The genetics of alcohol dependence and alcohol-related liver disease

The susceptibility to developing alcohol dependence and significant alcohol-related liver injury is determined by a number of constitutional, environmental and genetic factors, although the nature and level of interplay between them remains unclear. The familiality and heritability of alcohol dependence is well-documented but, to date, no strong candidate genes conferring increased risk have emerged, although variants in alcohol dehydrogenase and acetaldehyde dehydrogenase have been shown to confer protection, predominantly in individuals of East Asian ancestry. Population contamination with confounders such as drug co-dependence and psychiatric and physical co-morbidity may explain the essentially negative genome-wide association studies in this disorder. The familiality and hereditability of alcohol-related cirrhosis is not as well-documented but three strong candidate genes PNPLA3, TM6SF2 and MBOAT7, have been identified. The mechanisms by which variants in these genes confer risk and the nature of the functional interplay between them remains to be determined but, when elucidated, will undoubtedly increase our understanding of the pathophysiology of this disease. The way in which this genetic information could potentially inform patient management has yet to be determined and tested.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Electroencephalogram variability in patients with cirrhosis associates with the presence and severity of hepatic encephalopathy

BACKGROUND & AIMS: The outputs of physiological systems fluctuate in a complex manner even under resting conditions. Decreased variability or increased regularity of these outputs is documented in several disease states. Changes are observed in the spatial and temporal configuration of the electroencephalogram (EEG) in patients with hepatic encephalopathy (HE), but there is no information on the variability of the EEG signal in this condition. The aim of this study was to measure and characterize EEG variability in patients with cirrhosis and to determine its relationship to neuropsychiatric status. METHODS: Eyes-closed, awake EEGs were obtained from 226 patients with cirrhosis, classified, using clinical and psychometric criteria, as neuropsychiatrically unimpaired (n=127) or as having minimal (n=21) or overt (n=78) HE, and from a reference population of 137 healthy controls. Analysis of EEG signal variability was undertaken using continuous wavelet transform and sample entropy. RESULTS: EEG variability was reduced in the patients with cirrhosis compared with the reference population (coefficient of variation: 21.2% [19.3-23.4] vs. 22.4% [20.8-24.5]; p<0.001). A significant association was observed between EEG variability and neuropsychiatric status; thus, variability was increased in the patients with minimal HE compared with their neuropsychiatrically unimpaired counterparts (sample entropy: 0.98 [0.87-1.14] vs. 0.83 [0.75-0.95]; p=0.02), and compared with the patients with overt HE (sample entropy: 0.98 [0.87-1.14] vs. 0.82 [0.71-1.01]; p=0.01). CONCLUSIONS: Variability of the EEG is associated with both the presence and severity of HE. This novel finding may provide new insights into the pathophysiology of HE and provide a means for monitoring patients over time. LAY SUMMARY: Decreased variability or increased regularity of physiological systems is documented in several disease states. Variability of the electroencephalogram was found to be associated with both the presence and severity of brain dysfunction in patients with chronic liver disease

The European NEAT program: An integrated approach using acamprosate and psychosocial support for the prevention of relapse in alcohol-dependent patients with a statistical modeling of therapy success prediction

Background: A multicenter, prospective study was conducted in five European countries to observe outcome in alcohol misusers treated for 24 weeks with acamprosate and various psychosocial support techniques, within the setting of standard patient care. Methods: Patients diagnosed as alcohol dependent using DSM-III-R criteria were treated, for 24 weeks, with acamprosate and appropriate psychosocial support. Potential predictor variables were recorded at inclusion. Drinking behavior was monitored throughout; the proportion of cumulative abstinence days was the principal outcome measure. The influence of baseline clinical and demographic variables on outcome was assessed using multiple regression analysis. Adverse events were recorded systematically. Results: A total of 1289 patients were recruited; 1230 took at least one dose of the drug and provided at least one set of follow-up data; 543 (42.1%) patients were observed for the full 24-week period. The overall proportion of cumulative abstinence days was 0.48. Multiple physical and psychiatric comorbidities and a history of drug addiction were negatively correlated with outcome, as were, to a lesser extent, multiple previous episodes of detoxification, unemployment, and living alone. Older age and stable employment were positively associated with outcome. The difference in the unadjusted proportion of cumulative abstinence days between countries was significant (p < 0.001) but less so when adjusted for the predictive factors identified in the multivariate model (p < 0.019). Overall, outcome was not influenced by the nature of the psychosocial support provided. Adverse events were generally mild, with gastrointestinal disorders, which occurred in 21.5% of patients, being the most frequent. Conclusions: This open-label study confirms the efficacy and safety of acamprosate in the treatment of alcohol dependence in the setting of standard patient care. Treatment benefit was observed irrespective of the nature of the psychosocial support provided. Predictors of the response to treatment were identified; their heterogeneous distribution within the study population explained, at least in part, the differences in outcome between countries.SCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

Predicted estimates of resting energy expenditure have limited clinical utility in patients with cirrhosis: an individual patient data analysis

© 2022 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1016/j.jhep.2022.01.005Background & Aim: Malnutrition is associated with adverse clinical outcomes in patients with cirrhosis. Accurate assessment of energy requirements is needed to optimize dietary intake. Resting energy expenditure (REE), the major component of total energy expenditure, can be measured using indirect calorimetry (mREE) or estimated using prediction equations (pREE). This study assessed the usefulness of predicted estimates of REE in this patient population.  Methods: Individual mREE data were available for 900 patients with cirrhosis (mean [±1SD] age 55.7±11.6 yr; 70% men; 52% south-east Asian) and 282 healthy controls (mean age 36.0±12.8 yr; 52% men; 18% south-east Asian). Metabolic status was classified using thresholds based on the mean±1SD of the mREE in the healthy controls. Comparisons were made between mREE and pREE estimates obtained using the Harris-Benedict, Mifflin, Schofield and Henry equations. Stepwise regression was used to build three new prediction models which included sex, ethnicity, body composition measures, and MELD scores.  Results: The mean mREE was significantly higher in patients than controls when referenced to dry body weight (22.43.8 cf. 20.82.6 kcal/kg/24hr; p<0.001); there were no significant sex differences. The mean mREE was significantly higher in Caucasian than Asian patients (23.1±4.4 cf. 21.7±2.9 kcal/kg/24hr; p<0.001). Overall, 37.1% of Caucasians and 25.3% of Asians were classified as hypermetabolic. The differences between mREE and pREE were both statistically and clinically relevant; in the total patient population, pREE estimates ranged from 501 kcal/24hr less to 548 kcal/24hr more than the mREE. Newly-derived prediction equations provided better estimates of mREE but still had limited clinical utility.  Conclusions: Prediction equations do not provide useful estimates of REE in patients with cirrhosis. REE should be directly measured.Peer reviewe

Predicted estimates of resting energy expenditure have limited clinical utility in patients with cirrhosis

BACKGROUND & AIM: Malnutrition is associated with adverse clinical outcomes in patients with cirrhosis. Accurate assessment of energy requirements is needed to optimize dietary intake. Resting energy expenditure (REE), the major component of total energy expenditure, can be measured using indirect calorimetry (mREE) or estimated using prediction equations (pREE). This study assessed the usefulness of predicted estimates of REE in this patient population. METHODS: Individual mREE data were available for 900 patients with cirrhosis (mean [±1SD] age 55.7±11.6 yr; 70% men; 52% south-east Asian) and 282 healthy controls (mean age 36.0±12.8 yr; 52% men; 18% south-east Asian). Metabolic status was classified using thresholds based on the mean±1SD of the mREE in the healthy controls. Comparisons were made between mREE and pREE estimates obtained using the Harris-Benedict, Mifflin, Schofield and Henry equations. Stepwise regression was used to build three new prediction models which included sex, ethnicity, body composition measures, and MELD scores. RESULTS: The mean mREE was significantly higher in patients than controls when referenced to dry body weight (22.4±3.8 cf. 20.8±2.6 kcal/kg/24hr; p<0.001); there were no significant sex differences. The mean mREE was significantly higher in Caucasian than Asian patients (23.1±4.4 cf. 21.7±2.9 kcal/kg/24hr; p<0.001). Overall, 37.1% of Caucasians and 25.3% of Asians were classified as hypermetabolic. The differences between mREE and pREE were both statistically and clinically relevant; in the total patient population, pREE estimates ranged from 501 kcal/24hr less to 548 kcal/24hr more than the mREE. Newly-derived prediction equations provided better estimates of mREE but still had limited clinical utility. CONCLUSIONS: Prediction equations do not provide useful estimates of REE in patients with cirrhosis. REE should be directly measured

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

Objective Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (' Pi* Z' and ' Pi* S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. Design We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi* Z and Pi* S variants was performed. Results T he Pi* Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p< 0.0001). Accordingly, the Pi* Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi* Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p< 0.0001). Correspondingly, alcohol misusers carrying the Pi* Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi* S variant was not associated with NAFLDrelated cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). Conclusion T he Pi* Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi* S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi* Z carriers, this finding should be considered in genetic counselling of affected individuals

Proceedings of the 2016 Childhood Arthritis and Rheumatology Research Alliance (CARRA) Scientific Meeting: Toronto, Canada. 14-17 April 2016

Table of Contents P1 Serologic evidence of gut-driven systemic inflammation in juvenile idiopathic arthritis Lampros Fotis, Nur Shaikh, Kevin Baszis, Anthony French, Phillip Tarr P2 Oral health and anti-citrullinated peptide antibodies (ACPA) in juvenile idiopathic arthritis Sriharsha Grevich, Peggy Lee, Sarah Ringold, Brian Leroux, Hannah Leahey, Megan Yuasa, Jessica Foster, Jeremy Sokolove, Lauren Lahey, William Robinson, Joshua Newsom, Anne Stevens P3 Novel autoantigens for endothelial cell antibodies in pediatric rheumatic diseases identified by proteomics Rie Karasawa, Mayumi Tamaki, Megumi Tanaka, Toshiko Sato, Kazuo Yudoh, James N. Jarvis P4 Transcriptional profiling reveals monocyte signature associated with JIA patient poor response to methotrexate Halima Moncrieffe, Mark F. Bennett, Monica Tsoras, Lorie Luyrink, Huan Xu, Sampath Prahalad, Paula Morris, Jason Dare, Peter A. Nigrovic, Margalit Rosenkranz, Mara Becker, Kathleen M. O’Neil, Thomas Griffin, Daniel J. Lovell, Alexei A. Grom, Mario Medvedovic, Susan D. Thompson P5 A multi-dimensional genomic map for polyarticular juvenile idiopathic arthritis Lisha Zhu, Kaiyu Jiang, Laiping Wong, Michael J Buck, Yanmin Chen, Halima Moncrieffe, Laura Brungs, Tao Liu, Ting Wang, James N Jarvis P6 Tocilizumab for treatment of children with refractory JIA Khaled Alsaeid, Jasim Alfailakawi, Hamid Alenezi, Hazim Alsaeed P7 Clinical characteristics of the initial patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry Tim Beukelman, Marc Natter, Norm Ilowite, Kelly Mieszkalski, Grendel Burrell, Brian Best, Helen Bristow, Shannon Carr, Anne Dennos, Rachel Kaufmann, Yukiko Kimura, Laura Schanberg P8 Comparative performance of small and large clinical centers in a comprehensive pediatric rheumatology disease registry Peter R Blier P9 Clinical characteristics of children with membranous lupus nephritis: The Childhood Arthritis and Rheumatology Research Alliance Legacy Registry Alexis Boneparth, Scott E. Wenderfer, L. Nandini Moorthy, Suhas M. Radhakrishna, Anna Carmela P. Sagcal-Gironella, Emily von Scheven P10 Rituximab use in pediatric lupus anticoagulant hypoprothrombinemia syndrome - a two center experience Kader Cetin Gedik, Salma Siddique, Cassyanne L. Aguiar, Doruk Erkan P11 Predictors of complementary and alternative medicine use and response in children with musculoskeletal conditions Ezra Cohen, Yvonne Lee, Michelle Dossett, Darshan Mehta, Roger Davis P12 Comparison of pediatric rheumatology and nephrology survey results for the treatment of refractory proliferative lupus nephritis and renal flare in juvenile SLE Mileka Gilbert, Beatrice Goilav, Esra Meidan, Joyce Hsu, Alexis Boneparth, Anabelle Chua, Stacy Ardoin, Scott E. Wenderfer, Emily Von Scheven, Natasha M. Ruth P13 Transitioning lupus patients from pediatric to adult rheumatology Joyce Hui-Yuen, Kader Cetin Gedik, Liza Bermudez, Ashlea Cook, Lisa Imundo, Amy Starr, Andrew Eichenfield, Anca Askanase P14 The systemic juvenile idiopathic arthritis cohort of the Childhood Arthritis & Rheumatology Research Alliance Registry Ginger Janow, Laura E. Schanberg, Soko Setoguchi, Victor Hasselblad, Elizabeth D. Mellins, Rayfel Schneider, Yukiko Kimura, The CARRA Legacy Registry Investigators P15 Results of the pilot study of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans for new-onset systemic juvenile idiopathic arthritis Yukiko Kimura, Sriharsha Grevich, Timothy Beukelman, Esi Morgan, T Brent Graham, Maria Ibarra, Yonit Sterba Ruas, Marisa Klein-Gitelman, Karen Onel, Sampath Prahalad, Marilynn Punaro, Sarah Ringold, Dana Toib, Heather Van Mater, Jennifer E. Weiss, Pamela F. Weiss, Kelly Mieszkalski, Laura E. Schanberg P16 A systemic review of pain relief modalities in juvenile idiopathic arthritis: First step in developing a novel decision support intervention Timothy S. H. Kwok, Jacinthe Bisaillon, Christine Smith, Lucie Brosseau, Jennifer Stinson, Adam M. Huber, Ciaran M. Duffy, Karine Toupin April P17 Barriers and facilitators to care retention for pediatric systemic lupus erythematous patients in South Africa: A qualitative study Laura B Lewandowski, Christiaan Scott P18 Evaluating the feasibility of conducting comparative effectiveness studies in juvenile Localized Scleroderma (jLS) Suzanne C. Li, Kathryn S. Torok, C. Egla Rabinovich, Sandy D. Hong, Mara L Becker, Fatma Dedeoglu, Maria F. Ibarra, Polly J Ferguson, Rob C. Fuhbrigge, Katie G. Stewart, Elena Pope, Ronald M. Laxer, Thomas G. Mason, Gloria C. Higgins, Xiaohu Li, Marilynn G. Punaro, George Tomlinson, Eleanor Pullenayegum, John Matelski, Laura Schanberg, Brian M. Feldman P19 Tonsillar histology in patients with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome Kalpana Manthiram, Hernan Correa, Kathryn Edwards P20 Clinical course of juvenile dermatomyositis presenting as skin predominant disease Edward J. Oberle, Michelle Bayer, Dominic O. Co, Hatice Ezgi Baris, Yvonne Chiu, Adam Huber, Susan Kim P21 A Survey of musculoskeletal ultrasound practices of pediatric rheumatologists in North America Edward J Oberle, Timothy Beukelman P22 Assessment, classification and treatment of calcinosis as a complication of juvenile dermatomyositis: A survey of pediatric rheumatologists by the Childhood Arthritis and Rheumatology Research Alliance Amir B. Orandi, Kevin W. Baszis, Vikas Dharnidharka, Mark F. Hoeltzel, for the CARRA JDM Committee P23 CARRA dermatomyositis CTP pilot study Ann Reed, Adam Huber, George Tomlinson, Eleanor Pullenayegum, John Matelski, Y. Ingrid Goh, Laura Schanberg, Brian M. Feldman P24 Unexpectedly high incidences and prolonged disease activity in children with chronic non-bacterial osteomyelitis (CNO) as compared to bacterial osteomyelitis Anja Schnabel, Ursula Range, Gabriele Hahn, Timo Siepmann, Reinhard Berner, Christian Michael Hedrich P25 Juvenile systemic sclerosis cohort within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry: Follow up characteristics Brandi Stevens, Kathryn S. Torok, Suzanne Li, Nicole Hershey, Megan Curran, Gloria Higgins, Katharine Moore, Egla Rabinovich, Anne M. Stevens, for the CARRA Registry Investigators P26 Development and usability testing of an iPad and desktop psycho-educational game for children with Juvenile Idiopathic Arthritis and their parents Jennifer Stinson, Mark Connelly, Adam Huber, Nadia Luca, Lynn Spiegel, Argerie Tsimicalis, Stephanie Luca, Naweed Tajuddin, Roberta Berard, Julia Barsalou, Sarah Campillo, Paul Dancey, Ciaran Duffy, Brian Feldman, Nicole Johnson, Patrick McGrath, Natalie Shiff, Shirley Tse, Lori Tucker, Charles Victor P27 iCanCopeTM: User-centred design and development of a smartphone app to support self-management for youth with arthritis pain Jennifer Stinson, Chitra Lalloo, Lauren Harris, Joseph Cafazzo, Lynn Spiegel, Brian Feldman, Nadia Luca, Ronald Laxer P28 Accessing pediatric rheumatology care: Despite barriers, few parents prefer telemedicine Danielle R. Bullock, Richard K. Vehe, Lei Zhang, Colleen K. Correll1 P29 Exploration of factors contributing to time to achieve clinically inactive disease (CID) in juvenile idiopathic arthritis (JIA): A preliminary report Suhas Ganguli, Max Shenberger, Ritesh Korumilli, Beth Gottlieb P30 Pediatric rheumatology referral patterns: Presenting complaints of new patients at a large, urban academic center Martha Rodriguez, Deirdre de Ranieri, Karen Onel, Linda Wagner-Weiner, Melissa Tesher P31 Quality improvement (QI) initiatives in childhood systemic lupus erythematosus (cSLE) Elizabeth Roth Wojcicki, Kristyn L. Maletta, Dominic O. Co, Marsha Malloy, Sarah Thomson, Judyann C. Olson P32 Proliferative lupus nephritis in juvenile SLE: Support from the pediatric nephrology community for the definitions of responsiveness and flare in the 2012 consensus treatment plans Scott E. Wenderfer, Mileka Gilbert, Joyce Hsu, Sangeeta Sule, Tamar B. Rubinstein, Beatrice Goilav, Daryl M. Okamura, Annabelle Chua, Laurence A. Greenbaum, Jerome C. Lane, Emily von Scheven, Stacy P. Ardoin, Natasha M. Ruth P33 The steroid taper app: Making of a mobile app Jennifer M. P. Woo, Marsha M. Malloy, James A. Jegers, Dustin J. Hahn, Mary K. Hintermeyer, Stacey M. Martinetti, Gretchen R. Heckel, Elizabeth L. Roth-Wojcicki, Dominic O. C