJ, Siddiqui MS, Luketic V, White MB, Monteith P, Noble NA, Unser A, Bajaj JS. Diagnosis of covert hepatic encephalopathy without specialized tests. Clin Gastroenterol Hepatol 2014; 12:1384-1389.e2. [PMID: 24362049 PMCID: PMC4063880 DOI: 10.1016/j.cgh.2013.12.020] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 11/26/2013] [Accepted: 12/06/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Covert hepatic encephalopathy (CHE) impairs quality of life (QOL) and can be difficult to diagnose. Patient-administered methods that do not require specialized tests or equipment might increase rates of detection. We performed a longitudinal study to determine whether demographic data and responses to a validated QOL questionnaire, the Sickness Impact Profile (SIP), can identify patients with CHE. METHODS Patients with cirrhosis without prior overt HE were recruited from outpatient liver clinics at the Virginia Commonwealth University Medical Center, from August 2008 through February 2012. We performed cognitive tests on 170 patients (mean age, 55 y; mean model for end-stage liver disease score, 9; 50% with hepatitis C-associated and 11% with alcohol-associated cirrhosis). Patients also were given the SIP questionnaire (136 questions on 12 QOL topics, requiring a yes or no answer) at enrollment, at 6 months, and at 12 months. The proportion of patients that responded "yes" to each question was compared between those with and without CHE. Patient variables (noncognitive), demographics (age, education, sex, alcoholic etiology), and SIP questions that produced different responses between groups were analyzed by logistic regression and receiver operating characteristic analyses. RESULTS Based on cognitive test results, 93 patients (55%) had CHE when the study began. They had a higher proportion of "yes" responses to 54 questions on the SIP questionnaire, across all categories. We developed a formula to identify patients with CHE based on age, sex, and responses to 4 SIP questions (a SIP CHE score). Baseline SIP CHE scores greater than 0 identified patients with CHE with 80% sensitivity and 79% specificity. Of the 98 patients who returned for the 6-month evaluation, 50% had CHE (the SIP CHE identified these patients with 88% sensitivity). Of the 50 patients who returned for the 12-month evaluation, 32% had CHE (the SIP CHE score identified these patients with 81% sensitivity). CONCLUSIONS We developed a system to identify patients with CHE based on age, sex, and responses to 4 SIP questions; this formula identified patients with CHE with more than 80% sensitivity over a 12-month period after the initial enrollment. Patient-administered CHE screening strategies that do not include specialized tests could increase the detection of CHE and improve therapy.
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Affiliation(s)
- Eiman Nabi
- Division of Gastroenterology, Hepatology and Nutrition
| | | | - James B Wade
- Department of Psychiatry, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia
| | | | | | - Michael Fuchs
- Division of Gastroenterology, Hepatology and Nutrition
| | | | | | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition
| | | | | | | | | | | | - Ariel Unser
- Division of Gastroenterology, Hepatology and Nutrition
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia.
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Corrias M, Turco M, Rui MD, Gatta A, Angeli P, Merkel C, Amodio P, Schiff S, Montagnese S. Covert hepatic encephalopathy: does the mini-mental state examination help? J Clin Exp Hepatol 2014; 4:89-93. [PMID: 25755545 PMCID: PMC4116703 DOI: 10.1016/j.jceh.2013.12.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 12/31/2013] [Indexed: 12/12/2022] Open
Abstract
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.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Sara Montagnese
- Address for correspondence: Sara Montagnese, Dipartimento di Medicina, University of Padova, Via Giustiniani, 2, Padova 35128, Italy. Tel.: +39 (0) 49 8218675; fax: +39 (0) 49 7960903.
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Berlioux P, Robic MA, Poirson H, Métivier S, Otal P, Barret C, Lopez F, Péron JM, Vinel JP, Bureau C. Pre-transjugular intrahepatic portosystemic shunts (TIPS) prediction of post-TIPS overt hepatic encephalopathy: the critical flicker frequency is more accurate than psychometric tests. Hepatology 2014; 59:622-9. [PMID: 24620380 DOI: 10.1002/hep.26684] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
UNLABELLED Transjugular intrahepatic portosystemic shunts (TIPS) is a second-line treatment because of an increased incidence of overt hepatic encephalopathy (OHE). A better selection of patients to decrease this risk is needed and one promising approach could be the detection of minimal hepatic encephalopathy (MHE). The aim of the present prospective study was to determine whether pre-TIPS minimal hepatic encephalopathy was predictive of post-TIPS OHE and to compare Psychometric Hepatic Encephalopathy Sum Score(PHES) and the Critical Flicker Frequency (CFF) in this setting. From May 2008 to January 2011, 54 consecutive patients treated with TIPS were included. PHES and CFF were performed 1 to 7 days before and after TIPS at months 1, 3, 6, 9, and 12 or until liver transplantation or death. Before TIPS, MHE was detected by PHES and CFF in 33% and 39% of patients, respectively. After the TIPS procedure, 19 patients (35%) experienced a total of 64 episodes of OHE. OHE developed significantly more often inpatients for whom an indication for TIPS had been refractory ascites, with a history of OHE or of renal failure, lower hemoglobin level, or MHE as diagnosed by CFF. Post-TIPS OHE was more accurately predicted by CFF than by PHES. Absence of MHE at CFF had a good negative predictive value (91%) for the risk of post-TIPS recurrent OHE, defined as the occurrence of three or more episodes of OHE or of one episode which lasted more than 15 days. The absence of pre-TIPS history of OHE and a CFF value equal to or greater than 39 Hz had a 100% negative predictive value for post-TIPS recurrent OHE. CONCLUSION Aiming to decrease the rate of post-TIPS HE, the use of CFF could help selecting patients for TIPS.
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Affiliation(s)
- Pierre Berlioux
- Service d'hépato-gastro-entérologie CHU Toulouse Hopital Purpan et Université Paul Sabatier; Toulouse France
| | - Marie Angèle Robic
- Service d'hépato-gastro-entérologie CHU Toulouse Hopital Purpan et Université Paul Sabatier; Toulouse France
| | - Hélène Poirson
- Service d'hépato-gastro-entérologie CHU Toulouse Hopital Purpan et Université Paul Sabatier; Toulouse France
| | - Sophie Métivier
- Service d'hépato-gastro-entérologie CHU Toulouse Hopital Purpan et Université Paul Sabatier; Toulouse France
| | - Philippe Otal
- Service de radiologie Hopital Rangueil CHU Toulouse et Université Paul Sabatier; Toulouse France
| | - Carine Barret
- Service d'hépato-gastro-entérologie CHU Toulouse Hopital Purpan et Université Paul Sabatier; Toulouse France
| | - Frédéric Lopez
- Plateforme de Protéomique I2MC Inserm Rangueil Toulouse; France
| | - Jean Marie Péron
- Service d'hépato-gastro-entérologie CHU Toulouse Hopital Purpan et Université Paul Sabatier; Toulouse France
| | - Jean Pierre Vinel
- Service d'hépato-gastro-entérologie CHU Toulouse Hopital Purpan et Université Paul Sabatier; Toulouse France
| | - Christophe Bureau
- Service d'hépato-gastro-entérologie CHU Toulouse Hopital Purpan et Université Paul Sabatier; Toulouse France
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Goldbecker A, Weissenborn K, Hamidi Shahrezaei G, Afshar K, Rümke S, Barg-Hock H, Strassburg CP, Hecker H, Tryc AB. Comparison of the most favoured methods for the diagnosis of hepatic encephalopathy in liver transplantation candidates. Gut 2013; 62:1497-504. [PMID: 23297006 DOI: 10.1136/gutjnl-2012-303262] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Hepatic encephalopathy (HE) is a common complication of liver insufficiency. While there is widespread acceptance of its importance, there is no consensus on how best to diagnose and monitor HE. OBJECTIVE To compare the four most favoured methods for the diagnosis of HE. DESIGN 170 patients who were on the waiting list for liver transplantation as well as 86 healthy controls were included in the study. All patients and controls underwent the portosystemic encephalopathy syndrome test yielding the psychometric hepatic encephalopathy score (PHES), the repeatable battery for the assessment of neuropsychological status (RBANS), the inhibitory control test (ICT) and critical flicker frequency (CFF) measurement. RESULTS PHES and ICT targets had the best sensitivity (85.7% vs 85.7%) and specificity (96.5% vs 97.6%) for the diagnosis of overt HE. CFF showed inferior sensitivity (40.9%) for the diagnosis of HE and dependency from previous alcohol abuse (p=0.015). Multiple regression analysis showed that all test results apart from PHES were influenced by secondary diagnoses such as diabetes mellitus and renal insufficiency. CONCLUSIONS In the German population of patients awaiting liver transplantation, PHES is the most robust method for the diagnosis and follow-up of HE.
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Affiliation(s)
- Annemarie Goldbecker
- Integrated Research and Treatment Center (IFB) Transplantation, Hannover Medical School, , Hannover, Germany
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Butz M, May ES, Häussinger D, Schnitzler A. The slowed brain: Cortical oscillatory activity in hepatic encephalopathy. Arch Biochem Biophys 2013; 536:197-203. [DOI: 10.1016/j.abb.2013.04.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 04/04/2013] [Accepted: 04/08/2013] [Indexed: 12/12/2022]
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Torlot FJ, McPhail MJW, Taylor-Robinson SD. Meta-analysis: The diagnostic accuracy of critical flicker frequency in minimal hepatic encephalopathy. Aliment Pharmacol Ther 2013; 37:527-36. [PMID: 23293917 PMCID: PMC3761188 DOI: 10.1111/apt.12199] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Revised: 09/06/2012] [Accepted: 12/11/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND Minimal hepatic encephalopathy (MHE) reduces quality of life, increases the risk of road traffic incidents and predicts progression to overt hepatic encephalopathy and death. Current psychometry-based diagnostic methods are effective, but time-consuming and a universal 'gold standard' test has yet to be agreed upon. Critical Flicker Frequency (CFF) is a proposed language-independent diagnostic tool for MHE, but its accuracy has yet to be confirmed. AIM To assess the diagnostic accuracy of CFF for MHE by performing a systematic review and meta-analysis of all studies, which report on the diagnostic accuracy of this test. METHODS A systematic literature search was performed to locate all publications reporting on the diagnostic accuracy of CFF for MHE. Data were extracted from 2 × 2 tables or calculated from reported accuracy data. Collated data were meta-analysed for sensitivity, specificity, diagnostic odds ratio (DOR) and summary receiver operator curve (sROC) analysis. Prespecified subgroup analysis and meta-regression were also performed. RESULTS Nine studies with data for 622 patients were included. Summary sensitivity was 61% (95% CI: 55-67), specificity 79% (95% CI: 75-83) and DOR 10.9 (95% CI: 4.2-28.3). A symmetrical sROC gave an area under the receiver operator curve of 0.84 (SE = 0.06). The heterogeneity of the DOR was 74%. CONCLUSIONS Critical Flicker Frequency has a high specificity and moderate sensitivity for diagnosing minimal hepatic encephalopathy. Given the advantages of language independence and being both simple to perform and interpret, we suggest the use of critical flicker frequency as an adjunct (but not replacement) to psychometric testing.
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Affiliation(s)
- F J Torlot
- Hepatology & Gastroenterology Section, Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, St Mary's Hospital Campus, Imperial College London, UK
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