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1. Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA

Author

Hansen, B, Vandriel, S, Vig, P, Garner, W, Mogul, D, Loomes, K, Piccoli, D, Rand, E, Jankowska, I, Czubkowski, P, Gliwicz-Miedzinska, D, Gonzales, E, Jacquemin, E, Bouligand, J, D'Antiga, L, Nicastro, E, Arnell, H, Fischler, B, Sokal, E, Demaret, T, Siew, S, Stormon, M, Karpen, S, Romero, R, Ebel, N, Feinstein, J, Roberts, A, Evans, H, Sundaram, S, Chaidez, A, Hardikar, W, Shankar, S, Fischer, R, Lacaille, F, Debray, D, Lin, H, Jensen, M, Jaramillo, C, Karthikeyan, P, Indolfi, G, Verkade, H, Larson-Nath, C, Quiros-Tejeira, R, Valentino, P, Rogalidou, M, Dezsofi, A, Squires, J, Schwarz, K, Calvo, P, Bernabeu, J, Zizzo, A, Nebbia, G, Bulut, P, Santos-Silva, E, Fawaz, R, Nastasio, S, Karnsakul, W, Tamara, M, Busoms, C, Kelly, D, Sandahl, T, Jimenez-Rivera, C, Banales, J, Mujawar, Q, Li, L, She, H, Wang, J, Kim, K, Oh, S, Sanchez, M, Cavalieri, M, Lee, W, Hajinicolaou, C, Lertudomphonwanit, C, Waisbourd-Zinman, O, Arikan, C, Alam, S, Carvalho, E, Melere, M, Eshun, J, Onal, Z, Desai, D, Wiecek, S, Pinto, R, Wolters, V, Garcia, J, Beretta, M, Kerkar, N, Brecelj, J, Rock, N, Lurz, E, Blondet, N, Shah, U, Thompson, R, Kamath, B, Hansen B. E., Vandriel S. M., Vig P., Garner W., Mogul D. B., Loomes K. M., Piccoli D. A., Rand E. B., Jankowska I., Czubkowski P., Gliwicz-Miedzinska D., Gonzales E. M., Jacquemin E., Bouligand J., D'Antiga L., Nicastro E., Arnell H., Fischler B., Sokal E., Demaret T., Siew S., Stormon M., Karpen S. J., Romero R., Ebel N. H., Feinstein J. A., Roberts A. J., Evans H. M., Sundaram S. S., Chaidez A., Hardikar W., Shankar S., Fischer R. T., Lacaille F., Debray D., Lin H. C., Jensen M. K., Jaramillo C., Karthikeyan P., Indolfi G., Verkade H. J., Larson-Nath C., Quiros-Tejeira R. E., Valentino P. L., Rogalidou M., Dezsofi A., Squires J. E., Schwarz K., Calvo P. L., Bernabeu J. Q., Zizzo A. N., Nebbia G., Bulut P., Santos-Silva E., Fawaz R., Nastasio S., Karnsakul W., Tamara M. L., Busoms C. M., Kelly D. A., Sandahl T. D., Jimenez-Rivera C., Banales J. M., Mujawar Q., Li L. -T., She H., Wang J. -S., Kim K. M., Oh S. H., Sanchez M. C., Cavalieri M. L., Lee W. S., Hajinicolaou C., Lertudomphonwanit C., Waisbourd-Zinman O., Arikan C., Alam S., Carvalho E., Melere M., Eshun J., Onal Z., Desai D. M., Wiecek S., Pinto R. B., Wolters V. M., Garcia J., Beretta M., Kerkar N., Brecelj J., Rock N., Lurz E., Blondet N., Shah U., Thompson R. J., Kamath B. M., Hansen, B, Vandriel, S, Vig, P, Garner, W, Mogul, D, Loomes, K, Piccoli, D, Rand, E, Jankowska, I, Czubkowski, P, Gliwicz-Miedzinska, D, Gonzales, E, Jacquemin, E, Bouligand, J, D'Antiga, L, Nicastro, E, Arnell, H, Fischler, B, Sokal, E, Demaret, T, Siew, S, Stormon, M, Karpen, S, Romero, R, Ebel, N, Feinstein, J, Roberts, A, Evans, H, Sundaram, S, Chaidez, A, Hardikar, W, Shankar, S, Fischer, R, Lacaille, F, Debray, D, Lin, H, Jensen, M, Jaramillo, C, Karthikeyan, P, Indolfi, G, Verkade, H, Larson-Nath, C, Quiros-Tejeira, R, Valentino, P, Rogalidou, M, Dezsofi, A, Squires, J, Schwarz, K, Calvo, P, Bernabeu, J, Zizzo, A, Nebbia, G, Bulut, P, Santos-Silva, E, Fawaz, R, Nastasio, S, Karnsakul, W, Tamara, M, Busoms, C, Kelly, D, Sandahl, T, Jimenez-Rivera, C, Banales, J, Mujawar, Q, Li, L, She, H, Wang, J, Kim, K, Oh, S, Sanchez, M, Cavalieri, M, Lee, W, Hajinicolaou, C, Lertudomphonwanit, C, Waisbourd-Zinman, O, Arikan, C, Alam, S, Carvalho, E, Melere, M, Eshun, J, Onal, Z, Desai, D, Wiecek, S, Pinto, R, Wolters, V, Garcia, J, Beretta, M, Kerkar, N, Brecelj, J, Rock, N, Lurz, E, Blondet, N, Shah, U, Thompson, R, Kamath, B, Hansen B. E., Vandriel S. M., Vig P., Garner W., Mogul D. B., Loomes K. M., Piccoli D. A., Rand E. B., Jankowska I., Czubkowski P., Gliwicz-Miedzinska D., Gonzales E. M., Jacquemin E., Bouligand J., D'Antiga L., Nicastro E., Arnell H., Fischler B., Sokal E., Demaret T., Siew S., Stormon M., Karpen S. J., Romero R., Ebel N. H., Feinstein J. A., Roberts A. J., Evans H. M., Sundaram S. S., Chaidez A., Hardikar W., Shankar S., Fischer R. T., Lacaille F., Debray D., Lin H. C., Jensen M. K., Jaramillo C., Karthikeyan P., Indolfi G., Verkade H. J., Larson-Nath C., Quiros-Tejeira R. E., Valentino P. L., Rogalidou M., Dezsofi A., Squires J. E., Schwarz K., Calvo P. L., Bernabeu J. Q., Zizzo A. N., Nebbia G., Bulut P., Santos-Silva E., Fawaz R., Nastasio S., Karnsakul W., Tamara M. L., Busoms C. M., Kelly D. A., Sandahl T. D., Jimenez-Rivera C., Banales J. M., Mujawar Q., Li L. -T., She H., Wang J. -S., Kim K. M., Oh S. H., Sanchez M. C., Cavalieri M. L., Lee W. S., Hajinicolaou C., Lertudomphonwanit C., Waisbourd-Zinman O., Arikan C., Alam S., Carvalho E., Melere M., Eshun J., Onal Z., Desai D. M., Wiecek S., Pinto R. B., Wolters V. M., Garcia J., Beretta M., Kerkar N., Brecelj J., Rock N., Lurz E., Blondet N., Shah U., Thompson R. J., and Kamath B. M.

Abstract

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study. APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, p

Published
2024

2. Incidence of Isolated Biliary Atresia during the COVID Lockdown in Europe: Results from a Collaborative Project by RARE-Liver

Author

Nomden, M, Alizai, N, Betalli, P, Bruggink, J, Cananzi, M, Christensen, V, D'Antiga, L, Davenport, M, Fischler, B, Hindemith, L, Hukkinen, M, Johansen, L, de Kleine, R, Madadi-Sanjani, O, Ong, E, Pakarinen, M, Petersen, C, Ruiz, M, Schunn, M, Sturm, E, Verkade, H, Wildhaber, B, Hulscher, J, Nomden M., Alizai N. K., Betalli P., Bruggink J. L. M., Cananzi M., Christensen V. B., D'Antiga L., Davenport M., Fischler B., Hindemith L., Hukkinen M., Johansen L. S., de Kleine R. H., Madadi-Sanjani O., Ong E. G. P., Pakarinen M. P., Petersen C., Ruiz M., Schunn M., Sturm E., Verkade H. J., Wildhaber B. E., Hulscher J. B. F., Nomden, M, Alizai, N, Betalli, P, Bruggink, J, Cananzi, M, Christensen, V, D'Antiga, L, Davenport, M, Fischler, B, Hindemith, L, Hukkinen, M, Johansen, L, de Kleine, R, Madadi-Sanjani, O, Ong, E, Pakarinen, M, Petersen, C, Ruiz, M, Schunn, M, Sturm, E, Verkade, H, Wildhaber, B, Hulscher, J, Nomden M., Alizai N. K., Betalli P., Bruggink J. L. M., Cananzi M., Christensen V. B., D'Antiga L., Davenport M., Fischler B., Hindemith L., Hukkinen M., Johansen L. S., de Kleine R. H., Madadi-Sanjani O., Ong E. G. P., Pakarinen M. P., Petersen C., Ruiz M., Schunn M., Sturm E., Verkade H. J., Wildhaber B. E., and Hulscher J. B. F.

Abstract

Background: Biliary atresia (BA) is a rare cholangiopathy where one of the proposed aetiological mechanisms is an infectious viral trigger. Coronavirus disease-19 (COVID) lockdown restrictions were implemented to reduce the transmission of infections. Strictness of lockdown varied across European countries. This study aimed to investigate if there was an association between strictness of lockdown and change in isolated BA (IBA) incidence in Europe. Methods: We approached European centres involved in the European Reference Network RARE-LIVER. We included IBA patients born between 2015 and June 2020. We calculated the number of IBA patients born per centre per month. The Stringency Index (SI) was used as lockdown strictness indicator. The association between percentage change of mean number of IBA patients born per month and the SI was assessed. Results: We included 412 IBA patients from thirteen different centres. The median number of patients per month did not change: 6 (1–15) pre-lockdown and 7 (6–9) during lockdown (p = 0.34). There was an inverse association between SI and percentage change in IBA (B = -0.73, p = 0.03). Median age at Kasai portoenterostomy (days) did not differ between time periods (51 (9–179) vs. 53 (19–126), p = 0.73). Conclusion: In this European study, a stricter COVID-lockdown was seemingly accompanied by a simultaneous larger decrease in the number of IBA patients born per month in the lockdown. Results should be interpreted with caution due to the assumptions and limitations of the analysis.

Published
2023

3. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study

Author

Vandriel, S, Li, L, She, H, Wang, J, Gilbert, M, Jankowska, I, Czubkowski, P, Gliwicz-Miedzinska, D, Gonzales, E, Jacquemin, E, Bouligand, J, Spinner, N, Loomes, K, Piccoli, D, D'Antiga, L, Nicastro, E, Sokal, A, Demaret, T, Ebel, N, Feinstein, J, Fawaz, R, Nastasio, S, Lacaille, F, Debray, D, Arnell, H, Fischler, B, Siew, S, Stormon, M, Karpen, S, Romero, R, Kim, K, Baek, W, Hardikar, W, Shankar, S, Roberts, A, Evans, H, Jensen, M, Kavan, M, Sundaram, S, Chaidez, A, Karthikeyan, P, Sanchez, M, Cavalieri, M, Verkade, H, Lee, W, Squires, J, Hajinicolaou, C, Lertudomphonwanit, C, Fischer, R, Larson-Nath, C, Mozer-Glassberg, Y, Arikan, C, Lin, H, Bernabeu, J, Alam, S, Kelly, D, Carvalho, E, Ferreira, C, Indolfi, G, Quiros-Tejeira, R, Bulut, P, Calvo, P, Anal, Z, Valentino, P, Desai, D, Eshun, J, Rogalidou, M, Dezsofi, A, Wiecek, S, Nebbia, G, Pinto, R, Wolters, V, Tamara, M, Zizzo, A, Garcia, J, Schwarz, K, Beretta, M, Sandahl, T, Jimenez-Rivera, C, Kerkar, N, Brecelj, J, Mujawar, Q, Rock, N, Busoms, C, Karnsakul, W, Lurz, E, Santos-Silva, E, Blondet, N, Bujanda, L, Shah, U, Thompson, R, Hansen, B, Kamath, B, Vandriel S. M., Li L. -T., She H., Wang J. -S., Gilbert M. A., Jankowska I., Czubkowski P., Gliwicz-Miedzinska D., Gonzales E. M., Jacquemin E., Bouligand J., Spinner N. B., Loomes K. M., Piccoli D. A., D'Antiga L., Nicastro E., Sokal A., Demaret T., Ebel N. H., Feinstein J. A., Fawaz R., Nastasio S., Lacaille F., Debray D., Arnell H., Fischler B., Siew S., Stormon M., Karpen S. J., Romero R., Kim K. M., Baek W. Y., Hardikar W., Shankar S., Roberts A. J., Evans H. M., Jensen M. K., Kavan M., Sundaram S. S., Chaidez A., Karthikeyan P., Sanchez M. C., Cavalieri M. L., Verkade H. J., Lee W. S., Squires J. E., Hajinicolaou C., Lertudomphonwanit C., Fischer R. T., Larson-Nath C., Mozer-Glassberg Y., Arikan C., Lin H. C., Bernabeu J. Q., Alam S., Kelly D. A., Carvalho E., Ferreira C. T., Indolfi G., Quiros-Tejeira R. E., Bulut P., Calvo P. L., Anal Z., Valentino P. L., Desai D. M., Eshun J., Rogalidou M., Dezsofi A., Wiecek S., Nebbia G., Pinto R. B., Wolters V. M., Tamara M. L., Zizzo A. N., Garcia J., Schwarz K., Beretta M., Sandahl T. D., Jimenez-Rivera C., Kerkar N., Brecelj J., Mujawar Q., Rock N., Busoms C. M., Karnsakul W., Lurz E., Santos-Silva E., Blondet N., Bujanda L., Shah U., Thompson R. J., Hansen B. E., Kamath B. M., Vandriel, S, Li, L, She, H, Wang, J, Gilbert, M, Jankowska, I, Czubkowski, P, Gliwicz-Miedzinska, D, Gonzales, E, Jacquemin, E, Bouligand, J, Spinner, N, Loomes, K, Piccoli, D, D'Antiga, L, Nicastro, E, Sokal, A, Demaret, T, Ebel, N, Feinstein, J, Fawaz, R, Nastasio, S, Lacaille, F, Debray, D, Arnell, H, Fischler, B, Siew, S, Stormon, M, Karpen, S, Romero, R, Kim, K, Baek, W, Hardikar, W, Shankar, S, Roberts, A, Evans, H, Jensen, M, Kavan, M, Sundaram, S, Chaidez, A, Karthikeyan, P, Sanchez, M, Cavalieri, M, Verkade, H, Lee, W, Squires, J, Hajinicolaou, C, Lertudomphonwanit, C, Fischer, R, Larson-Nath, C, Mozer-Glassberg, Y, Arikan, C, Lin, H, Bernabeu, J, Alam, S, Kelly, D, Carvalho, E, Ferreira, C, Indolfi, G, Quiros-Tejeira, R, Bulut, P, Calvo, P, Anal, Z, Valentino, P, Desai, D, Eshun, J, Rogalidou, M, Dezsofi, A, Wiecek, S, Nebbia, G, Pinto, R, Wolters, V, Tamara, M, Zizzo, A, Garcia, J, Schwarz, K, Beretta, M, Sandahl, T, Jimenez-Rivera, C, Kerkar, N, Brecelj, J, Mujawar, Q, Rock, N, Busoms, C, Karnsakul, W, Lurz, E, Santos-Silva, E, Blondet, N, Bujanda, L, Shah, U, Thompson, R, Hansen, B, Kamath, B, Vandriel S. M., Li L. -T., She H., Wang J. -S., Gilbert M. A., Jankowska I., Czubkowski P., Gliwicz-Miedzinska D., Gonzales E. M., Jacquemin E., Bouligand J., Spinner N. B., Loomes K. M., Piccoli D. A., D'Antiga L., Nicastro E., Sokal A., Demaret T., Ebel N. H., Feinstein J. A., Fawaz R., Nastasio S., Lacaille F., Debray D., Arnell H., Fischler B., Siew S., Stormon M., Karpen S. J., Romero R., Kim K. M., Baek W. Y., Hardikar W., Shankar S., Roberts A. J., Evans H. M., Jensen M. K., Kavan M., Sundaram S. S., Chaidez A., Karthikeyan P., Sanchez M. C., Cavalieri M. L., Verkade H. J., Lee W. S., Squires J. E., Hajinicolaou C., Lertudomphonwanit C., Fischer R. T., Larson-Nath C., Mozer-Glassberg Y., Arikan C., Lin H. C., Bernabeu J. Q., Alam S., Kelly D. A., Carvalho E., Ferreira C. T., Indolfi G., Quiros-Tejeira R. E., Bulut P., Calvo P. L., Anal Z., Valentino P. L., Desai D. M., Eshun J., Rogalidou M., Dezsofi A., Wiecek S., Nebbia G., Pinto R. B., Wolters V. M., Tamara M. L., Zizzo A. N., Garcia J., Schwarz K., Beretta M., Sandahl T. D., Jimenez-Rivera C., Kerkar N., Brecelj J., Mujawar Q., Rock N., Busoms C. M., Karnsakul W., Lurz E., Santos-Silva E., Blondet N., Bujanda L., Shah U., Thompson R. J., Hansen B. E., and Kamath B. M.

Abstract

Background and Aims: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. Approach and Results: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver (p < 0.001). Conclusions: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.

Published
2023

4. Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)—A European Society of Organ Transplantation (ESOT) Consensus Statement

Author

Carbone, M, Della Penna, A, Mazzarelli, C, De Martin, E, Villard, C, Bergquist, A, Line, P, Neuberger, J, Al-Shakhshir, S, Trivedi, P, Baumann, U, Cristoferi, L, Hov, J, Fischler, B, Hadzic, N, Debray, D, D'Antiga, L, Selzner, N, Belli, L, Nadalin, S, Carbone M., Della Penna A., Mazzarelli C., De Martin E., Villard C., Bergquist A., Line P. D., Neuberger J. M., Al-Shakhshir S., Trivedi P. J., Baumann U., Cristoferi L., Hov J., Fischler B., Hadzic N. H., Debray D., D'Antiga L., Selzner N., Belli L. S., Nadalin S., Carbone, M, Della Penna, A, Mazzarelli, C, De Martin, E, Villard, C, Bergquist, A, Line, P, Neuberger, J, Al-Shakhshir, S, Trivedi, P, Baumann, U, Cristoferi, L, Hov, J, Fischler, B, Hadzic, N, Debray, D, D'Antiga, L, Selzner, N, Belli, L, Nadalin, S, Carbone M., Della Penna A., Mazzarelli C., De Martin E., Villard C., Bergquist A., Line P. D., Neuberger J. M., Al-Shakhshir S., Trivedi P. J., Baumann U., Cristoferi L., Hov J., Fischler B., Hadzic N. H., Debray D., D'Antiga L., Selzner N., Belli L. S., and Nadalin S.

Abstract

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines’ Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.

Published
2023

5. Long-term Outcome of Asymptomatic Patients with Graft Fibrosis in Protocol Biopsies after Pediatric Liver Transplantation

Author

Hartleif, S, Hodson, J, Lloyd, C, Cousin, V, Czubkowski, P, D'Antiga, L, Debray, D, Demetris, A, Di Giorgio, A, Evans, H, Fischler, B, Gonzales, E, Gouw, A, Hubscher, S, Jacquemin, E, Lacaille, F, Malenicka, S, Mclin, V, Markiewicz-Kijewska, M, Mazariegos, G, Rajanayagam, J, Scheenstra, R, Singer, S, Smets, F, Sokal, E, Squires, J, Sturm, E, Verkade, H, Kelly, D, Hartleif S., Hodson J., Lloyd C., Cousin V. L., Czubkowski P., D'Antiga L., Debray D., Demetris A., Di Giorgio A., Evans H. M., Fischler B., Gonzales E., Gouw A. S. H., Hubscher S. G., Jacquemin E., Lacaille F., Malenicka S., McLin V. A., Markiewicz-Kijewska M., Mazariegos G. V., Rajanayagam J. K., Scheenstra R., Singer S., Smets F., Sokal E., Squires J. E., Sturm E., Verkade H., Kelly D. A., Hartleif, S, Hodson, J, Lloyd, C, Cousin, V, Czubkowski, P, D'Antiga, L, Debray, D, Demetris, A, Di Giorgio, A, Evans, H, Fischler, B, Gonzales, E, Gouw, A, Hubscher, S, Jacquemin, E, Lacaille, F, Malenicka, S, Mclin, V, Markiewicz-Kijewska, M, Mazariegos, G, Rajanayagam, J, Scheenstra, R, Singer, S, Smets, F, Sokal, E, Squires, J, Sturm, E, Verkade, H, Kelly, D, Hartleif S., Hodson J., Lloyd C., Cousin V. L., Czubkowski P., D'Antiga L., Debray D., Demetris A., Di Giorgio A., Evans H. M., Fischler B., Gonzales E., Gouw A. S. H., Hubscher S. G., Jacquemin E., Lacaille F., Malenicka S., McLin V. A., Markiewicz-Kijewska M., Mazariegos G. V., Rajanayagam J. K., Scheenstra R., Singer S., Smets F., Sokal E., Squires J. E., Sturm E., Verkade H., and Kelly D. A.

Abstract

Background. The histological prevalence of allograft fibrosis in asymptomatic children after liver transplantation (LT) is well documented. However, long-term graft and patient survival remain unclear. This retrospective multicenter study aims to determine the prevalence of allograft fibrosis and analyze the long-term outcome for patients transplanted in childhood. Methods. We reviewed clinical data of children who had undergone 10-y protocol liver biopsies. We excluded patients with autoimmune hepatitis, primary sclerosing cholangitis, hepatitis B or C, and retransplantation. In total, 494 patients transplanted in childhood across 12 international transplant centers were included. We evaluated the development of fibrosis by comparing the results with biopsies obtained 5 and 15 y post-LT. Histological findings were correlated with graft and patient survival up to 20 y post-LT. Results. In the 10-y biopsies, periportal or pericentral fibrosis was observed in 253 patients (51%), 87 (18%) had bridging fibrosis, 30 (6%) had cirrhosis, and 124 (25%) had no fibrosis. The prevalence and stage of graft fibrosis significantly progressed from 5 to 10 y. At 10 y, the severity of fibrosis correlated significantly with inflammation. Patients with graft cirrhosis in the 10-y biopsy were more likely to die or require retransplantation subsequently (P = 0.027). Conclusions. At 10 y post-LT, most patients transplanted in childhood developed fibrosis, based on the protocol liver biopsies. Although mild-to-moderate graft fibrosis did not largely affect patient or graft survival up to 20 y post-LT, this progressive fibrosis finding has substantial implications for developing cirrhosis and portal hypertension in adult care.

Published
2023

6. Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)—A European Society of Organ Transplantation (ESOT) Consensus Statement

Author

Carbone, M., primary, Della Penna, A., additional, Mazzarelli, C., additional, De Martin, E., additional, Villard, C., additional, Bergquist, A., additional, Line, P. D., additional, Neuberger, J. M., additional, Al-Shakhshir, S., additional, Trivedi, P. J., additional, Baumann, U., additional, Cristoferi, L., additional, Hov, J., additional, Fischler, B., additional, Hadzic, N. H., additional, Debray, D., additional, D’Antiga, L., additional, Selzner, N., additional, Belli, L. S., additional, and Nadalin, S., additional

Published
2023
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7. Severe acute hepatitis and acute liver failure of unknown origin in children: a questionnaire-based study within 34 paediatric liver centres in 22 European countries and Israel, April 2022

Author

de Kleine, R, Lexmond, W, Buescher, G, Sturm, E, Kelly, D, Lohse, A, Lenz, D, Jorgensen, M, Protopapa, P, Shteyer, E, Iorio, R, Pukite, I, Kucinskiene, R, Grima, A, Koot, B, Pop, T, De Bruyne, R, Stephenne, Vukovic, J, Mitrova, K, Kvistgaard, H, Merras-Salmio, L, Hery, G, Debray, D, Ruiz, M, Schulz-Jurgensen, S, Lurz, E, Hives, V, Cananzi, M, D'Antiga, L, di Giorgio, A, Pinon, M, Kaminska, D, Costa, I, Brecelj, J, Bartolo, G, Quintero, J, Fischler, B, Mclin, V, de Kleine R. H., Lexmond W. S., Buescher G., Sturm E., Kelly D., Lohse A. W., Lenz D., Jorgensen M. H., Protopapa P., Shteyer E., Iorio R., Pukite I., Kucinskiene R., Grima A. -M., Koot B., Pop T. L., De Bruyne R., Vukovic J., Mitrova K., Kvistgaard H., Merras-Salmio L., Hery G., Debray D., Ruiz M., Schulz-Jurgensen S., Lurz E., Hives V., Cananzi M., D'Antiga L., di Giorgio A., Pinon M., Kaminska D., Costa I. G., Brecelj J., Bartolo G. M., Quintero J., Fischler B., McLin V., de Kleine, R, Lexmond, W, Buescher, G, Sturm, E, Kelly, D, Lohse, A, Lenz, D, Jorgensen, M, Protopapa, P, Shteyer, E, Iorio, R, Pukite, I, Kucinskiene, R, Grima, A, Koot, B, Pop, T, De Bruyne, R, Stephenne, Vukovic, J, Mitrova, K, Kvistgaard, H, Merras-Salmio, L, Hery, G, Debray, D, Ruiz, M, Schulz-Jurgensen, S, Lurz, E, Hives, V, Cananzi, M, D'Antiga, L, di Giorgio, A, Pinon, M, Kaminska, D, Costa, I, Brecelj, J, Bartolo, G, Quintero, J, Fischler, B, Mclin, V, de Kleine R. H., Lexmond W. S., Buescher G., Sturm E., Kelly D., Lohse A. W., Lenz D., Jorgensen M. H., Protopapa P., Shteyer E., Iorio R., Pukite I., Kucinskiene R., Grima A. -M., Koot B., Pop T. L., De Bruyne R., Vukovic J., Mitrova K., Kvistgaard H., Merras-Salmio L., Hery G., Debray D., Ruiz M., Schulz-Jurgensen S., Lurz E., Hives V., Cananzi M., D'Antiga L., di Giorgio A., Pinon M., Kaminska D., Costa I. G., Brecelj J., Bartolo G. M., Quintero J., Fischler B., and McLin V.

Abstract

To detect potential concern about severe acute hepatitis in children, we conducted a survey among 50 ERN RARE-LIVER centres. By 26 April 2022, 34 centres, including 25 transplant centres, reported an estimated median of 3-5, 0-2 and 3-5 cases in 2021, 2020 and 2019 and a mean of 2 (range: 0-8) cases between January and April 2022 (mean in 10 large liver transplant centres: 3). Twelve centres reported suspicion of an increase, but no rise. Following a report by the United Kingdom (UK) on 5 April 2022 on the occurrence of cases of severe acute hepatitis in children aged 16 years or under, the World Health Organization (WHO) raised concerns about the possibility of an epidemic [1,2]. By 21 April, 169 possible or confirmed cases were reported fulfilling the WHO case definition [3]. The cause of the hepatitis is unknown but a link to a virus infection has been suggested due to the epidemiological pattern of cases [4,5]. The hepatitis can progress to paediatric acute liver failure (pALF) necessitating urgent liver transplantation to avoid multi-organ failure [6]. We intended to assess whether a rise in incidence of severe acute hepatitis or pALF could be observed between 1 January and 26 April 2022 in comparison to previous years, within the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) [7].

Published
2022

8. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study

Author

Vandriel, SM, Li, L-T, She, H, Wang, J-S, Gilbert, MA, Jankowska, I, Czubkowski, P, Gliwicz-Miedzinska, D, Gonzales, EM, Jacquemin, E, Bouligand, J, Spinner, NB, Loomes, KM, Piccoli, DA, D'Antiga, L, Nicastro, E, Sokal, E, Demaret, T, Ebel, NH, Feinstein, JA, Fawaz, R, Nastasio, S, Lacaille, F, Debray, D, Arnell, H, Fischler, B, Siew, S, Stormon, M, Karpen, SJ, Romero, R, Kim, KM, Baek, WY, Hardikar, W, Shankar, S, Roberts, AJ, Evans, HM, Jensen, MK, Kavan, M, Sundaram, SS, Chaidez, A, Karthikeyan, P, Sanchez, MC, Cavalieri, ML, Verkade, HJ, Lee, WS, Squires, JE, Hajinicolaou, C, Lertudomphonwanit, C, Fischer, RT, Larson-Nath, C, Mozer-Glassberg, Y, Arikan, C, Lin, HC, Bernabeu, JQ, Alam, S, Kelly, DA, Carvalho, E, Ferreira, CT, Indolfi, G, Quiros-Tejeira, RE, Bulut, P, Calvo, PL, Onal, Z, Valentino, PL, Desai, DM, Eshun, J, Rogalidou, M, Dezsofi, A, Wiecek, S, Nebbia, G, Pinto, RB, Wolters, VM, Tamara, ML, Zizzo, AN, Garcia, J, Schwarz, K, Beretta, M, Sandahl, TD, Jimenez-Rivera, C, Kerkar, N, Brecelj, J, Mujawar, Q, Rock, N, Busoms, CM, Karnsakul, W, Lurz, E, Santos-Silva, E, Blondet, N, Bujanda, L, Shah, U, Thompson, RJ, Hansen, BE, Kamath, BM, Vandriel, SM, Li, L-T, She, H, Wang, J-S, Gilbert, MA, Jankowska, I, Czubkowski, P, Gliwicz-Miedzinska, D, Gonzales, EM, Jacquemin, E, Bouligand, J, Spinner, NB, Loomes, KM, Piccoli, DA, D'Antiga, L, Nicastro, E, Sokal, E, Demaret, T, Ebel, NH, Feinstein, JA, Fawaz, R, Nastasio, S, Lacaille, F, Debray, D, Arnell, H, Fischler, B, Siew, S, Stormon, M, Karpen, SJ, Romero, R, Kim, KM, Baek, WY, Hardikar, W, Shankar, S, Roberts, AJ, Evans, HM, Jensen, MK, Kavan, M, Sundaram, SS, Chaidez, A, Karthikeyan, P, Sanchez, MC, Cavalieri, ML, Verkade, HJ, Lee, WS, Squires, JE, Hajinicolaou, C, Lertudomphonwanit, C, Fischer, RT, Larson-Nath, C, Mozer-Glassberg, Y, Arikan, C, Lin, HC, Bernabeu, JQ, Alam, S, Kelly, DA, Carvalho, E, Ferreira, CT, Indolfi, G, Quiros-Tejeira, RE, Bulut, P, Calvo, PL, Onal, Z, Valentino, PL, Desai, DM, Eshun, J, Rogalidou, M, Dezsofi, A, Wiecek, S, Nebbia, G, Pinto, RB, Wolters, VM, Tamara, ML, Zizzo, AN, Garcia, J, Schwarz, K, Beretta, M, Sandahl, TD, Jimenez-Rivera, C, Kerkar, N, Brecelj, J, Mujawar, Q, Rock, N, Busoms, CM, Karnsakul, W, Lurz, E, Santos-Silva, E, Blondet, N, Bujanda, L, Shah, U, Thompson, RJ, Hansen, BE, and Kamath, BM

Abstract

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. APPROACH AND RESULTS: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001). CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.

Published
2023

11. Natural history of liver disease in a large international cohort of children with Alagille syndrome: results from The GALA Study

Author

Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Vandriel, S.M.; Li, L.T.; She, H.; Wang, J.S.; Gilbert, M.A.; Jankowska, I.; Czubkowski, P.; Gliwicz-Miedzi?ska, D.; Gonzales, E.M.; Jacquemin, E.; Bouligand, J.; Spinner, N.B.; Loomes, K.M.; Piccoli, D.A.; D'Antiga, L.; Nicastro, E.; Sokal, É.; Demaret, T.; Ebel, N.H.; Feinstein, J.A.; Fawaz, R.; Nastasio, S.; Lacaille, F.; Debray, D.; Arnell, H.; Fischler, B.; Siew, S.; Stormon, M.; Karpen, S.J.; Romero, R.; Kim, K.M.; Baek, W.Y.; Hardikar, W.; Shankar, S.; Roberts, A.J.; Evans, H.M.; Jensen, M.K.; Kavan, M.; Sundaram, S.S.; Chaidez, A.; Karthikeyan, P.; Sanchez, M.C.; Cavalieri, M.L.; Verkade, H.J.; Lee, W.S.; Squires, J.E.; Hajinicolaou, C.; Lertudomphonwanit, C.; Fischer, R.T.; Larson-Nath, C.; Mozer-Glassberg, Y.; Lin, H.C.; Quintero, Bernabeu J.; Alam, S.; Kelly, D.; Carvalho, E.; Ferreira, C.T.; Indolfi, G.; Quiros-Tejeira, R.E.; Bulut, P.; Calvo, P.L.; Önal, Z.; Valentino, P.L.; Desai, D.M.; Eshun, J.; Rogalidou, M.; Dezs?fi, A.; Wiecek, S.; Nebbia, G.; Borges Pinto, R.; Wolters, V.M.; Tamara, M.L.; Zizzo, A.N.; Garcia, J.; Schwarz, K.; Beretta, M.; Sandahl, T.D.; Jimenez-Rivera, C.; Kerkar, N.; Brecelj, J.; Mujawar, Q.; Rock, N.; Busoms, C.M.; Karnsakul, W.; Lurz, E.; Santos-Silva, E.; Blondet, N.; Bujanda, L.; Shah, U.; Thompson, R.J.; Hansen, B.E.; Kamath, B.M.; Global ALagille Alliance (GALA) Study Group, Koç University Hospital, School of Medicine, Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Vandriel, S.M.; Li, L.T.; She, H.; Wang, J.S.; Gilbert, M.A.; Jankowska, I.; Czubkowski, P.; Gliwicz-Miedzi?ska, D.; Gonzales, E.M.; Jacquemin, E.; Bouligand, J.; Spinner, N.B.; Loomes, K.M.; Piccoli, D.A.; D'Antiga, L.; Nicastro, E.; Sokal, É.; Demaret, T.; Ebel, N.H.; Feinstein, J.A.; Fawaz, R.; Nastasio, S.; Lacaille, F.; Debray, D.; Arnell, H.; Fischler, B.; Siew, S.; Stormon, M.; Karpen, S.J.; Romero, R.; Kim, K.M.; Baek, W.Y.; Hardikar, W.; Shankar, S.; Roberts, A.J.; Evans, H.M.; Jensen, M.K.; Kavan, M.; Sundaram, S.S.; Chaidez, A.; Karthikeyan, P.; Sanchez, M.C.; Cavalieri, M.L.; Verkade, H.J.; Lee, W.S.; Squires, J.E.; Hajinicolaou, C.; Lertudomphonwanit, C.; Fischer, R.T.; Larson-Nath, C.; Mozer-Glassberg, Y.; Lin, H.C.; Quintero, Bernabeu J.; Alam, S.; Kelly, D.; Carvalho, E.; Ferreira, C.T.; Indolfi, G.; Quiros-Tejeira, R.E.; Bulut, P.; Calvo, P.L.; Önal, Z.; Valentino, P.L.; Desai, D.M.; Eshun, J.; Rogalidou, M.; Dezs?fi, A.; Wiecek, S.; Nebbia, G.; Borges Pinto, R.; Wolters, V.M.; Tamara, M.L.; Zizzo, A.N.; Garcia, J.; Schwarz, K.; Beretta, M.; Sandahl, T.D.; Jimenez-Rivera, C.; Kerkar, N.; Brecelj, J.; Mujawar, Q.; Rock, N.; Busoms, C.M.; Karnsakul, W.; Lurz, E.; Santos-Silva, E.; Blondet, N.; Bujanda, L.; Shah, U.; Thompson, R.J.; Hansen, B.E.; Kamath, B.M.; Global ALagille Alliance (GALA) Study Group, Koç University Hospital, and School of Medicine

Abstract

Background and aims: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. Approach and results: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced >= 1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and <= 12 months) with median total bilirubin (TB) levels between >= 5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those >= 10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those 10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to >= 5.0 mg/dl, with 79% reaching adulthood with native liver (p < 0.001). Conclusions: in this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies., This study received funding support from the following agencies: The Alagille Syndrome Alliance, Mirum Pharmaceuticals Inc. and Albireo Pharma, Inc. who provided unrestricted educational grants to the Hospital for Sick Children (SickKids Foundation). The study sponsors were not involved in the conduct of the research study or preparation of the manuscript.

Published
2022

12. Proceedings of ESPGHAN Monothematic Conference 2020: 'acute Liver Failure in Children': Diagnosis and Initial Management

Author

Zellos, A. Debray, D. Indolfi, G. Czubkowski, P. Samyn, M. Hadzic, N. Gupte, G. Fischler, B. Smets, F. De Cléty, S.C. Grenda, R. Mozer, Y. Mancell, S. Jahnel, J. Auzinger, G. Worth, A. Lisman, T. Staufner, C. Baumann, U. Dhawan, A. Alonso, E. Squires, R.H. Verkade, H.J.

Abstract

Objectives:The Hepatology Committee of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) aims to educate pediatric gastroenterologists, members of ESPGHAN and professionals from other specialties promoting an exchange of clinical expertise in the field of pediatric hepatology. Herewith we have concentrated on detailing the recent advances in acute liver failure in infants and children.Methods:The 2020 ESPGHAN monothematic three-day conference on pediatric hepatology disease, entitled "acute liver failure" (ALF), was organized in Athens, Greece. ALF is a devastating disease with high mortality and most cases remain undiagnosed. As knowledge in diagnosis and treatment of ALF in infants and children has increased in the past decades, the objective was to update physicians in the field with the latest research and developments in early recognition, curative therapies and intensive care management, imaging techniques and treatment paradigms in these age groups.Results:In the first session, the definition, epidemiology, various causes of ALF, in neonates and older children and recurrent ALF (RALF) were discussed. The second session was dedicated to new aspects of ALF management including hepatic encephalopathy (HE), coagulopathy, intensive care interventions, acute on chronic liver failure, and the role of imaging in treatment and prognosis. Oral presentations by experts in various fields are summarized highlighting key learning points.Conclusions:The current report summarizes the major learning points from this meeting. It also identifies areas where there is gap of knowledge, thereby identifying the research agenda for the near future. © 2022 Lippincott Williams and Wilkins. All rights reserved.

Published
2022

14. Treatment and monitoring of children with chronic hepatitis C in the Pre-DAA era: A European survey of 38 paediatric specialists

Author

Indolfi, G, Bailey, H, Serranti, D, Giaquinto, C, Thorne, C, Sokal, E, Debray, D, Girard, M, Feiterna-Sperling, C, Wirth, S, Guidi, R, Verucchi, G, D'Antiga, L, Nicastro, E, Maggiore, G, Trapani, S, Ricci, S, Resti, M, Giacomet, V, Benincaso, A, Nebbia, G, Iorio, R, Cananzi, M, Riva, S, Bossi, G, Dodi, I, Nobili, V, Comparcola, D, Garazzino, S, Calvo, P, Pokorska-Spiewak, M, Pawlowska, M, Goncalves, C, Goncalves, I, Bals, M, Tudor, A, Noguera-Julian, A, Ramos, J, Fischler, B, Mclin, V, Brown, M, Kelly, D, Davison, S, Turkova, A, Bamford, A, Indolfi G., Bailey H., Serranti D., Giaquinto C., Thorne C., Sokal E., Debray D., Girard M., Feiterna-Sperling C., Wirth S., Guidi R., Verucchi G., D'Antiga L., Nicastro E., Maggiore G., Trapani S., Ricci S., Resti M., Giacomet V., Benincaso A. R., Nebbia G., Iorio R., Cananzi M., Riva S., Bossi G., Dodi I., Nobili V., Comparcola D., Garazzino S., Calvo P. L., Pokorska-Spiewak M., Pawlowska M., Goncalves C., Goncalves I., Bals M., Tudor A. M., Noguera-Julian A., Ramos J. T., Fischler B., McLin V., Brown M., Kelly D., Davison S., Turkova A., Bamford A., Indolfi, G, Bailey, H, Serranti, D, Giaquinto, C, Thorne, C, Sokal, E, Debray, D, Girard, M, Feiterna-Sperling, C, Wirth, S, Guidi, R, Verucchi, G, D'Antiga, L, Nicastro, E, Maggiore, G, Trapani, S, Ricci, S, Resti, M, Giacomet, V, Benincaso, A, Nebbia, G, Iorio, R, Cananzi, M, Riva, S, Bossi, G, Dodi, I, Nobili, V, Comparcola, D, Garazzino, S, Calvo, P, Pokorska-Spiewak, M, Pawlowska, M, Goncalves, C, Goncalves, I, Bals, M, Tudor, A, Noguera-Julian, A, Ramos, J, Fischler, B, Mclin, V, Brown, M, Kelly, D, Davison, S, Turkova, A, Bamford, A, Indolfi G., Bailey H., Serranti D., Giaquinto C., Thorne C., Sokal E., Debray D., Girard M., Feiterna-Sperling C., Wirth S., Guidi R., Verucchi G., D'Antiga L., Nicastro E., Maggiore G., Trapani S., Ricci S., Resti M., Giacomet V., Benincaso A. R., Nebbia G., Iorio R., Cananzi M., Riva S., Bossi G., Dodi I., Nobili V., Comparcola D., Garazzino S., Calvo P. L., Pokorska-Spiewak M., Pawlowska M., Goncalves C., Goncalves I., Bals M., Tudor A. M., Noguera-Julian A., Ramos J. T., Fischler B., McLin V., Brown M., Kelly D., Davison S., Turkova A., and Bamford A.

Abstract

The burden of paediatric Hepatitis C virus (HCV) infection across Europe is unknown, as are current policies regarding monitoring and treatment. This collaborative study aimed to collect aggregate data to characterise the population of ≤18-year-olds with HCV infection in specialist follow up in a 12-month period (2016) across the PENTAHep European consortium, and investigate current policies around monitoring and treatment. A cross-sectional, web-based survey was distributed in April 2017 to 50 paediatricians in 19 European countries, covering patients' profile, and monitoring and treatment practices. Responses were received from 38/50 clinicians collectively caring for 663 children with chronic HCV infection of whom three-quarters were aged ≥6 years and 90% vertically infected. HCV genotype 1 was the most common (n 380; 57.3%), followed by genotype 3, 4 and 2. Seventeen children (3%) with chronic HCV infection were diagnosed with cirrhosis, and six were reported to have received liver transplantation for HCV-related liver disease. The majority (n 425; 64.1%) of the European children with HCV infection remained treatment-naive in 2016. Age affected clinicians' attitudes towards treatment; 94% reported being willing to use direct-acting antivirals, if available, in adolescents (aged ≥11 years), 78% in children aged 6-10 and 42% in those 3-5 years of age (Pearson correlation coefficient −0.98; P 0.0001). This survey provides the largest characterisation of the population of children in clinical follow-up for chronic HCV infection in Europe, alongside important contextual information on their management and treatment. Discussion is needed around strategies and criteria for use of direct-acting antivirals in these children.

Published
2019

15. Similarities and differences in allocation policies for pediatric liver transplantation across the world

Author

Fischler, B, Baumann, U, D'Agostino, D, D'Antiga, L, Dezsofi, A, Debray, D, Durmaz, O, Evans, H, Frauca, E, Hadzic, N, Jahnel, J, Loveland, J, Mclin, V, Ng, V, Nobili, V, Pawłowska, J, Sharif, K, Smets, F, Verkade, H, Hsu, E, Horslen, S, Bucuvalas, J, Fischler B., Baumann U., D'Agostino D., D'Antiga L., Dezsofi A., Debray D., Durmaz O., Evans H., Frauca E., Hadzic N., Jahnel J., Loveland J., McLin V., Ng V. L., Nobili V., Pawłowska J., Sharif K., Smets F., Verkade H. J., Hsu E., Horslen S., Bucuvalas J., Fischler, B, Baumann, U, D'Agostino, D, D'Antiga, L, Dezsofi, A, Debray, D, Durmaz, O, Evans, H, Frauca, E, Hadzic, N, Jahnel, J, Loveland, J, Mclin, V, Ng, V, Nobili, V, Pawłowska, J, Sharif, K, Smets, F, Verkade, H, Hsu, E, Horslen, S, Bucuvalas, J, Fischler B., Baumann U., D'Agostino D., D'Antiga L., Dezsofi A., Debray D., Durmaz O., Evans H., Frauca E., Hadzic N., Jahnel J., Loveland J., McLin V., Ng V. L., Nobili V., Pawłowska J., Sharif K., Smets F., Verkade H. J., Hsu E., Horslen S., and Bucuvalas J.

Abstract

Objectives:We aimed to investigate national allocation policies for pediatric liver transplantation (LT).Method:A survey was prepared by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Hepatology Committee in collaboration with the North American Studies of Pediatric Liver Transplantation consortium. The survey was sent to pediatric hepatologists and transplant surgeons worldwide. National data were obtained from centrally based registries.Results:Replies were obtained from 15 countries from 5 of the world continents. Overall donation rate varied between 9 and 35 per million inhabitants. The number of pediatric LTs was 4 to 9 per million inhabitants younger than 18 years for 13 of the 15 respondents. In children younger than 2 years mortality on the waiting list (WL) varied between 0 and 20%. In the same age group, there were large differences in the ratio of living donor LT to deceased donor LT and in the ratio of split liver segments to whole liver. These differences were associated with possible discrepancies in WL mortality.Conclusions:Similarities but also differences between countries were detected. The described data may be of importance when trying to reduce WL mortality in the youngest children.

Published
2019

17. Impact of genotype, serum bile acids, and surgical biliary diversion on native liver survival in FIC1 deficiency

Author

Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), van Wessel, D. B. E.; Thompson, R. J.; Gonzales, E.; Jankowska, I.; Shneider, B. L.; Sokal, E.; Grammatikopoulos, T.; Kadaristiana, A.; Jacquemin, E.; Spraul, A.; Lipiński, P.; Czubkowski, P.; Rock, N.; Shagrani, M.; Broering, D.; Algoufi, T.; Mazhar, N.; Nicastro, E.; Kelly, D.; Nebbia, G.; Arnell, H.; Fischler, B.; Hulscher, J. B. F.; Serranti, D.; Debray, D.; Lacaille, F.; Goncalves, C.; Hierro, L.; Muñoz Bartolo, G.; Mozer-Glassberg, Y.; Azaz, A.; Brecelj, J.; Dezsőfi, A.; Luigi Calvo, P.; Krebs-Schmitt, D.; Hartleif, S.; van der Woerd, W. L.; Wang, J. S.; Li, L. T.; Durmaz, Ö.; Kerkar, N.; Hørby Jørgensen, M.; Fischer, R.; Jimenez-Rivera, C.; Alam, S.; Cananzi, M.; Laverdure, N.; Ferreira, C. T.; Ordonez, F.; Wang, H.; Sency, V.; Kim, K. M.; Chen, H. L.; Carvalho, E.; Fabre, A.; Quintero Bernabeu, J.; Alonso, E. M.; Sokol, R. J.; Suchy, F. J.; Loomes, K. M.; McKiernan, P. J.; Rosenthal, P.; Turmelle, Y.; Rao, G. S.; Horslen, S.; Kamath, B. M.; Rogalidou, M.; Karnsakul, W. W.; Hansen, B.; Verkade, H. J., Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), and van Wessel, D. B. E.; Thompson, R. J.; Gonzales, E.; Jankowska, I.; Shneider, B. L.; Sokal, E.; Grammatikopoulos, T.; Kadaristiana, A.; Jacquemin, E.; Spraul, A.; Lipiński, P.; Czubkowski, P.; Rock, N.; Shagrani, M.; Broering, D.; Algoufi, T.; Mazhar, N.; Nicastro, E.; Kelly, D.; Nebbia, G.; Arnell, H.; Fischler, B.; Hulscher, J. B. F.; Serranti, D.; Debray, D.; Lacaille, F.; Goncalves, C.; Hierro, L.; Muñoz Bartolo, G.; Mozer-Glassberg, Y.; Azaz, A.; Brecelj, J.; Dezsőfi, A.; Luigi Calvo, P.; Krebs-Schmitt, D.; Hartleif, S.; van der Woerd, W. L.; Wang, J. S.; Li, L. T.; Durmaz, Ö.; Kerkar, N.; Hørby Jørgensen, M.; Fischer, R.; Jimenez-Rivera, C.; Alam, S.; Cananzi, M.; Laverdure, N.; Ferreira, C. T.; Ordonez, F.; Wang, H.; Sency, V.; Kim, K. M.; Chen, H. L.; Carvalho, E.; Fabre, A.; Quintero Bernabeu, J.; Alonso, E. M.; Sokol, R. J.; Suchy, F. J.; Loomes, K. M.; McKiernan, P. J.; Rosenthal, P.; Turmelle, Y.; Rao, G. S.; Horslen, S.; Kamath, B. M.; Rogalidou, M.; Karnsakul, W. W.; Hansen, B.; Verkade, H. J.

Abstract

Mutations in ATP8B1 can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1 (PFIC1). The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide novel insights by using the largest genetically defined cohort of FIC1 deficiency patients to date. This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication); FIC1-A (n=67; no PPTM), FIC1-B (n=29; one PPTM) or FIC1-C (n=34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18y. NLS was comparable between FIC1-A, FIC1-B, and FIC1-C (%NLS at age 10y: 67%, 41%, and 59%, respectively; P=0.12), despite FIC1-C undergoing SBD less often (%SBD at age 10y: 65%, 57%, and 45%, respectively; P=0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10y; sBAs <194 µmol/L: 49% versus sBAs ≥194 µmol/L: 15%; P=0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] μmol/L; P=0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P=0.06) and post-SBD sBA concentrations <65μmol/L (P=0.05) tended to be associated with improved NLS. Conclusion: Less than half of FIC1 deficiency patients reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.

Published
2021

20. Estimating the sample mean and standard deviation from commonly reported quantiles in meta-analysis

Author

McGrath, S, Zhao, X, Steele, R, Thombs, BD, Benedetti, A, Levis, B, Riehm, KE, Saadat, N, Levis, AW, Azar, M, Rice, DB, Sun, Y, Krishnan, A, He, C, Wu, Y, Bhandari, PM, Neupane, D, Imran, M, Boruff, J, Cuijpers, P, Gilbody, S, Ioannidis, JPA, Kloda, LA, McMillan, D, Patten, SB, Shrier, I, Ziegelstein, RC, Akena, DH, Arroll, B, Ayalon, L, Baradaran, HR, Baron, M, Beraldi, A, Bombardier, CH, Butterworth, P, Carter, G, Chagas, MH, Chan, JCN, Cholera, R, Chowdhary, N, Clover, K, Conwell, Y, Ginkel, JMDM-V, Delgadillo, J, Fann, JR, Fischer, FH, Fischler, B, Fung, D, Gelaye, B, Goodyear-Smith, F, Greeno, CG, Hall, BJ, Harrison, PA, Harter, M, Hegerl, U, Hides, L, Hobfoll, SE, Hudson, M, Hyphantis, T, Inagaki, M, Ismail, K, Jette, N, Khamseh, ME, Kiely, KM, Kwan, Y, Lamers, F, Liu, S-I, Lotrakul, M, Loureiro, SR, Loewe, B, Marsh, L, McGuire, A, Sidik, SM, Munhoz, TN, Muramatsu, K, Osorio, FL, Patel, V, Pence, BW, Persoons, P, Picardi, A, Reuter, K, Rooney, AG, Santos, IS, Shaaban, J, Sidebottom, A, Simning, A, Stafford, L, Sung, SC, Tan, PLL, Turner, A, van der Feltz-Cornelis, CM, van Weert, HC, Vohringer, PA, White, J, Whooley, MA, Winkley, K, Yamada, M, Zhang, Y, McGrath, S, Zhao, X, Steele, R, Thombs, BD, Benedetti, A, Levis, B, Riehm, KE, Saadat, N, Levis, AW, Azar, M, Rice, DB, Sun, Y, Krishnan, A, He, C, Wu, Y, Bhandari, PM, Neupane, D, Imran, M, Boruff, J, Cuijpers, P, Gilbody, S, Ioannidis, JPA, Kloda, LA, McMillan, D, Patten, SB, Shrier, I, Ziegelstein, RC, Akena, DH, Arroll, B, Ayalon, L, Baradaran, HR, Baron, M, Beraldi, A, Bombardier, CH, Butterworth, P, Carter, G, Chagas, MH, Chan, JCN, Cholera, R, Chowdhary, N, Clover, K, Conwell, Y, Ginkel, JMDM-V, Delgadillo, J, Fann, JR, Fischer, FH, Fischler, B, Fung, D, Gelaye, B, Goodyear-Smith, F, Greeno, CG, Hall, BJ, Harrison, PA, Harter, M, Hegerl, U, Hides, L, Hobfoll, SE, Hudson, M, Hyphantis, T, Inagaki, M, Ismail, K, Jette, N, Khamseh, ME, Kiely, KM, Kwan, Y, Lamers, F, Liu, S-I, Lotrakul, M, Loureiro, SR, Loewe, B, Marsh, L, McGuire, A, Sidik, SM, Munhoz, TN, Muramatsu, K, Osorio, FL, Patel, V, Pence, BW, Persoons, P, Picardi, A, Reuter, K, Rooney, AG, Santos, IS, Shaaban, J, Sidebottom, A, Simning, A, Stafford, L, Sung, SC, Tan, PLL, Turner, A, van der Feltz-Cornelis, CM, van Weert, HC, Vohringer, PA, White, J, Whooley, MA, Winkley, K, Yamada, M, and Zhang, Y

Abstract

Researchers increasingly use meta-analysis to synthesize the results of several studies in order to estimate a common effect. When the outcome variable is continuous, standard meta-analytic approaches assume that the primary studies report the sample mean and standard deviation of the outcome. However, when the outcome is skewed, authors sometimes summarize the data by reporting the sample median and one or both of (i) the minimum and maximum values and (ii) the first and third quartiles, but do not report the mean or standard deviation. To include these studies in meta-analysis, several methods have been developed to estimate the sample mean and standard deviation from the reported summary data. A major limitation of these widely used methods is that they assume that the outcome distribution is normal, which is unlikely to be tenable for studies reporting medians. We propose two novel approaches to estimate the sample mean and standard deviation when data are suspected to be non-normal. Our simulation results and empirical assessments show that the proposed methods often perform better than the existing methods when applied to non-normal data.

Published
2020

25. Early and Late Factors Impacting Patient and Graft Outcome in Pediatric Liver Transplantation: Summary of an ESPGHAN Monothematic Conference

Author

Mclin, V, Allen, U, Boyer, O, Bucuvalas, J, Colledan, M, Cuturi, M, D'Antiga, L, Debray, D, Dezsofi, A, de Goyet, J, Dhawan, A, Durmaz, O, Falk, C, Feng, S, Fischler, B, Franchi-Abella, S, Frauca, E, Ganschow, R, Gottschalk, S, Hadzic, N, Hierro, L, Horslen, S, Hubscher, S, Karam, V, Kelly, D, Maecker-Kolhoff, B, Mazariegos, G, Mckiernan, P, Melk, A, Nobili, V, Ozgenc, F, Reding, R, Sciveres, M, Sharif, K, Socha, P, Toso, C, Vajro, P, Verma, A, Wildhaber, B, Baumann, U, Mclin VA, Allen U, Boyer O, Bucuvalas J, Colledan M, Cuturi MC, d'Antiga L, Debray D, Dezsofi A, de Goyet JD, Dhawan A, Durmaz O, Falk C, Feng S, Fischler B, Franchi-Abella S, Frauca E, Ganschow R, Gottschalk S, Hadzic N, Hierro L, Horslen S, Hubscher S, Karam V, Kelly D, Maecker-Kolhoff B, Mazariegos G, McKiernan P, Melk A, Nobili V, Ozgenc F, Reding R, Sciveres M, Sharif K, Socha P, Toso C, Vajro P, Verma A, Wildhaber BE, Baumann U, Mclin, V, Allen, U, Boyer, O, Bucuvalas, J, Colledan, M, Cuturi, M, D'Antiga, L, Debray, D, Dezsofi, A, de Goyet, J, Dhawan, A, Durmaz, O, Falk, C, Feng, S, Fischler, B, Franchi-Abella, S, Frauca, E, Ganschow, R, Gottschalk, S, Hadzic, N, Hierro, L, Horslen, S, Hubscher, S, Karam, V, Kelly, D, Maecker-Kolhoff, B, Mazariegos, G, Mckiernan, P, Melk, A, Nobili, V, Ozgenc, F, Reding, R, Sciveres, M, Sharif, K, Socha, P, Toso, C, Vajro, P, Verma, A, Wildhaber, B, Baumann, U, Mclin VA, Allen U, Boyer O, Bucuvalas J, Colledan M, Cuturi MC, d'Antiga L, Debray D, Dezsofi A, de Goyet JD, Dhawan A, Durmaz O, Falk C, Feng S, Fischler B, Franchi-Abella S, Frauca E, Ganschow R, Gottschalk S, Hadzic N, Hierro L, Horslen S, Hubscher S, Karam V, Kelly D, Maecker-Kolhoff B, Mazariegos G, McKiernan P, Melk A, Nobili V, Ozgenc F, Reding R, Sciveres M, Sharif K, Socha P, Toso C, Vajro P, Verma A, Wildhaber BE, and Baumann U

Abstract

As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications. Copyright © 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Published
2017

41. Treatment of Chronic Hepatitis C Virus Infection in Children. A Position Paper by the Hepatology Committee of European Society of Paediatric Gastroenterology, Hepatology and Nutrition.

Author

UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Indolfi, G, Hierro, L., Jahnel, J., Debray, D., Hadzic, N., Czubowski, P., Gupte, G, Mozer-Glassberg, Y., Van der Woerd, W., Smets, Françoise, Verkade, HJ, Fischler, B, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Indolfi, G, Hierro, L., Jahnel, J., Debray, D., Hadzic, N., Czubowski, P., Gupte, G, Mozer-Glassberg, Y., Van der Woerd, W., Smets, Françoise, Verkade, HJ, and Fischler, B

Abstract

OBJECTIVES: In 2017, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) approved the use of the fixed-dose combination of ledipasvir/sofosbuvir and of the combination of sofosbuvir and ribavirin for treatment of adolescents (12-17 years, weighing more than 35 kg) with chronic hepatitis C virus (HCV) genotype 1, 4, 5 and 6 and genotype 2 and 3 infections, respectively. Although trials with direct acting antivirals (DAAs) are ongoing for younger children, the only available treatment in US and Europe for those < 12 years is still the dual therapy of pegylated interferon (PEG IFN) and ribavirin. There is currently a lack of a systematic approach to the care of these patients. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) developed an evidence-based position paper for the management of chronic HCV infection in children. METHODS: A systematic literature search and meta-analysis were performed using MEDLINE and Embase from June 1, 2007 to June 1, 2017. The approach of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was applied to evaluate outcomes. ESPGHAN Hepatology Committee members voted on each recommendation, using the nominal voting technique. RESULTS: The efficacy of the different DAAs combinations tested was higher, the relapse and the treatment discontinuation rates lower when compared to PEG IFN and ribavirin. CONCLUSIONS: This position paper addresses therapeutic management issues including goals, endpoints, indications, contra-indications and the optimal treatment regimen in children with chronic HCV infection.

Published
2018

42. Transition of adolescents with pediatric-onset hepatobiliary diseases: systematic review of literature

Author

UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Guercio Nuzio, S., Fischler, B., Baumann, U., Burra, P., Debray, D., Dezsofi, A., Hadzic, N., Hierro, L., Jahnel, J., Lamirau, Th., McKiernan, P., McLin, V., Nobili, v., Smets, F., Socha, P., Verkade, HJ, Vajro P., 50th Annual Meeting ESPGHAN, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Guercio Nuzio, S., Fischler, B., Baumann, U., Burra, P., Debray, D., Dezsofi, A., Hadzic, N., Hierro, L., Jahnel, J., Lamirau, Th., McKiernan, P., McLin, V., Nobili, v., Smets, F., Socha, P., Verkade, HJ, Vajro P., and 50th Annual Meeting ESPGHAN

Abstract

Objectives and Study: Long-term prognosis of adolescents with chronic paediatric-onset hepatobiliary diseases (POHD) has dramatically improved in recent decades. Since there is no accepted pathway of care for transition from paediatric (P) to adult (A) hepatologists, we aimed to provide a) a systematic review of literature, and b) an analysis of existing information derived from documents borrowed from other chronic diseases transition experiences. Method: Out of 657 screened studies published between 1980 and August 2017, identified on Pubmed and Google Scholar by means of keywords (“transition of care” or “health care” and “pediatrics” or “adolescence” or “young adults”), 87 were considered appropriate to be evaluated with the GRADE system (Grading of Recommendations Assessment, Development and Evaluation). Evaluation of international corporate documents included American Academy of Paediatrics, Got transition, ON TRAC (Transitioning Responsibly to Adult Care), Good 2 Go, Stepping Up, National Institute for Health and Care Excellence guidelines. Results: Existing models of transition have rarely been assessed in randomized controlled trials (RCTs) with outcomes' measurements. Eighty-five per cent of the retrieved studies have a low level of evidence (C/D) according to GRADE system. Consistent with them, transition is generally defined as an active and evolving process that may benefit from a unified approach by P/A staff. Timing of transition should consider the young person's mental and physical development, the socio-economic family circumstances, and the availability of A physicians rather than chronological age only (usually 18 years). Although only 50% of the programs have performed a valid assessment of adolescents readiness for self-empowerment, it is accepted that early training predicts a successful transition. To implement an effective program, a well-coordinated multi-professional team and a integrated and multidisciplinary approach, is requested. Sever

Published
2018

43. Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations.

Author

Andersson, ER, Chivukula, IV, Hankeova, S, Sjöqvist, M, Tsoi, YL, Ramsköld, D, Masek, J, Elmansuri, A, Hoogendoorn, A, Vazquez, E, Storvall, H, Netušilová, J, Huch, M, Fischler, B, Ellis, E, Contreras, A, Nemeth, A, Chien, KC, Clevers, H, Sandberg, R, Bryja, V, Lendahl, U, Andersson, ER, Chivukula, IV, Hankeova, S, Sjöqvist, M, Tsoi, YL, Ramsköld, D, Masek, J, Elmansuri, A, Hoogendoorn, A, Vazquez, E, Storvall, H, Netušilová, J, Huch, M, Fischler, B, Ellis, E, Contreras, A, Nemeth, A, Chien, KC, Clevers, H, Sandberg, R, Bryja, V, and Lendahl, U

Abstract

BACKGROUND & AIMS: Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations. Most cases are associated with mutations in JAGGED1 (JAG1), which encodes a Notch ligand, although it is not clear how these contribute to disease development. We aimed to develop a mouse model of Alagille syndrome to elucidate these mechanisms. METHODS: Mice with a missense mutation (H268Q) in Jag1 (Jag1+/Ndr mice) were outbred to a C3H/C57bl6 background to generate a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice). Liver tissues were collected at different timepoints during development, analyzed by histology, and liver organoids were cultured and analyzed. We performed transcriptome analysis of Jag1Ndr/Ndr livers and livers from patients with Alagille syndrome, cross-referenced to the Human Protein Atlas, to identify commonly dysregulated pathways and biliary markers. We used species-specific transcriptome separation and ligand-receptor interaction assays to measure Notch signaling and the ability of JAG1Ndr to bind or activate Notch receptors. We studied signaling of JAG1 and JAG1Ndr via NOTCH 1, NOTCH2, and NOTCH3 and resulting gene expression patterns in parental and NOTCH1-expressing C2C12 cell lines. RESULTS: Jag1Ndr/Ndr mice had many features of Alagille syndrome, including eye, heart, and liver defects. Bile duct differentiation, morphogenesis, and function were dysregulated in newborn Jag1Ndr/Ndr mice, with aberrations in cholangiocyte polarity, but these defects improved in adult mice. Jag1Ndr/Ndr liver organoids collapsed in culture, indicating structural instability. Whole-transcriptome sequence analyses of liver tissues from mice and patients with Alagille syndrome identified dysregulated genes encoding proteins enriched at the apical side of cholangiocytes, including CFTR and SLC5A1, as well as reduced expression of IGF1. Exposure of Notch-expressing cells to JAG

Published
2018

44. Living Planet Report 2018: Aiming Higher

Author

Barrett, M., Belward, A., Bladen, S, Breeze, T., Burgess, N., Butchart, S., Clewclow, H., Cornell, S., Cottam, A., Croft, S., de Carlo, G., de Felice, L., de Palma, A., Deinet, S., Downie, R., Drijver, C., Fischler, B., Freeman, R., Gaffney, O., Galli, A, Gamblin, P., Garratt, M., Gorelick, N., Green, J., Grooten, M., Hanscom, L., Hill, S., Hilton-Taylor, C., Jones, A., Juniper, T., Khan, H., Kroodsma, D., Leclere, D., Llewellyn, G., Mace, G., McRae, L., Mo, K., Opperman, J., Orgiazzi, A., Orr, S., Pacheco, P., Palomares, D., Pauly, D., Pekel, J.-F., Pendleton, L., Purvis, A., Radcliffe, N., Roxburgh, T., Scholes, B, Senapathi, D., Tanzer, D., Thieme, M., Tickner, D., Tittonell, P., Trathan, P., Visconti, P., Wackernagel, M., West, C., Zwaal, N., Barrett, M., Belward, A., Bladen, S, Breeze, T., Burgess, N., Butchart, S., Clewclow, H., Cornell, S., Cottam, A., Croft, S., de Carlo, G., de Felice, L., de Palma, A., Deinet, S., Downie, R., Drijver, C., Fischler, B., Freeman, R., Gaffney, O., Galli, A, Gamblin, P., Garratt, M., Gorelick, N., Green, J., Grooten, M., Hanscom, L., Hill, S., Hilton-Taylor, C., Jones, A., Juniper, T., Khan, H., Kroodsma, D., Leclere, D., Llewellyn, G., Mace, G., McRae, L., Mo, K., Opperman, J., Orgiazzi, A., Orr, S., Pacheco, P., Palomares, D., Pauly, D., Pekel, J.-F., Pendleton, L., Purvis, A., Radcliffe, N., Roxburgh, T., Scholes, B, Senapathi, D., Tanzer, D., Thieme, M., Tickner, D., Tittonell, P., Trathan, P., Visconti, P., Wackernagel, M., West, C., and Zwaal, N.

Published
2018

45. Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition

Author

Socha, P, Janczyk, W, Dhawan, A, Baumann, U, D'Antiga, L, Tanner, S, Iorio, R, Vajro, P, Houwen, R, Fischler, B, Dezsofi, A, Hadzic, N, Hierro, L, Jahnel, J, Mclin, V, Nobili, V, Smets, F, Verkade, H, Debray, D, McLin, V, Verkade, HJ, Socha, P, Janczyk, W, Dhawan, A, Baumann, U, D'Antiga, L, Tanner, S, Iorio, R, Vajro, P, Houwen, R, Fischler, B, Dezsofi, A, Hadzic, N, Hierro, L, Jahnel, J, Mclin, V, Nobili, V, Smets, F, Verkade, H, Debray, D, McLin, V, and Verkade, HJ

Abstract

Background: Clinical presentations of Wilson's disease (WD) in childhood ranges from asymptomatic liver disease to cirrhosis or acute liver failure, whereas neurological and psychiatric symptoms are rare. The basic diagnostic approach includes serum ceruloplasmin and 24-hour urinary copper excretion. Final diagnosis of WD can be established using a diagnostic scoring system based on symptoms, biochemical tests assessing copper metabolism, and molecular analysis of mutations in the ATP7B gene. Pharmacological treatment is life-long and aims at removal of copper excess by chelating agents as D-penicillamine, trientine, or inhibition of intestinal copper absorption with zinc salts. Acute liver failure often requires liver transplantation. This publication aims to provide recommendations for diagnosis, treatment, and follow-up of WD in children. Methods: Questions addressing the diagnosis, treatment, and follow-up of WD in children were formulated by a core group of ESPGHAN members. A systematic literature search on WD using MEDLINE, EMBASE, Cochrane Database from 1990 to 2016 was performed focusing on prospective and retrospective studies in children. Quality of evidence was assessed according to the GRADE system. Expert opinion supported recommendations where the evidence was regarded as weak. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using the nominal voting technique.

Published
2018

46. Chronic graft injury and long-term outcome after paediatric liver transplantation

Author

Hartleif, S., Rajanayagam, J., Cousin, V., Debray, D., Demetris, A. J., Evans, H., Fischler, B., Gonzales, E., Gouw, A., Haller, W., Hubscher, S., Lacaille, F., Malenicka, S., McLin, V., Mazariegos, G., Scheenstra, R., Squires, J., Verkade, H., Kelly, D., Sturm, E., Groningen Institute for Organ Transplantation (GIOT), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Lifestyle Medicine (LM)

Published
2017

47. The natural course of FIC1 deficiency and BSEP deficiency: Initial results from the NAPPED-consortium (Natural course and Prognosis of PFIC and Effect of biliary Diversion)

Author

van Wessel, D., primary, Thompson, R., additional, Grammatikopoulos, T., additional, Kadaristiana, A., additional, Jankowska, I., additional, Lipiński, P., additional, Czubkowski, P., additional, Gonzales, E., additional, Jacquemin, E., additional, Spraul, A., additional, Sokal, E., additional, Shagrani, M.A., additional, Broering, D.C., additional, Algoufi, T., additional, Mazhar, N., additional, Nicastro, E., additional, Kelly, D., additional, Nebbia, G., additional, Arnell, H., additional, Fischler, B., additional, Sankaranarayanan, S., additional, Hulscher, J., additional, Serranti, D., additional, Arikan, C., additional, Polat, E., additional, Debray, D., additional, Lacaille, F., additional, Goncalves, C., additional, Hierro, L., additional, Bartolo, G.M., additional, Mozer-Glassberg, Y., additional, Azaz, A., additional, Brecelj, J., additional, Dezsőfi, A., additional, Calvo, P.L., additional, Pizzol, A., additional, Schmitt, D., additional, Sturm, E., additional, van der Woerd, W., additional, Hansen, B., additional, and Verkade, H., additional

Published
2018
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48. Correlation of autotaxin levels, serum bile acids, and pruritus in a multiple-dose, open-label, multinational study of the ileal bile acid transport inhibitor A4250

Author

Gonzales, E., primary, Sturm, E., additional, Baumann, U., additional, Lacaille, F., additional, Arnell, H., additional, Fischler, B., additional, Jørgensen, M.H., additional, Thompson, R., additional, Mattsson, J., additional, Ekelund, M., additional, Lindstrom, E., additional, Gillberg, P.-G., additional, Torfgard, K., additional, and Soni, P., additional

Published
2018
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50. Impaired intention-to-treat survival after listing for liver transplantation in children with biliary atresia compared to other chronic liver diseases: 20 years’ experience from the Nordic countries

Author

Malenicka, S., primary, Ericzon, B.-G., additional, Jørgensen, M. H., additional, Isoniemi, H., additional, Karlsen, T. H., additional, Krantz, M., additional, Naeser, V., additional, Olausson, M., additional, Rasmussen, A., additional, Rönnholm, K., additional, Sanengen, T., additional, Scholz, T., additional, Fischler, B., additional, and Nemeth, A., additional

Published
2016
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