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3. Improvements in Disease‐Specific Health‐Related Quality of Life of Pediatric Liver Transplant Recipients During Immunosuppression Withdrawal

Author

Mohammad, Saeed, Sundaram, Shikha S, Mason, Kristen, Lobritto, Steven, Martinez, Mercedes, Turmelle, Yumirle P, Bucuvalas, John, Feng, Sandy, and Alonso, Estella M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Organ Transplantation, Clinical Research, Clinical Trials and Supportive Activities, Liver Disease, Digestive Diseases, Transplantation, Rare Diseases, Good Health and Well Being, Child, Fatigue, Humans, Immunosuppression Therapy, Liver Transplantation, Male, Prospective Studies, Quality of Life, Surgery, Clinical sciences
Abstract

Long-term immunosuppression (IS) leads to systemic complications affecting health-related quality of life (HRQOL) in pediatric liver transplantation (LT) recipients. We serially assessed HRQOL using the PedsQL Generic and Multidimensional Fatigue Scales and Family Impact and Transplant Modules as part of a multicenter prospective immunosuppression withdrawal (ISW) trial between 2012 and 2018. Participants received a primary LT ≥4 years before the study and were on stable IS with normal liver tests and without rejection in the prior 2 years. IS was withdrawn in 7 steps over 36 to 48 weeks. HRQOL was assessed at regular intervals. The primary endpoint was change in disease-specific HRQOL measured by the PedsQL Transplant Module. Generic HRQOL was measured by the PedsQL Generic Scale and was compared with an age-matched and sex-matched multicenter cohort. Of the 88 participants, 39 were boys, median age was 11 years (range, 8-13), and time since transplant was 9 years (range, 6-11). For 36 months, disease-specific HRQOL improved for all participants, whereas generic HRQOL was unchanged. Neither generic nor disease-specific HRQOL changed for the 35 participants who developed acute rejection during ISW. In the first use of patient-reported outcome measures during an ISW trial, we found improvements in disease-specific HRQOL in all participants and no lasting detrimental effects in those who experienced rejection.

Published
2021

4. Heterogeneous liver on research ultrasound identifies children with cystic fibrosis at high risk of advanced liver disease

Author

Siegel, Marilyn J, Leung, Daniel H., Molleston, Jean P, Ye, Wen, Paranjape, Shruti M, Freeman, A Jay, Palermo, Joseph J, Stoll, Janis, Masand, Prakash, Karmazyn, Boaz, Harned, Roger, Ling, Simon C, Navarro, Oscar M, Karnsakul, Wikrom, Alazraki, Adina, Schwarzenberg, Sarah Jane, Towbin, Alex J, Alonso, Estella M, Nicholas, Jennifer L., Green, Nicole, Otto, Randolph K, Magee, John C, and Narkewicz, Michael R

Published
2023
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5. Long-term follow-up and liver outcomes in children with cystic fibrosis and nodular liver on ultrasound in a multi-center study

Author

Leung, Daniel H., Ye, Wen, Schwarzenberg, Sarah J., Freeman, A. Jay, Palermo, Joseph J., Weymann, Alexander, Alonso, Estella M., Karnsakul, Wikrom W., Murray, Karen F., Stoll, Janis M., Huang, Suiyuan, Karmazyn, Boaz, Masand, Prakash, Magee, John C., Alazraki, Adina L., Towbin, Alexander J., Nicholas, Jennifer L., Green, Nicole, Otto, Randolph K., Siegel, Marilyn J., Ling, Simon C., Navarro, Oscar M., Harned, Roger K., Narkewicz, Michael R., and Molleston, Jean P.

Published
2023
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6. Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Author

Felzen, Antonia, van Wessel, Daan B.E., Gonzales, Emmanuel, Thompson, Richard J., Jankowska, Irena, Shneider, Benjamin L., Sokal, Etienne, Grammatikopoulos, Tassos, Kadaristiana, Agustina, Jacquemin, Emmanuel, Spraul, Anne, Lipiński, Patryk, Czubkowski, Piotr, Rock, Nathalie, Shagrani, Mohammad, Broering, Dieter, Nicastro, Emanuele, Kelly, Deirdre, Nebbia, Gabriella, Arnell, Henrik, Fischler, Björn, Hulscher, Jan B.F., Serranti, Daniele, Arikan, Cigdem, Polat, Esra, Debray, Dominique, Lacaille, Florence, Goncalves, Cristina, Hierro, Loreto, Muñoz Bartolo, Gema, Mozer-Glassberg, Yael, Azaz, Amer, Brecelj, Jernej, Dezsőfi, Antal, Calvo, Pier Luigi, Grabhorn, Enke, Hartleif, Steffen, van der Woerd, Wendy J., Kamath, Binita M., Wang, Jian-She, Li, Liting, Durmaz, Özlem, Kerkar, Nanda, Jørgensen, Marianne Hørby, Fischer, Ryan, Jimenez-Rivera, Carolina, Alam, Seema, Cananzi, Mara, Laverdure, Noemie, Ferreira, Cristina Targa, Guerrero, Felipe Ordoñez, Wang, Heng, Sency, Valerie, Kim, Kyung Mo, Chen, Huey-Ling, de Carvalho, Elisa, Fabre, Alexandre, Bernabeu, Jesus Quintero, Zellos, Aglaia, Alonso, Estella M., Sokol, Ronald J., Suchy, Frederick J., Loomes, Kathleen M., McKiernan, Patrick J., Rosenthal, Philip, Turmelle, Yumirle, Horslen, Simon, Schwarz, Kathleen, Bezerra, Jorge A., Wang, Kasper, Hansen, Bettina E., and Verkade, Henkjan J.

Published
2023
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7. Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome

Author

Berauer, John‐Paul, Mezina, Anya I, Okou, David T, Sabo, Aniko, Muzny, Donna M, Gibbs, Richard A, Hegde, Madhuri R, Chopra, Pankaj, Cutler, David J, Perlmutter, David H, Bull, Laura N, Thompson, Richard J, Loomes, Kathleen M, Spinner, Nancy B, Rajagopalan, Ramakrishnan, Guthery, Stephen L, Moore, Barry, Yandell, Mark, Harpavat, Sanjiv, Magee, John C, Kamath, Binita M, Molleston, Jean P, Bezerra, Jorge A, Murray, Karen F, Alonso, Estella M, Rosenthal, Philip, Squires, Robert H, Wang, Kasper S, Finegold, Milton J, Russo, Pierre, Sherker, Averell H, Sokol, Ronald J, Karpen, Saul J, and Network, for the Childhood Liver Disease Research

Subjects
Perinatal Period - Conditions Originating in Perinatal Period, Kidney Disease, Digestive Diseases, Genetics, Chronic Liver Disease and Cirrhosis, Liver Disease, Rare Diseases, Congenital Structural Anomalies, Human Genome, Pediatric, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Congenital, Oral and gastrointestinal, Abnormalities, Multiple, Biliary Atresia, Child, Databases, Factual, Female, Gene Expression Regulation, Developmental, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Polycystic Kidney Diseases, Retrospective Studies, Spleen, Syndrome, Exome Sequencing, Childhood Liver Disease Research Network, Medical Biochemistry and Metabolomics, Clinical Sciences, Immunology, Gastroenterology & Hepatology
Abstract

Biliary atresia (BA) is the most common cause of end-stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations-a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole-exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient-parent trios, from the National Institute of Diabetes and Digestive and Kidney Diseases-supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a prespecified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious biallelic variants in polycystic kidney disease 1 like 1 (PKD1L1), a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice, and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other noncholestatic diseases. Conclusion: WES identified biallelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN data set; the dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a biologically plausible, cholangiocyte-expressed candidate gene for the BASM syndrome.

Published
2019

10. Evidence of Chronic Allograft Injury in Liver Biopsies From Long-term Pediatric Recipients of Liver Transplants

Author

Feng, Sandy, Bucuvalas, John C, Demetris, Anthony J, Burrell, Bryna E, Spain, Katherine M, Kanaparthi, Sai, Magee, John C, Ikle, David, Lesniak, Andrew, Lozano, Juan J, Alonso, Estella M, Bray, Robert A, Bridges, Nancy E, Doo, Edward, Gebel, Howard M, Gupta, Nitika A, Himes, Ryan W, Jackson, Annette M, Lobritto, Steven J, Mazariegos, George V, Ng, Vicky L, Rand, Elizabeth B, Sherker, Averell H, Sundaram, Shikha, Turmelle, Yumirle P, and Sanchez-Fueyo, Alberto

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Chronic Liver Disease and Cirrhosis, Transplantation, Liver Disease, Clinical Research, Rare Diseases, Digestive Diseases, Genetics, Organ Transplantation, Oral and gastrointestinal, Adolescent, Allografts, Biopsy, Child, Chronic Disease, Cross-Sectional Studies, Female, Graft Rejection, Humans, Liver, Liver Function Tests, Liver Transplantation, Male, Time Factors, Young Adult, ALT, DSA, Immune Response, Prognostic Factor, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsA substantial proportion of pediatric liver transplant recipients develop subclinical chronic allograft injury. We studied whether there are distinct patterns of injury based on histopathologic features and identified associated immunologic profiles.MethodsWe conducted a cross-sectional study of 157 stable, long-term pediatric recipients of transplanted livers (70 boys; > 6 years old at time of transplantation; mean, 8.9 ± 3.46 years after liver transplantation) who underwent liver biopsy analysis from August 13, 2012, through May 1, 2014. Participants had received livers from a living or deceased donor and had consistently normal results from liver tests. Liver biopsy specimens were scored by a central pathologist; an unsupervised hierarchical cluster analysis of histologic features was used to sort biopsy samples into 3 clusters. We conducted transcriptional and cytometric analyses of liver tissue samples and performed a systems biology analysis that incorporated clinical, serologic, histologic, and transcriptional data.ResultsThe mean level of alanine aminotransferase in participants was 27.6 ± 14.57 U/L, and the mean level of γ-glutamyl transferase was 17.4 ± 7.93 U/L. Cluster 1 was characterized by interface activity (n = 34), cluster 2 was characterized by periportal or perivenular fibrosis without interface activity (n = 45), and cluster 3 had neither feature (n = 78). We identified a module of genes whose expression correlated with levels of alanine aminotransferase, class II donor-specific antibody, portal inflammation, interface activity, perivenular inflammation, portal and perivenular fibrosis, and cluster assignment. The module was enriched in genes that regulate T-cell-mediated rejection (TCMR) of liver and other transplanted organs. Functional pathway analysis showed overrepresentation of TCMR gene sets for cluster 1 but not clusters 2 or 3.ConclusionIn an analysis of biopsies from an apparently homogeneous group of stable, long-term pediatric liver transplant recipients with consistently normal liver test results, we found evidence of chronic graft injury (inflammation and/or fibrosis). Biopsy samples with interface activity had a gene expression pattern associated with TCMR.

Published
2018

11. Self-Management Measurement and Prediction of Clinical Outcomes in Pediatric Transplant

Author

Annunziato, Rachel A, Bucuvalas, John C, Yin, Wanrong, Arnand, Ravinder, Alonso, Estella M, Mazariegos, George V, Venick, Robert S, Stuber, Margaret L, Shneider, Benjamin L, and Shemesh, Eyal

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Patient Safety, Clinical Research, Pediatric, Transplantation, Behavioral and Social Science, Organ Transplantation, Digestive Diseases, Liver Disease, Management of diseases and conditions, 7.1 Individual care needs, Adolescent, Child, Child, Preschool, Cohort Studies, Female, Graft Rejection, Humans, Infant, Liver Transplantation, Male, Medication Adherence, Parents, Prospective Studies, Psychometrics, Reproducibility of Results, Self-Management, Surveys and Questionnaires, Treatment Outcome, United States, adherence, pediatric transplant, self-management, transition, Human Movement and Sports Sciences, Paediatrics and Reproductive Medicine, Pediatrics, Paediatrics
Abstract

ObjectiveTo further refine a measure of self-management, the Responsibility and Familiarity with Illness Survey (REFILS), and to determine if this score predicts medication adherence and, thus, fewer instances of allograft rejection among pediatric liver transplant recipients.Study designParticipants were 400 liver transplant recipients and their parents recruited for the Medication Adherence in Children Who Had a Liver Transplant study, from 5 US pediatric transplant centers. The REFILS was administered to participants (ages 9-17 years) and their parents at enrollment (n = 213 completed dyads). The REFILS scores, and a discrepancy score calculated between patient and parent report of the patient's self-management, were used to predict Medication Level Variability Index (MLVI), a measure of medication adherence (higher MLVI = more variability in medication levels) and central pathologist-diagnosed rejection over a 2-year follow-up.ResultsWhen patients reported greater self-management, their adherence was lower (higher MLVI, r = 0.26, P

Published
2018

12. Health-related quality of life in a prospective study of ultrasound to detect cystic fibrosis-related liver disease in children

Author

Schwarzenberg, Sarah Jane, Palermo, Joseph J., Ye, Wen, Huang, Suiyuan, Magee, John C., Alazraki, Adina, Freeman, A. Jay, Harned, Roger, Karmazyn, Boaz, Karnsakul, Wikrom, Leung, Daniel H., Ling, Simon C., Masand, Prakash, Molleston, Jean P., Murray, Karen F., Navarro, Oscar M., Nicholas, Jennifer L., Otto, Randolph K., Paranjape, Shruti M., Siegel, Marilyn J., Stoll, Janis, Towbin, Alexander J., Narkewicz, Michael R., and Alonso, Estella M.

Published
2022
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13. Five‐year histological and serological follow‐up of operationally tolerant pediatric liver transplant recipients enrolled in WISP‐R

Author

Feng, Sandy, Demetris, Anthony J, Spain, Katharine M, Kanaparthi, Sai, Burrell, Bryna E, Ekong, Udeme D, Alonso, Estella M, Rosenthal, Philip, Turka, Laurence A, Ikle, David, and Tchao, Nadia K

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Organ Transplantation, Liver Disease, Transplantation, Digestive Diseases, Chronic Liver Disease and Cirrhosis, 2.1 Biological and endogenous factors, Aetiology, Allografts, Biopsy, Needle, Child, Child, Preschool, Female, Follow-Up Studies, Graft Rejection, Graft Survival, Humans, Immunoglobulin G, Immunohistochemistry, Immunosuppressive Agents, Isoantibodies, Liver Diseases, Liver Transplantation, Living Donors, Male, Prospective Studies, Risk Assessment, Time Factors, Transplantation Immunology, Treatment Outcome, Medical Biochemistry and Metabolomics, Immunology, Gastroenterology & Hepatology, Clinical sciences
Abstract

Pediatric liver transplant recipients arguably have the most to gain and the most to lose from discontinuing immunosuppression (IS). Whereas IS undoubtedly exerts a cumulative toll, there is concern that insufficient or no IS may contribute to allograft deterioration. Twelve pediatric recipients of parental living donor liver grafts, identified as operationally tolerant through complete IS withdrawal (WISP-R; NCT00320606), were followed for a total of 5 years (1 year of IS withdrawal and 4 years off IS) with serial liver tests and autoantibody and alloantibody assessments. Liver biopsies were performed 2 and 4 years off IS, and, at these time points, immunoglobulin G (IgG) subclass and C1q binding activity for donor-specific antibodies (DSAs) were determined. There were no cases of chronic rejection, graft loss, or death. Allografts did not exhibit progressive increase in inflammation or fibrosis. Smooth-muscle actin expression by stellate cells and CD34 expression by liver sinusoidal endothelial cells remained stable, consistent with the absence of progressive graft injury. Three subjects never exhibited DSA. However, 3 subjects showed intermittent de novo class I DSA, 4 subjects showed persistent de novo class II DSA, and 5 subjects showed persistent preexisting class II DSA. Class II DSA was predominantly against donor DQ antigens, often of high mean fluorescence intensity, rarely of the IgG3 subclass, and often capable of binding C1q.ConclusionOperationally tolerant pediatric liver transplant recipients maintain generally stable allograft histology in spite of apparently active humoral allo-immune responses. The absence of increased inflammation or progressive fibrosis suggests that a subset of liver allografts seem resistant to the chronic injury that is characteristic of antibody-mediated damage. (Hepatology 2017;65:647-660).

Published
2017

15. Diagnostic accuracy of serum matrix metalloproteinase-7 as a biomarker of biliary atresia in a large North American cohort.

Author

Pandurangi, Sindhu, Mourya, Reena, Nalluri, Shreya, Fei, Lin, Dong, Shun, Harpavat, Sanjiv, Guthery, Stephen L., Molleston, Jean P., Rosenthal, Philip, Sokol, Ronald J., Wang, Kasper S., Ng, Vicky, Alonso, Estella M., Hsu, Evelyn K., Karpen, Saul J., Loomes, Kathleen M., Magee, John C., Shneider, Benjamin L., Horslen, Simon P., and Teckman, Jeffrey H.

Published
2024
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16. Heterogeneous Liver on Research Ultrasound Identifies Children with Cystic Fibrosis at High Risk of Advanced Liver Disease: Interim Results of a Prospective Observational Case-Controlled Study

Author

Siegel, Marilyn J., Freeman, A. Jay, Ye, Wen, Palermo, Joseph J., Molleston, Jean P., Paranjape, Shruti M., Stoll, Janis, Leung, Daniel H., Masand, Prakash, Karmazyn, Boaz, Harned, Roger, Ling, Simon C., Navarro, Oscar M., Karnsakul, Wikrom, Alazraki, Adina, Schwarzenberg, Sarah Jane, Seidel, Frank Glen, Towbin, Alex, Alonso, Estella M., Nicholas, Jennifer L., Murray, Karen F., Otto, Randolph K., Sherker, Averell H., Magee, John C., and Narkewicz, Michael R.

Published
2020
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19. Quality of Life and Its Determinants in a Multicenter Cohort of Children with Alagille Syndrome

Author

Kamath, Binita M, Chen, Zhen, Romero, Rene, Fredericks, Emily M, Alonso, Estella M, Arnon, Ronen, Heubi, James, Hertel, Paula M, Karpen, Saul J, Loomes, Kathleen M, Murray, Karen F, Rosenthal, Philip, Schwarz, Kathleen B, Subbarao, Girish, Teckman, Jeffrey H, Turmelle, Yumirle P, Wang, Kasper S, Sherker, Averell H, Sokol, Ronald J, Magee, John C, and Network, Childhood Liver Disease Research

Subjects
Clinical Research, Liver Disease, Pediatric, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Adolescent, Alagille Syndrome, Case-Control Studies, Child, Child, Preschool, Cohort Studies, Emotions, Female, Health Status, Humans, Male, Quality of Life, Social Behavior, Surveys and Questionnaires, alpha 1-Antitrypsin Deficiency, Childhood Liver Disease Research Network, Human Movement and Sports Sciences, Paediatrics and Reproductive Medicine, Pediatrics
Abstract

ObjectivesTo assess health-related quality of life (HRQOL) in children with Alagille syndrome (ALGS) in comparison with healthy and other liver disease cohorts, and to identify determinants of HRQOL in patients with ALGS.Study designWithin the Childhood Liver Disease Research Network prospective study of cholestasis, Pediatric Quality of Life Inventory (PedsQL) questionnaires were administered to 70 children with ALGS, 95 children with alpha-1-antitrypsin deficiency (A1ATD), and 49 children with other causes of chronic intrahepatic cholestasis (IHC) aged 5-18 years. Parent proxy PedsQL scores were recorded for children aged 2-18 years (98 ALGS, 123 A1ATD, and 68 IHC).ResultsMean ages and total bilirubin (mg/dL) were ALGS 9.4 years; 4.4, A1ATD 9.5 years; 0.7, and IHC 10.3 years; 2.9. ALGS child PedsQL scores were lower than in healthy children and children with A1ATD (mean 73 vs 83; P = .001). Children with ALGS and IHC were similar, except in physical scores (73 vs 79; P = .05). Parents of children with ALGS perceived their children to have worse HRQOL than A1ATD (P ≤ .001) and marginally lower compared with IHC. Univariate analysis revealed ALGS child-reported scores were positively associated with better growth and inversely with total bilirubin. Growth failure, elevated international normalized ratio, and an intracardiac defect were predictive of poor parental scores (P ≤ .05). In multivariate analysis, only weight z-score remained significant for child- and parent-reported scores.ConclusionsHRQOL is impaired in children with ALGS compared with healthy and children with A1ATD, similar to children with IHC and is associated with growth failure, which is a potentially treatable cause of impaired HRQOL.

Published
2015

23. Contributors

Author

A-Kader, H. Hesham, primary, Abdulhai, Sophia, additional, Abu-Elmagd, Kareem, additional, Abu-El-Haija, Maisam, additional, Adler, Douglas G., additional, Albenberg, Lindsey, additional, Alonso, Estella M., additional, Amin, Ruchi, additional, Atay, Orhan, additional, Auricchio, Renata, additional, Baker, Robert D., additional, Baker, Susan S., additional, Baldwin, Katherine, additional, Barry, Jessica, additional, Baron, Todd H., additional, Barth, Bradley, additional, Bass, Dorsey M., additional, Bass, Lee M., additional, Belkind-Gerson, Jaime, additional, Benninga, Marc A., additional, Bhesania, Natalie, additional, Bischoff, Andrea, additional, Bitton, Samuel, additional, Blanchard, Samra S., additional, Bousvaros, Athos, additional, Boyle, Brendan, additional, Brewer, Jennifer, additional, Brownell, Jefferson N., additional, Bruch, Steven W., additional, Campbell, Brendan T., additional, Campbell, Jacob, additional, Caty, Michael Gerard, additional, Cerezo, Carolina S., additional, Chagpar, Ryaz, additional, Chatfield, Beth, additional, Cherry, Rebecca N., additional, Cohen, Gail, additional, Cohen, Mitchell B., additional, Coran, Arnold G., additional, Costa, Guilherme, additional, Cresci, Gail A.M., additional, Crowley, Eileen, additional, Cruise, Michael, additional, Czinn, Steven J., additional, Davidovics, Zev, additional, Torre, Luis De La, additional, DeRoss, Anthony L., additional, Devadason, David, additional, Venkatesh, Rajitha Devadoss, additional, Di Lorenzo, Carlo, additional, Dotson, Jennifer L., additional, Ediger, Tracy R., additional, Eghtesad, Bijan, additional, Eisses, John F., additional, El Yousif, Mounif, additional, McBride Emerick, Karan, additional, Erdman, Steven H., additional, Fawaz, Rima, additional, Feldstein, Ariel E., additional, Fernandes, Melissa, additional, Finn, Laura S., additional, Fiorino, Kristin Nicole, additional, Fishman, Douglas S., additional, Friedlander, Joel A., additional, Fujiki, Masato, additional, Fung, John, additional, Fuss, Ivan, additional, Galloway, David, additional, George, Donald E., additional, Ghishan, Fayez K., additional, Girlanda, Raffaelle, additional, Gitt, Donna, additional, Goldman, Deborah A., additional, Goodine, Sue, additional, Gourley, Glenn R., additional, Green, Nicole, additional, Grisotti, Gabrielle, additional, Gupta, Sandeep K., additional, Hadzic, Nedim, additional, Harpavat, Sanjiv, additional, Hashimoto, Koji, additional, Hassan, Maheen, additional, Heubi, James E., additional, Husain, Sohail Z., additional, Hussey, Séamus, additional, Hyams, Jeffrey S., additional, Hyer, Warren, additional, Hyman, Paul E., additional, Iben, Sabine, additional, Issac, Veronica E., additional, Jonas, Maureen M., additional, Kay, Marsha, additional, Kehar, Mohit, additional, Kelly, Deidre, additional, Kovacic, Karlo, additional, Kunisaki, Shaun Michael, additional, Kurowski, Jacob A., additional, Langer, Jacob C., additional, Lee, Frances C., additional, Lee, Rose, additional, LeLeiko, Neal S., additional, Liacouras, Chris A., additional, Lin, Henry, additional, Liu, Quin Y., additional, Loomes, Kathleen M., additional, Lu, Peter L., additional, Lusman, Sarah Shrager, additional, Mack, Cara, additional, Maheshwari, Anshu, additional, Mamula, Petar, additional, Manfredi, Michael A., additional, Markowitz, James F., additional, Markowitz, Jonathan E., additional, Mascarenhas, Maria R., additional, Mayer, Ryann, additional, McKiernan, Patrick, additional, Mezoff, Adam G., additional, Mezoff, Ethan A., additional, Mieli-Vergani, Giorgina, additional, Mohr, Franziska, additional, Mokha, Jasmeet, additional, Mousa, Hayat, additional, Moye, Lindsay, additional, Murch, Simon, additional, Murray, Karen F., additional, Naples, Robert, additional, Nathan, Jaimie D., additional, Lee Ng, Vicky, additional, Nguyen, Vi, additional, Nurko, Samuel, additional, Oauhed, Jodie, additional, Ogholikhan, Tina, additional, Oldham, Keith T., additional, Osman, Mohammed, additional, Ovchinsky, Nadia, additional, Panganiban, Jennifer, additional, Pena, Alberto, additional, Petras, Robert E., additional, Pfefferkorn, Marian D., additional, Piccoli, David, additional, Piester, Travis, additional, Pinkos, Beth, additional, Plesec, Thomas, additional, Polites, Stephanie, additional, Ponsky, Todd, additional, Rader, Christine, additional, Radhakrishnan, Kadakkal, additional, Reissis, Yannis, additional, Rodriguez, Leonel, additional, Rodriguez, Ricardo J., additional, Rojas, Isabel, additional, Rome, Ellen S., additional, Rosh, Joel R., additional, Ruiz, Rachel M., additional, Sahn, Benjamin, additional, Saleem, Atif, additional, Samela, Kate A., additional, Santucci, Neha R., additional, Saps, Miguel, additional, Sato, Eleanor H., additional, Sato, Thomas T., additional, Savage, Erica C., additional, Seifarth, Federico G., additional, Conjeevaram Selvakumar, Praveen Kumar, additional, Shapiro, Jason, additional, Siperstein, Allan E., additional, Skelton, Joseph, additional, Snapper, Scott, additional, Soldes, Oliver S., additional, Sood, Manu R., additional, Stahl, Marisa Gallant, additional, Sundaram, Shikha S., additional, Sylvester, Francisco A., additional, Teitelbaum, Jonathan E., additional, Terry, Natalie A., additional, Townsend, Peter, additional, Troncone, Riccardo, additional, Vance, Kate, additional, Vandenplas, Yvan, additional, Venick, Robert S., additional, Vitale, David S., additional, Vockley, Jerry, additional, Vortia, Eugene, additional, Vriesman, Mana H., additional, Wahbeh, Ghassan T., additional, Walsh, R. Matthew, additional, Warner, Suz, additional, Wyllie, Robert, additional, Yasuda, Jessica L., additional, Zeiter, Donna, additional, and Zheng, Hengqi (Betty), additional

Published
2021
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27. Medical Status of 219 Children with Biliary Atresia Surviving Long-Term with Their Native Livers: Results from a North American Multicenter Consortium

Author

Ng, Vicky Lee, Haber, Barbara H, Magee, John C, Miethke, Alexander, Murray, Karen F, Michail, Sonia, Karpen, Saul J, Kerkar, Nanda, Molleston, Jean P, Romero, Rene, Rosenthal, Philip, Schwarz, Kathleen B, Shneider, Benjamin L, Turmelle, Yumirle P, Alonso, Estella M, Sherker, Averell H, Sokol, Ronald J, and Network, Childhood Liver Disease Research and Education

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Rare Diseases, Clinical Research, Liver Disease, Pediatric, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Perinatal Period - Conditions Originating in Perinatal Period, Oral and gastrointestinal, Good Health and Well Being, Biliary Atresia, Canada, Child, Enterostomy, Female, Health Status, Humans, Liver, Male, Quality of Life, Survivors, Time Factors, United States, Childhood Liver Disease Research and Education Network, Human Movement and Sports Sciences, Paediatrics and Reproductive Medicine, Pediatrics, Paediatrics
Abstract

ObjectivesTo examine the medical status of children with biliary atresia (BA) with their native livers after hepato- portoenterostomy (HPE) surgery.Study designThe Childhood Liver Disease Research and Education Network database was utilized to examine subjects with BA living with their native livers 5 or more years after HPE and to describe the prevalence of subjects with BA with an "ideal" outcome, defined as no clinical evidence of chronic liver disease, normal liver biochemical indices (aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, platelet count, total bilirubin, international normalized ratio, and albumin), and normal health-related quality of life 5 or more years after HPE.ResultsChildren with BA (n = 219; 43% male) with median age 9.7 years were studied. Median age at HPE was 56 (range 7-125) days. Median age- and sex-adjusted height and weight z-scores at 5-year follow-up were 0.487 (IQR -0.27 to 1.02) and 0.00 (IQR -0.74 to 0.70), respectively. During the 12 preceding months, cholangitis and bone fractures occurred in 17% and 5.5%, respectively. Health-related quality of life was reported normal by 53% of patients. However, only 1.8% met the study definition of "ideal" outcome. Individual tests of liver synthetic function (total bilirubin, albumin, and international normalized ratio) were normal in 75%, 85%, and 73% of the study cohort.ConclusionCholangitis and fractures in long-term survivors underscore the importance of ongoing medical surveillance. Over 98% of this North American cohort of subjects with BA living with native livers 5 or more years after HPE have clinical or biochemical evidence of chronic liver disease.

Published
2014

29. A Learning Collaborative Approach Increases Specificity of Diagnosis of Acute Liver Failure in Pediatric Patients

Author

Squires, Robert H., Bukauskas, Kathryn, Schulte, Madeline, Narkewicz, Michael R., Hite, Michelle, Loomes, Kathleen M., Rand, Elizabeth B., Piccoli, David, Kawchak, Deborah, Seidman, Christa, Romero, Rene, Karpen, Saul, de la Cruz-Tracy, Liezl, Ng, Vicky, Hunt, Kelsey, Subbarao, Girish C., Klipsch, Ann, Munson, Sarah, Alonso, Estella M., Sorenson, Lisa, Kelly, Susan, Neighbors, Katie, Rosenthal, Philip, Fleck, Shannon, Leonis, Mike A., Bucuvalas, John, Horning, Tracie, Rodriguez Baez, Norberto, Montanye, Shirley, Cowie, Margaret, Horslen, Simon P., Murray, Karen, Young, Melissa, Nielson, Heather, Klein, Jani, Rudnick, David A., Shepherd, Ross W., Harris, Kathy, Karpen, Saul J., De La Torre, Alejandro, Dell Olio, Dominic, Kelly, Deirdre, Lloyd, Carla, Lobritto, Steven J., Bakhsh, Sumerah, Jonas, Maureen, Elifoson, Scott A., Raza, Roshan, Schwarz, Kathleen B., Karnsakul, Wikrom W., Alford, Mary Kay, Dhawan, Anil, Fitzpatrick, Emer, Shneider, Benjamin L., Kerkar, Nanda N., Haydel, Brandy, Narayanappa, Sreevidya, Lopez, M. James, Shieck, Victoria, Doo, Edward, Sherker, Averell H., Belle, Steven H., Horslen, Simon, Hardison, Regina M., Rodriguez-Baez, Norberto, Ng, Vicky L., and Li, Ruosha

Published
2018
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30. Impact of Steroid Therapy on Early Growth in Infants with Biliary Atresia: The Multicenter Steroids in Biliary Atresia Randomized Trial

Author

Alonso, Estella M., Ye, Wen, Hawthorne, Kieran, Venkat, Veena, Loomes, Kathleen M., Mack, Cara L., Hertel, Paula M., Karpen, Saul J., Kerkar, Nanda, Molleston, Jean P., Murray, Karen F., Romero, Rene, Rosenthal, Philip, Schwarz, Kathleen B., Shneider, Benjamin L., Suchy, Frederick J., Turmelle, Yumirle P., Wang, Kasper S., Sherker, Averell H., Sokol, Ronald J., Bezerra, Jorge A., and Magee, John C.

Published
2018
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31. Health Related Quality of Life and Neurocognitive Outcomes in the First Year after Pediatric Acute Liver Failure

Author

Bukauskas, Kathryn, Schulte, Madeline, Narkewicz, Michael R., Hite, Michelle, Rand, Elizabeth B., Piccoli, David, Kawchak, Deborah, Seidman, Christa, Romero, Rene, Karpen, Saul, de la Cruz-Tracy, Liezl, Hunt, Kelsey, Subbarao, Girish C., Klipsch, Ann, Munson, Sarah, Kelly, Susan, Rosenthal, Philip J., Fleck, Shannon, Leonis, Mike A., Bucuvalas, John, Horning, Tracie, Baez, Norberto Rodriguez, Montanye, Shirley, Cowie, Margaret, Horslen, Simon P., Murray, Karen, Young, Melissa, Nielson, Heather, Klein, Jani, Rudnick, David A., Shepherd, Ross W., Harris, Kathy, Karpen, Saul J., De La Torre, Alejandro, Dell Olio, Dominic, Kelly, Deirdre, Lloyd, Carla, Lobritto, Steven J., Bakhsh, Sumerah, Jonas, Maureen, Elifoson, Scott A., Raza, Roshan, Schwarz, Kathleen B., Karnsakul, Wikrom W., Alford, Mary Kay, Dhawan, Anil, Fitzpatrick, Emer, Kerkar, Nanda N., Haydel, Brandy, Narayanappa, Sreevidya, Lopez, M. James, Shieck, Victoria, Sorensen, Lisa G., Neighbors, Katie, Hardison, Regina M., Loomes, Kathleen M., Varni, James W., Ng, Vicky L., Squires, Robert H., and Alonso, Estella M.

Published
2018
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32. Neurodevelopmental Outcome of Young Children with Biliary Atresia and Native Liver: Results from the ChiLDReN Study

Author

Hertel, Paula M., Harpavat, Sanjiv, Brandt, Mary L., Leung, Daniel H., Karnsakul, Wikrom, Torrance, Rebecca, Hall, Sherry, Doo, Edward, Hoofnagle, Jay H., Whitington, Peter, Bass, Lee, Miethke, Alexander G., Heubi, James E., Setchell, Kenneth, Bove, Kevin E., Tiao, Greg, Mack, Cara L., Narkewicz, Michael R., Feldman, Amy G., Sundaram, Shikha S., Suchy, Frederick J., Karrer, Frederick M., Lovell, Mark, Van Hove, Johan L., Rand, Elizabeth B., Squires, James E., Venkat, Veena L., Sindhi, Rakesh, Ranganathan, Sarangarajan, Bull, Laura, Teckman, Jeffrey, Bozic, Molly, Subbarao, Girish, Horslen, Simon, Hsu, Evelyn, Finn, Laura, Healey, Patrick, Kohli, Rohit, Thomas, Danny, Soufi, Nisreen, Michail, Sonia, Clifton, Matt, Gupta, Nitika, Romero, Rene, Vos, Miriam, Caltharp, Shelley, Kamath, Binita M., Ling, Simon C., Gold, Anna, Fecteau, Annie, Guthery, Stephen L., Jensen, Kyle, Meyers, Rebecka, Lowichik, Amy, Book, Linda, Merion, Robert M., Spino, Cathie, Jones, Karen, Ng, Vicky L., Sorensen, Lisa G., Alonso, Estella M., Fredericks, Emily M., Ye, Wen, Moore, Jeff, Karpen, Saul J., Shneider, Benjamin L., Molleston, Jean P., Bezerra, Jorge A., Murray, Karen F., Loomes, Kathleen M., Rosenthal, Philip, Squires, Robert H., Wang, Kasper, Arnon, Ronen, Schwarz, Kathleen B., Turmelle, Yumirle P., Haber, Barbara H., Sherker, Averell H., Magee, John C., and Sokol, Ronald J.

Published
2018
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34. Frailty in Children with Liver Disease: A Prospective Multicenter Study

Author

Lurz, Eberhard, Quammie, Claudia, Englesbe, Michael, Alonso, Estella M., Lin, Henry C., Hsu, Evelyn K., Furuya, Katryn N., Gupta, Nitika A., Venkat, Veena L., Daniel, James F., Leonis, Mike A., Miloh, Tamir, Telega, Grzegorz W., Yap, Jason, Menendez, Jerome, Book, Linda S., Himes, Ryan W., Sundaram, Shikha S., Parekh, Rulan, Sonnenday, Chris, Bucuvalas, John, Ng, Vicky L., and Kamath, Binita M.

Published
2018
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37. Health Related Quality of Life in Patients with Biliary Atresia Surviving with their Native Liver

Author

Sundaram, Shikha S, Alonso, Estella M, Haber, Barbara, Magee, John C, Fredericks, Emily, Kamath, Binita, Kerkar, Nanda, Rosenthal, Philip, Shepherd, Ross, Limbers, Christine, Varni, James W, Robuck, Patricia, Sokol, Ronald J, and Network, Childhood Liver Disease Research and Education

Subjects
Paediatrics, Biomedical and Clinical Sciences, Clinical Research, Transplantation, Digestive Diseases, Organ Transplantation, Congenital Structural Anomalies, Minority Health, Perinatal Period - Conditions Originating in Perinatal Period, Liver Disease, Pediatric, Chronic Liver Disease and Cirrhosis, Rare Diseases, 7.1 Individual care needs, Adolescent, Adult, Biliary Atresia, Child, Child, Preschool, Cohort Studies, Cross-Sectional Studies, Female, Humans, Liver, Liver Transplantation, Male, Models, Statistical, Multivariate Analysis, Pediatrics, Quality of Life, Regression Analysis, Young Adult, Childhood Liver Disease Research and Education Network, ALT, Alanine aminotransferase, GI, Gastrointestinal, HPE, HRQOL, Health related quality of life, Hepatic portoenterostomy, ICC, Intra-class correlation coefficient, LT, Liver transplant, Pediatric Quality of Life Inventory, PedsQL, Human Movement and Sports Sciences, Paediatrics and Reproductive Medicine
Abstract

ObjectivesTo quantify health related quality of life (HRQOL) of patients with biliary atresia with their native livers and compare them with healthy children and patients with biliary atresia post-liver transplant (LT) and to examine the relationship between HRQOL and medical variables.Study designA cross-sectional HRQOL study of patients with biliary atresia with their native livers (ages 2-25 years) was conducted and compared with healthy and post-LT biliary atresia samples using Pediatric Quality of Life Inventory 4.0 child self and parent proxy reports, a validated measure of physical/psychosocial functioning.Results221 patients with biliary atresia with native livers (54% female, 67% white) were studied. Patient self and parent proxy reports showed significantly poorer HRQOL than healthy children across all domains (P < .001), particularly in emotional and psychosocial functioning. Child self and parent proxy HRQOL scores from patients with biliary atresia with their native livers and post-LT biliary atresia were similar across all domains (P = not significant). Child self and parent proxy reports showed moderate agreement across all scales, except social functioning (poor to fair agreement). On multivariate regression analysis, black race and elevated total bilirubin were associated with lower Total and Psychosocial HRQOL summary scores.ConclusionsHRQOL in patients with biliary atresia with their native livers is significantly poorer than healthy children and similar to children with post-LT biliary atresia. These findings identify significant opportunities to optimize the overall health of patients with biliary atresia.

Published
2013

39. Immunosuppression-Free Life after Pediatric Liver Transplant: A Case-Control Study from the Society of Pediatric Liver Transplant (SPLIT) Registry

Author

Kortbeek, Simone, primary, Anderson, Sarah G., additional, Alonso, Estella M., additional, Rand, Elizabeth B., additional, Bucuvalas, John, additional, Mazariegos, George V., additional, Campbell, Kathleen M., additional, Lobritto, Steven J., additional, Feldman, Amy G., additional, Mysore, Krupa R., additional, Anand, Ravinder, additional, Selzner, Nazia, additional, and Ng, Vicky L., additional

Published
2023
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41. Protein biomarkers GDF15 and FGF21 to differentiate mitochondrial hepatopathies from other pediatric liver diseases.

Author

Van Hove, Johan L. K., Friederich, Marisa W., Strode, Dana K., Van Hove, Roxanne A., Miller, Kristen R., Sharma, Rohit, Shah, Hardik, Estrella, Jane, Gabel, Linda, Horslen, Simon, Kohli, Rohit, Lovell, Mark A., Miethke, Alexander G., Molleston, Jean P., Romero, Rene, Squires, James E., Alonso, Estella M., Guthery, Stephen L., Kamath, Binita M., and Loomes, Kathleen M.

Published
2024
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44. Neurodevelopmental Outcomes in Preschool and School Aged Children With Biliary Atresia and Their Native Liver

Author

Squires, James E., Ng, Vicky Lee, Hawthorne, Kieran, Henn, Lisa L., Sorensen, Lisa G., Fredericks, Emily M., Alonso, Estella M., Murray, Karen F., Loomes, Kathleen M., Karpen, Saul J., Cavallo, Laurel A., Molleston, Jean P., Bezerra, Jorge A., Rosenthal, Philip, Squires, Robert H., Wang, Kasper S., Schwarz, Kathleen B., Arnon, Ronen, Magee, John C., and Sokol, Ronald J.

Published
2020
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46. Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Author

UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Felzen, Antonia, van Wessel, Daan B.E., Gonzales, Emmanuel, Thompson, Richard J., Jankowska, Irena, Shneider, Benjamin L., Sokal, Etienne, Grammatikopoulos, Tassos, Kadaristiana, Agustina, Jacquemin, Emmanuel, Spraul, Anne, Lipiński, Patryk, Czubkowski, Piotr, Rock, Nathalie, Shagrani, Mohammad, Broering, Dieter, Nicastro, Emanuele, Kelly, Deirdre, Nebbia, Gabriella, Arnell, Henrik, Fischler, Björn, Hulscher, Jan B.F., Serranti, Daniele, Arikan, Cigdem, Polat, Esra, Debray, Dominique, Lacaille, Florence, Goncalves, Cristina, Hierro, Loreto, Muñoz Bartolo, Gema, Mozer-Glassberg, Yael, Azaz, Amer, Brecelj, Jernej, Dezsőfi, Antal, Calvo, Pier Luigi, Grabhorn, Enke, Hartleif, Steffen, van der Woerd, Wendy J., Kamath, Binita M., Wang, Jian-She, Li, Liting, Durmaz, Özlem, Kerkar, Nanda, Jørgensen, Marianne Hørby, Fischer, Ryan, Jimenez-Rivera, Carolina, Alam, Seema, Cananzi, Mara, Laverdure, Noemie, Ferreira, Cristina Targa, Guerrero, Felipe Ordoñez, Wang, Heng, Sency, Valerie, Kim, Kyung Mo, Chen, Huey-Ling, de Carvalho, Elisa, Fabre, Alexandre, Bernabeu, Jesus Quintero, Zellos, Aglaia, Alonso, Estella M., Sokol, Ronald J., Suchy, Frederick J., Loomes, Kathleen M., McKiernan, Patrick J., Rosenthal, Philip, Turmelle, Yumirle, Horslen, Simon, Schwarz, Kathleen, Bezerra, Jorge A., Wang, Kasper, Hansen, Bettina E., Verkade, Henkjan J., UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Felzen, Antonia, van Wessel, Daan B.E., Gonzales, Emmanuel, Thompson, Richard J., Jankowska, Irena, Shneider, Benjamin L., Sokal, Etienne, Grammatikopoulos, Tassos, Kadaristiana, Agustina, Jacquemin, Emmanuel, Spraul, Anne, Lipiński, Patryk, Czubkowski, Piotr, Rock, Nathalie, Shagrani, Mohammad, Broering, Dieter, Nicastro, Emanuele, Kelly, Deirdre, Nebbia, Gabriella, Arnell, Henrik, Fischler, Björn, Hulscher, Jan B.F., Serranti, Daniele, Arikan, Cigdem, Polat, Esra, Debray, Dominique, Lacaille, Florence, Goncalves, Cristina, Hierro, Loreto, Muñoz Bartolo, Gema, Mozer-Glassberg, Yael, Azaz, Amer, Brecelj, Jernej, Dezsőfi, Antal, Calvo, Pier Luigi, Grabhorn, Enke, Hartleif, Steffen, van der Woerd, Wendy J., Kamath, Binita M., Wang, Jian-She, Li, Liting, Durmaz, Özlem, Kerkar, Nanda, Jørgensen, Marianne Hørby, Fischer, Ryan, Jimenez-Rivera, Carolina, Alam, Seema, Cananzi, Mara, Laverdure, Noemie, Ferreira, Cristina Targa, Guerrero, Felipe Ordoñez, Wang, Heng, Sency, Valerie, Kim, Kyung Mo, Chen, Huey-Ling, de Carvalho, Elisa, Fabre, Alexandre, Bernabeu, Jesus Quintero, Zellos, Aglaia, Alonso, Estella M., Sokol, Ronald J., Suchy, Frederick J., Loomes, Kathleen M., McKiernan, Patrick J., Rosenthal, Philip, Turmelle, Yumirle, Horslen, Simon, Schwarz, Kathleen, Bezerra, Jorge A., Wang, Kasper, Hansen, Bettina E., and Verkade, Henkjan J.

Abstract

Background & aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until

Published
2023

47. Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Author

Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Felzen, Antonia; van Wessel, Daan B.E.; Gonzales, Emmanuel; Thompson, Richard J.; Jankowska, Irena; Shneider, Benjamin L.; Sokal, Etienne; Grammatikopoulos, Tassos; Kadaristiana, Agustina; Jacquemin, Emmanuel; Spraul, Anne; Lipi?ski, Patryk; Czubkowski, Piotr; Rock, Nathalie; Shagrani, Mohammad; Broering, Dieter; Nicastro, Emanuele; Kelly, Deirdre; Nebbia, Gabriella; Arnell, Henrik; Fischler, Björn; Hulscher, Jan B.F.; Serranti, Daniele; Polat, Esra; Debray, Dominique; Lacaille, Florence; Goncalves, Cristina; Hierro, Loreto; Muñoz Bartolo, Gema; Mozer-Glassberg, Yael; Azaz, Amer; Brecelj, Jernej; Dezs?fi, Antal; Calvo, Pier Luigi; Grabhorn, Enke; Hartleif, Steffen; van der Woerd, Wendy J.; Kamath, Binita M.; Wang, Jian-She; Li, Liting; Durmaz, Özlem; Kerkar, Nanda; Jørgensen, Marianne Hørby; Fischer, Ryan; Jimenez-Rivera, Carolina; Alam, Seema; Cananzi, Mara; Laverdure, Noemie; Ferreira, Cristina Targa; Guerrero, Felipe Ordoñez; Wang, Heng; Sency, Valerie; Kim, Kyung Mo; Chen, Huey-Ling; de Carvalho, Elisa; Fabre, Alexandre; Bernabeu, Jesus Quintero; Zellos, Aglaia; Alonso, Estella M.; Sokol, Ronald J.; Suchy, Frederick J.; Loomes, Kathleen M.; McKiernan, Patrick J.; Rosenthal, Philip; Turmelle, Yumirle; Horslen, Simon; Schwarz, Kathleen; Bezerra, Jorge A.; Wang, Kasper; Hansen, Bettina E.; Verkade, Henkjan J., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Felzen, Antonia; van Wessel, Daan B.E.; Gonzales, Emmanuel; Thompson, Richard J.; Jankowska, Irena; Shneider, Benjamin L.; Sokal, Etienne; Grammatikopoulos, Tassos; Kadaristiana, Agustina; Jacquemin, Emmanuel; Spraul, Anne; Lipi?ski, Patryk; Czubkowski, Piotr; Rock, Nathalie; Shagrani, Mohammad; Broering, Dieter; Nicastro, Emanuele; Kelly, Deirdre; Nebbia, Gabriella; Arnell, Henrik; Fischler, Björn; Hulscher, Jan B.F.; Serranti, Daniele; Polat, Esra; Debray, Dominique; Lacaille, Florence; Goncalves, Cristina; Hierro, Loreto; Muñoz Bartolo, Gema; Mozer-Glassberg, Yael; Azaz, Amer; Brecelj, Jernej; Dezs?fi, Antal; Calvo, Pier Luigi; Grabhorn, Enke; Hartleif, Steffen; van der Woerd, Wendy J.; Kamath, Binita M.; Wang, Jian-She; Li, Liting; Durmaz, Özlem; Kerkar, Nanda; Jørgensen, Marianne Hørby; Fischer, Ryan; Jimenez-Rivera, Carolina; Alam, Seema; Cananzi, Mara; Laverdure, Noemie; Ferreira, Cristina Targa; Guerrero, Felipe Ordoñez; Wang, Heng; Sency, Valerie; Kim, Kyung Mo; Chen, Huey-Ling; de Carvalho, Elisa; Fabre, Alexandre; Bernabeu, Jesus Quintero; Zellos, Aglaia; Alonso, Estella M.; Sokol, Ronald J.; Suchy, Frederick J.; Loomes, Kathleen M.; McKiernan, Patrick J.; Rosenthal, Philip; Turmelle, Yumirle; Horslen, Simon; Schwarz, Kathleen; Bezerra, Jorge A.; Wang, Kasper; Hansen, Bettina E.; Verkade, Henkjan J., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Abstract

Background & Aims: bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: from the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: the groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: this manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until, 1. MD/PhD scholarship from the University of Groningen, Groningen, The Netherlands 2. ESPGHAN Networking Grant 2019 3. ChiLDReN and CTSA National Institutes of Health grants: Ann & Robert H. Lurie Children's Hospital, Chicago: U01DK062436; University of Colorado, Denver: U01DK62453, UL1 TR002535; Baylor college of Medicine, Houston: U01DK103149; Children's Hospital of Philadelphia, Philadelphia: U01DK062481, UL1TR000003; Children's Hospital of Pittsburgh, Pittsburgh: U01DK062466; University of California, San Francisco U01DK062500; University of California, San Francisco CTSI grant UL1TR001872; Riley Hospital for Children, Indianapolis: U01DK084536; Seattle Children’s Hospital, Seattle: DK084575; Children’s Hospital Los Angeles, California: U01DK084538. 4. Unrestrictive research grant from Albireo 5. Unrestrictive research grant from Mirum Pharmaceuticals. 6. C&W de Boer Stichting research grant.

Published
2023

48. Clinical Course among Cases of Acute Liver Failure of Indeterminate Diagnosis

Author

Bukauskas, Kathryn, Narkewicz, Michael R., Hite, Michelle, Loomes, Kathleen M., Rand, Elizabeth B., Piccoli, David, Kawchak, Deborah, Romero, Rene, Karpen, Saul, de la Cruz-Tracy, Liezl, Ng, Vicky, Hunt, Kelsey, Subbarao, Girish C., Klipsch, Ann, Alonso, Estella M., Sorenson, Lisa, Kelly, Susan, Delute, Dhey, Neighbors, Katie, Rosenthal, Philip J., Fleck, Shannon, Leonis, Mike A., Bucuvalas, John, Horning, Tracie, Baez, Norberto Rodriguez, Montanye, Shirley, Cowie, Margaret, Murray, Karen, Young, Melissa, Vendettuoli, Heather, Rudnick, David A., Shepherd, Ross W., Harris, Kathy, Karpen, Saul J., De La Torre, Alejandro, Dell Olio, Dominic, Kelly, Deirdre, Lloyd, Carla, Lobritto, Steven J., Bakhsh, Sumerah, Jonas, Maureen, Elifoson, Scott A., Raza, Roshan, Schwarz, Kathleen B., Karnsakul, Wikrom W., Alford, Mary Kay, Dhawan, Anil, Fitzpatrick, Emer, Kerkar, Nanda N., Haydel, Brandy, Narayanappa, Sreevidya, Lopez, M. James, Shieck, Victoria, Li, Ruosha, Belle, Steven H., Horslen, Simon, Chen, Ling-wan, Zhang, Song, and Squires, Robert H.

Published
2016
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