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1. Classical autoimmune hepatitis and the IgG4-associated autoimmune hepatitis in paediatric patients

Author

Dominika Kaps-Kopiec, Małgorzata Woźniak, Dorota Jarzębicka, Renata Grzywa-Czuba, Joanna Pawłowska, Piotr Czubkowski, and Joanna Cielecka-Kuszyk

Subjects
autoimmune hepatitis, immunoglobulin g4-related diseases, children, Medicine
Abstract

The IgG4-associated autoimmune hepatitis (IgG4-AIH) is a newly proposed disease entity characterised by the accumulation of the IgG4-expressing plasma cells in the liver. Its pathophysiology and clinical significance remain unclear and have poor evidence in the paediatric population. Thus, our study aims at comparing the group of paediatric patients with classical AIH and the IgG4-AIH. We carried out a retrospective analysis of 23 children (median age 8.5 years) diagnosed with AIH, who were compared according to the presence of IgG4-positive plasma cells in the liver biopsy. IgG4-AIH was defined if 10 or more IgG4 positive plasma cells/high-power field were found in the biopsy. The presence of the IgG4 component seems to be clinically insignificant. That is why, the conventional immunosuppressive protocol should be considered the standard treatment in the case of the IgG4-associated AIH.

Published
2024
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2. 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

3. Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis

Author

Richard J. Thompson, Reha Artan, Ulrich Baumann, Pier Luigi Calvo, Piotr Czubkowski, Buket Dalgic, Lorenzo D’Antiga, Angelo Di Giorgio, Özlem Durmaz, Emmanuel Gonzalès, Tassos Grammatikopoulos, Girish Gupte, Winita Hardikar, Roderick H.J. Houwen, Binita M. Kamath, Saul J. Karpen, Florence Lacaille, Alain Lachaux, Elke Lainka, Kathleen M. Loomes, Cara L. Mack, Jan P. Mattsson, Patrick McKiernan, Quanhong Ni, Hasan Özen, Sanjay R. Rajwal, Bertrand Roquelaure, Eyal Shteyer, Etienne Sokal, Ronald J. Sokol, Nisreen Soufi, Ekkehard Sturm, Mary Elizabeth Tessier, Wendy L. van der Woerd, Henkjan J. Verkade, Jennifer M. Vittorio, Terese Wallefors, Natalie Warholic, Qifeng Yu, Patrick Horn, and Lise Kjems

Subjects
Liver diseases, Bile acids and salts, Clinical trial, Enterohepatic circulation, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 μg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22–24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0–4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22–24 of PEDFIC 2 in sBAs was -201 μmol/L (p

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

Author

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

Subjects
BSEP, PFIC2, compound heterozygosity, interruption of the enterohepatic circulation, genotype, phenotype, Diseases of the digestive system. Gastroenterology, RC799-869
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

Published
2023
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5. Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies.

Author

Bull, Laura N, Pawlikowska, Ludmila, Strautnieks, Sandra, Jankowska, Irena, Czubkowski, Piotr, Dodge, Jennifer L, Emerick, Karan, Wanty, Catherine, Wali, Sami, Blanchard, Samra, Lacaille, Florence, Byrne, Jane A, van Eerde, Albertien M, Kolho, Kaija-Leena, Houwen, Roderick, Lobritto, Steven, Hupertz, Vera, McClean, Patricia, Mieli-Vergani, Giorgina, Sokal, Etienne, Rosenthal, Philip, Whitington, Peter F, Pawlowska, Joanna, and Thompson, Richard J

Abstract

Progressive familial intrahepatic cholestasis (PFIC) with normal circulating gamma-glutamyl transpeptidase levels can result from mutations in the ATP8B1 gene (encoding familial intrahepatic cholestasis 1 [FIC1] deficiency) or the ABCB11 gene (bile salt export protein [BSEP] deficiency). We investigated the outcomes of partial external biliary diversion, ileal exclusion, and liver transplantation in these two conditions. We conducted a retrospective multicenter study of 42 patients with FIC1 deficiency (FIC1 patients) and 60 patients with BSEP deficiency (BSEP patients) who had undergone one or more surgical procedures (57 diversions, 6 exclusions, and 57 transplants). For surgeries performed prior to transplantation, BSEP patients were divided into two groups, BSEP-common (bearing common missense mutations D482G or E297G, with likely residual function) and BSEP-other. We evaluated clinical and biochemical outcomes in these patients. Overall, diversion improved biochemical parameters, pruritus, and growth, with substantial variation in individual response. BSEP-common or FIC1 patients survived longer after diversion without developing cirrhosis, being listed for or undergoing liver transplantation, or dying, compared to BSEP-other patients. Transplantation resolved cholestasis in all groups. However, FIC1 patients commonly developed hepatic steatosis, diarrhea, and/or pancreatic disease after transplant accompanied by biochemical abnormalities and often had continued poor growth. In BSEP patients with impaired growth, this generally improved after transplantation. Conclusion: Diversion can improve clinical and biochemical status in FIC1 and BSEP deficiencies, but outcomes differ depending on genetic etiology. For many patients, particularly BSEP-other, diversion is not a permanent solution and transplantation is required. Although transplantation resolves cholestasis in patients with FIC1 and BSEP deficiencies, the overall outcome remains unsatisfactory in many FIC1 patients; this is mainly due to extrahepatic manifestations. (Hepatology Communications 2018;2:515-528).

Published
2018

6. European Guideline on IgG4-related Digestive Disease — UEG and SGF Evidence-based Recommendations

Author

J.-M. Lohr, U. Beuers, M. Vujasinovic, D. Alvaro, J. B. Frøkjær, F. Buttgereit, G. Capurso, E. L. Culver, E. de-Madaria, E. Della-Torre, S. Detlefsen, E. Dominguez-Munoz, P. Czubkowski, N. Ewald, L. Frulloni, N. Gubergrits, D. G. Duman, Th. Hackert, J. Iglesias-Garcia, N. Kartalis, A. Laghi, F. Lammert, F. Lindgren, A. Okhlobystin, G. Oracz, A. Parniczky, R. M. P. Mucelli, V. Rebours, J. Rosendahl, N. Schleinitz, A. Schneider, E. FH van Bommel, C. S. Verbeke, M. P. Vullierme, H. Witt, and the UEG guideline working group

Subjects
igg4-related, digestive, disease, glucocorticoids, other organ involvement, biomarkers, autoimmune pancreatitis type 1, immune-related cholangitis, cancer, diabetes mellitus, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6-0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2-4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added.

Published
2021

7. Case Report: Liver as a Source of Hematopoietic Stem Cells After Liver Transplantation Following Hematopoietic Stem Cell Transplantation

Author

Tomasz Jarmoliński, Monika Rosa, Blanka Rybka, Renata Ryczan-Krawczyk, Kornelia Gajek, Katarzyna Bogunia-Kubik, Maja Klaudel-Dreszler, Piotr Czubkowski, Piotr Kaliciński, Joanna Teisseyre, Marek Stefanowicz, Ewa Gorczyńska, Krzysztof Kałwak, and Marek Ussowicz

Subjects
Fanconi anemia, liver transplantation, pediatric, hematopoiesis, graft-versus-host disease (GVHD), Pediatrics, RJ1-570
Abstract

We report a child with Fanconi anemia who, after hematopoietic stem cell transplantation (HSCT) complicated by acute graft-versus-host disease (GVHD), underwent orthotopic liver transplantation (OLT). Approximately 1 month after OLT, the presence of third-party genetic material from the liver donor was noted and in the next few weeks, the chimerism assessment revealed 100% liver donor leukocytes in the peripheral blood. The rapidly progressing GVHD with gut involvement resulted in patient’s death 6 months after OLT. The liver can act as a clinically significant source of hematopoietic stem cells, and the liver donor’s young age must be emphasized as potentially predisposing to this phenomenon. Transfer of OLT hematopoietic stem cells may not have clinical significance unless the patient is not immunocompetent or develops liver-transplantation associated GVHD, that can result in lymphocyte mediated elimination of original hematopoiesis. Patients with preexisting immunity disorder (such as primary or secondary immunodeficiency) might require intensified immunosuppressive therapy in peritransplant period as a prevention of liver-transplantation associated GVHD. Close monitoring of hematopoietic chimerism after OLT is warranted in patients at risk, because cytopenia or OLT hematopoiesis can reflect subclinical GVHD and further studies are necessary to elucidate this phenomenon.

Published
2022
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8. Case Report: Sequential Liver After Kidney Transplantation in a Patient With Sensenbrenner Syndrome (Cranioectodermal Dysplasia)

Author

Joanna Ryżko, Joanna Walczak-Sztulpa, Piotr Czubkowski, Anna Latos-Bieleńska, Adam Kowalski, Marek Stefanowicz, Wioletta Jarmużek, Ryszard Grenda, and Joanna Pawłowska

Subjects
ciliopathy, Sensenbrenner syndrome (cranioectodermal dysplasia), renal failure, liver disease, kidney and liver transplantation, Pediatrics, RJ1-570
Abstract

Sensenbrenner syndrome, also known as cranioectodermal dysplasia (CED), is a rare ciliopathy clinically characterized by congenital craniofacial, skeletal, and ectodermal defects. Chronic kidney and liver insufficiency are also present in this disorder. Cranioectodermal dysplasia is an autosomal recessive and heterogeneous genetic disease. Six genes (IFT122, WDR35, IFT140, IFT43, IFT52, and WDR19) are known to be associated with this syndrome. Until 2021 more than 70 patients have been reported with CED, however, an orthotopic liver transplantation has been reported only in one case. Here, we present a case report of sequential liver-after-kidney transplantation in a male patient affected by CED. The kidney and liver transplantation was performed at the age of 7 and 12 years, respectively. Patients with Sensenbrenner syndrome require a multidisciplinary medical management and should regularly be followed-up by hepatologists and nephrologists, as the liver and kidney diseases are the major cause of morbidity and mortality.

Published
2022
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10. 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

11. 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

12. Awareness, referral and age at Kasai surgery for biliary atresia in Europe: A survey of the Quality‐of‐Care Task Force of ESPGHAN

Author

Lacaille, Florence, Nicastro, Emanuele, Czubkowski, Piotr, Gonçalves, Cristina Campos, Le Thi, Thu Giang, and Koletzko, Sibylle

Abstract

To identify infants with biliary atresia (BA), European Society of Paediatric Gastroenteroloy and Nutrition (ESPGHAN)/North American Society of Pediatric Gastroenteroloy and Nutrition (NASPGHAN) guidelines recommend measurement of conjugated/direct bilirubin in infants with prolonged jaundice and using a stool colour card (SCC). The ‘Quality of Care’ Task Force of ESPGHAN performed two surveys to assess current case finding for BA and age at Kasai portoenterostomy (KPE). The first survey approached 26 European hepatology centres to report age at referral and age at KPE of all infants diagnosed with BA from 2015 to 2019. The second survey targeted paediatricians in France to assess awareness and compliance with the recently introduced SCC. Data from 785 patients with BA from 18 centres in 15 countries revealed a mean age at referral to tertiary centre of 55 days (median 53, IQR 48–60) (n= 636). The mean age at KPE was 61 days (median 60; IQR 54–67) (n= 772). For 6% of patients, cirrhosis was too advanced for surgery. Of 392 paediatricians answering the second survey, 53% felt familiar with the target diseases, 80% correctly identified cholestasis and 59% always inquired about the infant's stool colour. If abnormal, 93% would order blood tests and 85% call for advice. The SCC screening was considered helpful for case finding and improving knowledge of cholestatic diseases by 62% and 45% paediatricians, respectively. Referral of infants for KPE remains late, indicating low adherence to search for cholestasis in icteric infants by age 2−3 weeks. Knowledge and structures need improvement to allow earlier guideline conform case finding, diagnosis and therapy. Timely diagnosis and Kasai hepatoportoenterostomy in infants with biliary atresia (BA) is vital to improve survival and to avoid complications and liver transplantation.Prolonged jaundice (>2 weeks) in exclusively breastfed babies is common and mostly benign. The risk of missing cholestatic diseases without structured screening is high.The European Society of Paediatric Gastroenteroloy and Nutrition (ESPGHAN)/North American Society of Pediatric Gastroenteroloy and Nutrition (NASPGHAN) guidelines recommend to measure total/conjugated bilirubin in all neonates with prolonged jaundice, if breastfed latest by 3 weeks of age. Timely diagnosis and Kasai hepatoportoenterostomy in infants with biliary atresia (BA) is vital to improve survival and to avoid complications and liver transplantation. Prolonged jaundice (>2 weeks) in exclusively breastfed babies is common and mostly benign. The risk of missing cholestatic diseases without structured screening is high. The European Society of Paediatric Gastroenteroloy and Nutrition (ESPGHAN)/North American Society of Pediatric Gastroenteroloy and Nutrition (NASPGHAN) guidelines recommend to measure total/conjugated bilirubin in all neonates with prolonged jaundice, if breastfed latest by 3 weeks of age. Our survey covering >50% of infants diagnosed with BA from 2015 to 2019 in the European Union, UK and Switzerland disclosed a mean age at Kasai surgery of 60 days, similar to results obtained in Europe 10–30 years earlier.Screening with a stool colour card improves awareness, but additional efforts are required to reduce the age at Kasai surgery below 30 days. Our survey covering >50% of infants diagnosed with BA from 2015 to 2019 in the European Union, UK and Switzerland disclosed a mean age at Kasai surgery of 60 days, similar to results obtained in Europe 10–30 years earlier. Screening with a stool colour card improves awareness, but additional efforts are required to reduce the age at Kasai surgery below 30 days.

Published
2024
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13. Anthropometric assessment: ESPGHAN quality of care survey from paediatric hospitals in 28 European countries

Author

Litwin, Anna, Le Thi, Thu Giang, Pancheva, Rouzha, Niseteo, Tena, Hauer, Almuthe Christina, Kindermann, Angelika, Lacaille, Florence, Nicastro, Emanuele, Czubkowski, Piotr, Ikrath, Katharina, Gerasimidis, Konstantinos, and Koletzko, Sibylle

Abstract

Assessment of anthropometric data is essential for paediatric healthcare. We surveyed the implementation of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) evidence‐based guidelines and practical recommendations on nutritional care, particularly regarding anthropometric measurements. Paediatric hospitals from 28 European countries provided pseudonymized data through online questionnaires on hospital characteristics and their standards of nutritional care. Practical tasks assessed an unbiased collection and reporting of anthropometric measurements in random patients' files and discharge letters. Of 114 hospitals (67% academic), 9% have no nutritionist/dietitian available, 18% do not provide standard policy to assess weight and height and 15% lack training for nursing staff for accurate performance. A wall‐mounted stadiometer to measure standing height and equipment for sitting weight is unavailable in 9% and 32%, respectively. Infant length is measured by one instead of two healthcare professionals and with a tape instead of a rigid length measuring board in 58% and 15% of hospitals, respectively. The practical tasks reviewed 1414 random patients, thereof 446 younger than 2 years of age. Missing documentation occurred significantly more often for height versus weight and their percentiles in infants ≤2 years versus older children, and in general paediatric versus gastrointestinal patients, with no difference between academic and nonacademic hospitals. Review of documented anthropometric data in discharge letters disclosed that consultants significantly underestimated the deficits in their units compared to documented data. The survey revealed significant gaps in performance and documentation of anthropometry in the participating hospitals. A resurvey will assess changes in quality of care over time. Assessment of nutritional status is essential for paediatric healthcare.Accurate measurement of weight, length/height and head circumference and plotting on percentiles are mandatory for nutritional assessment.Data are scarce regarding availability of tools for nutritional assessment and performance of anthropometry in routine practice in paediatric hospitals in Europe. Assessment of nutritional status is essential for paediatric healthcare. Accurate measurement of weight, length/height and head circumference and plotting on percentiles are mandatory for nutritional assessment. Data are scarce regarding availability of tools for nutritional assessment and performance of anthropometry in routine practice in paediatric hospitals in Europe. The Quality of Care Survey of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) identified some deficits in performance and reporting of anthropometric assessment, unrelated to hospital size or type (academic/nonacademic).Physicians/consultants appear often unaware of the identified gaps.Implementing standard operation procedures, training healthcare professionals and providing essential equipment could improve the quality of anthropometric assessment. The Quality of Care Survey of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) identified some deficits in performance and reporting of anthropometric assessment, unrelated to hospital size or type (academic/nonacademic). Physicians/consultants appear often unaware of the identified gaps. Implementing standard operation procedures, training healthcare professionals and providing essential equipment could improve the quality of anthropometric assessment.

Published
2024
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14. Liver Histopathology in Late Protocol Biopsies after Pediatric Liver Transplantation

Author

Małgorzata Markiewicz-Kijewska, Sylwia Szymańska, Michal Pyzlak, Piotr Kaliciński, Joanna Teisseyre, Adam Kowalski, Irena Jankowska, Piotr Czubkowski, and Hor Ismail

Subjects
pediatric liver transplantation, liver biopsy, histopathology, long term follow-up, Pediatrics, RJ1-570
Abstract

Liver transplantation has become a routine treatment for children with end stage liver failure. Recently, the long term survival of pediatric patients after liver transplantation has improved, with a life expectancy much longer than that of adult recipients, but also with longer exposition of the graft to various injuries, including immunological, inflammatory and others. Biochemical tests, although important, do not always reflect graft injury. The aim of our study was to analyze the histopathology of the graft in late protocol biopsies and correlate it with the clinical and biochemical status of these patients. We analyzed 61 protocol liver biopsies taken from 61 patients. Biopsies were taken 9.03–17.09 years (mean 12.68, median 11.74 years) after transplantation. Liver specimens were examined particularly for the presence and stage of liver fibrosis, inflammation, steatosis, and acute or chronic cellular and humoral rejection. We did not find any abnormalities in 26 (42.6%) liver specimens. None of the patients had signs of cellular or antibody mediated rejection or chronic rejection. In 23 liver biopsies (37.7%), we found non-specific lymphoid infiltrates. Another problem was fibrosis (equal to or more than three on the Ishak scale)—we found it in 17 patients, including seven liver specimens (11.5%) with severe fibrosis (Ishak 5–6). Conclusions: Various pathomorphological abnormalities were found in more than half of patients with a median 11.74 years post-transplant follow-up. Most of them presented normal laboratory liver tests at the same time, suggesting a slow subclinical process leading to pathomorphological abnormalities. No single factor for the development of these abnormalities was found, but our study supports the need for protocol liver biopsies even in patients with normal/almost normal biochemical liver tests.

Published
2021
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15. Long-Term Follow-Up of Renal Function in Children after Liver Transplantation—A Single Center Retrospective Study

Author

Grzegorz Kowalewski, Piotr Kaliciński, Marek Stefanowicz, Ryszard Grenda, Piotr Czubkowski, and Marek Szymczak

Subjects
liver transplantation, chronic kidney disease, immunosuppression, Pediatrics, RJ1-570
Abstract

Chronic kidney disease (CKD) is a common complication after liver transplantation (LT). Its prevalence with modern immunosuppression regimens, especially in children, is variable depending on the transplantation era. The study included 61 pediatric patients with at least 10 years of follow-up after liver transplantation remaining under constant care of the Department of Pediatric Surgery and Organ Transplantation. The analysis included several tests: estimated glomerular function (eGFR), results of screening for renal tubular defects and blood concentrations of basic immunosuppressive drug-tacrolimus. CKD was diagnosed in 3% of children at 12 years after LT. The maintaining of tacrolimus concentrations >4 ng/mL in long-term observation was associated with a significant increase of microalbuminuria. The presence of microalbuminuria, regarded as a risk factor of CKD, confirmed the necessity of regular comprehensive assessment of patients in long-term follow-up.

Published
2021
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16. 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

17. Immune Status in Children Before Liver Transplantation—A Cross-Sectional Analysis Within the ChilsSFree Multicentre Cohort Study

Author

Tamara Möhring, André Karch, Christine S. Falk, Tobias Laue, Lorenzo D'Antiga, Dominique Debray, Loreto Hierro, Deirdre Kelly, Valerie McLin, Patrick McKiernan, Joanna Pawlowska, Piotr Czubkowski, Rafael T. Mikolajczyk, Ulrich Baumann, and Imeke Goldschmidt

Subjects
pediatric, liver transplantation, immune monitoring, cytokines, pre-transplant, hepatology, Immunologic diseases. Allergy, RC581-607
Abstract

Background: Both, markers of cellular immunity and serum cytokines have been proposed as potential biomarkers for graft rejection after liver transplantation. However, no good prognostic model is available for the prediction of acute cellular rejection. The impact of underlying disease and demographic factors on immune status before pediatric liver transplantation (pLTx) is still poorly understood. We investigated expression of immune markers before pLTx, in order to better understand the pre-transplant immune status. Improved knowledge of the impact of pre-transplant variables may enhance our understanding of immunological changes post pLTx in the future.Methods: This is a cross-sectional analysis of data from the ChilSFree study, a European multicentre cohort study investigating the longitudinal patterns of immune response before and after pLTx. Immune cell counts and soluble immune markers were measured in 155 children 1–30 days before pLTx by TruCount analysis and BioPlex assays. Results were logarithmised due to skewed distributions and then compared according to age, sex, and diagnosis using t-tests, ANOVAs, and Tukey post-hoc tests. The association between immune markers at time of pLTx and patients' age was assessed using a fractional polynomial approach. Multivariable regression models were used to assess the relative contribution of each factor.Results: Sex had no effect on immune status. We found strong evidence for age-specific differences in the immune status. The majority of immune markers decreased in a log-linear way with increasing age. T and B cells showed a sharp increase within the first months of life followed by a log-linear decline in older age groups. Several immune markers were strongly associated with underlying diagnoses. The effects of age and underlying disease remained virtually unchanged when adjusting for each other in multivariable models.Discussion: We show for the first time that age and diagnosis are major independent determinants of cellular and soluble immune marker levels in children with end-stage liver disease. These results need to be considered for future research on predictive immune monitoring after pLTx.

Published
2019
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18. The limited prognostic value of liver histology in children with biliary atresia

Author

Piotr Czubkowski, Joanna Cielecka-Kuszyk, Malgorzata Rurarz, M.D., Diana Kaminska, Malgorzata Markiewicz-Kijewska, and Joanna Pawlowska

Subjects
Biliary atresia, Liver biopsy, Prognosis, Portal hypertension, Liver transplantation, Ductular proliferation, Specialties of internal medicine, RC581-951
Abstract

Background and rationale for the study. The aim of the study was to determine the prognostic value of histopathological findings with special care to the severity of liver fibrosis at the moment of hepatopor-toenterostomy (HPE) in children with biliary atresia (BA). We performed analysis of 142 wedge liver biopsies taken at the time of HPE. All patients were operated by the same surgical team between 1995 and 2007. According to the outcome 6 months after HPE patients were divided into prognostic groups: group 1-bilirubin level < 2 mg% (n = 65), group 2-bilirubin level > 2 mg% (n = 77). Liver biopsies were re-evaluated according to the extended histopathological protocol and then were compared between the prognostic groups. Survival with native liver (SNL) estimates were performed in regard to severity of liver fibrosis.Results. Survival with native liver estimates after 2, 5 and 10 years in patients after successful operation were 96%, 91%, 75% vs. 30%, 11%, and 5% if operation failed (p < 0.001). There was no difference between groups in the following variables: fibrosis (p = 0.69), portal inflammation (p = 0.99), lobular inflammation (p = 0.95), cholangiolitis (p = 0.23), accumulation of bile pigments (zone 1:p = 0.49; zone 2:p = 0.51; zone 3:p = 0.48), bile plugs in canaliculi (p = 0.12), bile plugs in ducts (p = 0.32), bilirubinostasis in hepatocytes (p = 0.45), bile ductular proliferation (p = 0.59), ductal plate malformation (p = 0.12), focal necrosis (p = 0.44), giant cell transformation (p = 0.45), haematopoesis (p = 0.52), ductopenia (p = 0.46), microabscesses (p = 0.49), ballooning of hepatocytes (p = 0.08). The actuarial 5/10-year SNL was not dependent on severity of liver fibrosis (log-rank test p = 0.84). The severity of fibrosis corresponded neither with the age at HPE nor with the laboratory findings before operation but increased the risk of portal hypertension.Conclusion. Liver histology at the time of HPE is of limited value in prognosis making in BA.

Published
2015
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19. Risk factors and outcomes associated with recurrent autoimmune hepatitis following liver transplantation

Author

Montano-Loza, A.J., Ronca, V., Ebadi, M., Hansen, B.E., Hirschfield, G., Elwir, S., Alsaed, M., Milkiewicz, P., Janik, M.K., Marschall, H.U., Burza, M.A., Efe, C., Caliskan, A.R., Harputluoglu, M., Kabacam, G., Terrabuio, D., Onofrio, F.D., Selzner, N., Bonder, A., Pares, A., Llovet, L., Akyildiz, M., Arikan, C., Manns, M.P., Taubert, R., Weber, A.L., Schiano, T.D., Haydel, B., Czubkowski, P., Socha, P., Oldak, N., Akamatsu, N., Tanaka, A., Levy, C., Martin, E.F., Goel, A., Sedki, M., Jankowska, I., Ikegami, T., Rodriguez, M., Sterneck, M., Weiler-Normann, C., Schramm, C., Donato, M.F., Lohse, A., Andrade, R.J., Patwardhan, V.R., Hoek, B. van, Biewenga, M., Kremer, A.E., Ueda, Y., Deneau, M., Pedersen, M., Mayo, M.J., Floreani, A., Burra, P., Secchi, M.F., Beretta-Piccoli, B.T., Sciveres, M., Maggiore, G., Jafri, S.M., Debray, D., Girard, M., Lacaille, F., Lytvyak, E., Mason, A.L., Heneghan, M., Oo, Y.H., and Int Autoimmune Hepatitis Grp IAIHG

Subjects
Adult, Male, Hepatology, liver transplantation, recurrent disease, autoimmune liver disease, graft survival, Mycophenolic Acid, survival, Hepatitis, Autoimmune, Recurrence, Risk Factors, Immunoglobulin G, Humans, Female, Immunosuppressive Agents
Abstract

Background & Aims: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival.Methods: We included 736 patients (77% female, mean age 42 +/- 1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis.Results: AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT

Published
2022

20. Successful pregnancy after ileal exclusion in progressive familial intrahepatic cholestasis type 2

Author

Piotr Czubkowski, Irena Jankowska, and Joanna Pawłowska

Subjects
Partial external biliary diversion, Quality of life, Maternity, External stoma, Bile acids, Specialties of internal medicine, RC581-951
Abstract

Progressive familial intrahepatic cholestasis type 2 (PFIC 2) results from mutations in ABCB11 gene coding bile salt export pump (BSEP). Medical treatment is usually unsuccessful and surgery intervention is necessary. Partial external biliary diversion (PEBD) is regarded as the first choice of surgical treatment. Ileal exclusion (IE) is an alternative operation if external stoma is not tolerated; however, a favorable outcome is uncertain. In chronic liver diseases pregnancy brings additional risk of deterioration of liver function and generally is not recommended. We present the first case report of successful pregnancy in a genetically confirmed PFIC 2 patient after surgical conversion from PEBD to IE.

Published
2015
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21. 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

22. 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

23. Efficacy and safety of prolonged-release tacrolimus in stable pediatric allograft recipients converted from immediate-release tacrolimus – a Phase 2, open-label, single-arm, one-way crossover study

Author

Rubik, J, Debray, D, Kelly, D, Iserin, F, Webb, N, Czubkowski, P, Vondrak, K, Sellier-Leclerc, A, Rivet, C, Riva, S, Tonshoff, B, D'Antiga, L, Marks, S, Reding, R, Kazeem, G, Undre, N, Rubik J., Debray D., Kelly D., Iserin F., Webb N. J. A., Czubkowski P., Vondrak K., Sellier-Leclerc A. -L., Rivet C., Riva S., Tonshoff B., D'Antiga L., Marks S. D., Reding R., Kazeem G., Undre N., Rubik, J, Debray, D, Kelly, D, Iserin, F, Webb, N, Czubkowski, P, Vondrak, K, Sellier-Leclerc, A, Rivet, C, Riva, S, Tonshoff, B, D'Antiga, L, Marks, S, Reding, R, Kazeem, G, Undre, N, Rubik J., Debray D., Kelly D., Iserin F., Webb N. J. A., Czubkowski P., Vondrak K., Sellier-Leclerc A. -L., Rivet C., Riva S., Tonshoff B., D'Antiga L., Marks S. D., Reding R., Kazeem G., and Undre N.

Abstract

There are limited clinical data regarding prolonged-release tacrolimus (PR-T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR-T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate-release tacrolimus (IR-T), on a 1:1 mg total-daily-dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy-confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole-blood trough levels (target 3.5–15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6–17.7% of patients across follow-up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug-related treatment-emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR-T to PR-T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.

Published
2019

24. Comparative pharmacokinetics of tacrolimus in stable pediatric allograft recipients converted from immediate-release tacrolimus to prolonged-release tacrolimus formulation

Author

Rubik, J, Debray, D, Iserin, F, Vondrak, K, Sellier-Leclerc, A, Kelly, D, Czubkowski, P, Webb, N, Riva, S, D'Antiga, L, Marks, S, Rivet, C, Tonshoff, B, Kazeem, G, Undre, N, Rubik J., Debray D., Iserin F., Vondrak K., Sellier-Leclerc A. -L., Kelly D., Czubkowski P., Webb N. J. A., Riva S., D'Antiga L., Marks S. D., Rivet C., Tonshoff B., Kazeem G., Undre N., Rubik, J, Debray, D, Iserin, F, Vondrak, K, Sellier-Leclerc, A, Kelly, D, Czubkowski, P, Webb, N, Riva, S, D'Antiga, L, Marks, S, Rivet, C, Tonshoff, B, Kazeem, G, Undre, N, Rubik J., Debray D., Iserin F., Vondrak K., Sellier-Leclerc A. -L., Kelly D., Czubkowski P., Webb N. J. A., Riva S., D'Antiga L., Marks S. D., Rivet C., Tonshoff B., Kazeem G., and Undre N.

Abstract

This study was a Phase II, open-label, multicenter, single-arm, cross-over study comparing the pharmacokinetics (PK) of tacrolimus in stable pediatric kidney, liver, or heart allograft recipients converted from immediate-release tacrolimus (IR-T) to prolonged-release tacrolimus (PR-T). In Days −30 to −1 of screening period, patients received their IR-T-based regimen; during Days 1-7, patients received study IR-T (same dose as screening). On Day 7, the first 24-hours PK profile was taken; patients were then converted to PR-T (1 mg:1 mg), with a second 24-hours PK profile taken on Day 14. The primary end-point was tacrolimus area under the blood concentration–time curve over 24 hours (AUC24); secondary end-points were maximum concentration Cmaxand concentration at 24 hours C24. The predefined similarity interval for confidence intervals (CIs) of least squares mean (LSM) ratios was 80%-125%. The PK analysis set comprised 74 pediatric transplant recipients (kidney, n = 45; liver, n = 28; heart, n = 1). PR-T:IR-T LSM ratio (90% CI) was similar overall for AUC24, max, and C24, and for kidney and liver recipients for AUC24 (LSM ratio, kidney 91.8%; liver 104.1%) and C24 (kidney 90.5%; liver 89.9%). Linear relationship was similar between AUC24 and C24, and between PR-T and IR-T (rho 0.89 and 0.84, respectively), suggesting that stable pediatric transplant recipients can be converted from IR-T to PR-T at the same total daily dose, using the same therapeutic drug monitoring method.

Published
2019

25. Immune status in children before liver transplantation — A cross-sectional analysis within the ChilsSFree multicentre cohort study

Author

Mohring, T, Karch, A, Falk, C, Laue, T, D'Antiga, L, Debray, D, Hierro, L, Kelly, D, Mclin, V, Mckiernan, P, Pawlowska, J, Czubkowski, P, Mikolajczyk, R, Baumann, U, Goldschmidt, I, Mohring T., Karch A., Falk C. S., Laue T., D'Antiga L., Debray D., Hierro L., Kelly D., McLin V., McKiernan P., Pawlowska J., Czubkowski P., Mikolajczyk R. T., Baumann U., Goldschmidt I., Mohring, T, Karch, A, Falk, C, Laue, T, D'Antiga, L, Debray, D, Hierro, L, Kelly, D, Mclin, V, Mckiernan, P, Pawlowska, J, Czubkowski, P, Mikolajczyk, R, Baumann, U, Goldschmidt, I, Mohring T., Karch A., Falk C. S., Laue T., D'Antiga L., Debray D., Hierro L., Kelly D., McLin V., McKiernan P., Pawlowska J., Czubkowski P., Mikolajczyk R. T., Baumann U., and Goldschmidt I.

Abstract

Background: Both, markers of cellular immunity and serum cytokines have been proposed as potential biomarkers for graft rejection after liver transplantation. However, no good prognostic model is available for the prediction of acute cellular rejection. The impact of underlying disease and demographic factors on immune status before pediatric liver transplantation (pLTx) is still poorly understood. We investigated expression of immune markers before pLTx, in order to better understand the pre-transplant immune status. Improved knowledge of the impact of pre-transplant variables may enhance our understanding of immunological changes post pLTx in the future. Methods: This is a cross-sectional analysis of data from the ChilSFree study, a European multicentre cohort study investigating the longitudinal patterns of immune response before and after pLTx. Immune cell counts and soluble immune markers were measured in 155 children 1–30 days before pLTx by TruCount analysis and BioPlex assays. Results were logarithmised due to skewed distributions and then compared according to age, sex, and diagnosis using t-tests, ANOVAs, and Tukey post-hoc tests. The association between immune markers at time of pLTx and patients' age was assessed using a fractional polynomial approach. Multivariable regression models were used to assess the relative contribution of each factor. Results: Sex had no effect on immune status. We found strong evidence for age-specific differences in the immune status. The majority of immune markers decreased in a log-linear way with increasing age. T and B cells showed a sharp increase within the first months of life followed by a log-linear decline in older age groups. Several immune markers were strongly associated with underlying diagnoses. The effects of age and underlying disease remained virtually unchanged when adjusting for each other in multivariable models. Discussion: We show for the first time that age and diagnosis are major independent determina

Published
2019

26. European Guideline on IgG4-related digestive disease - UEG and SGF evidence-based recommendations

Author

Lohr, J. -M., Beuers, U., Vujasinovic, M., Alvaro, D., Frokjaer, J. B., Buttgereit, F., Capurso, G., Culver, E. L., De-Madaria, E., Della-Torre, E., Detlefsen, S., Dominguez-Mu~noz, E., Czubkowski, P., Ewald, N., Frulloni, L., Gubergrits, N., Duman, D. G., Hackert, T., Iglesias-Garcia, J., Kartalis, N., Laghi, A., Lammert, F., Lindgren, F., Okhlobystin, A., Oracz, G., Parniczky, A., Mucelli, R. M. P., Rebours, V., Rosendahl, J., Schleinitz, N., Schneider, A., van Bommel, E. F. H., Verbeke, C. S., Vullierme, M. P., Witt, H., Besselink, M. G., Bruno, M. J., Czako, L., Chiaro, M., Filippova, O., Fukuda, A., Gaujoux, S., Hart, P. A., Hegyi, P., Jonas, E., Kahraman, A., Kleger, A., Kuryata, O., Laukkarinen, J., Lerch, M. M., Marchegiani, G., Marschall, H. -U., Matos, C., Molad, Y., Oguz, D., Pukitis, A., Satoi, S., Stone, J. H., Verheij, J., Vries, N., Lohr, J-Matthias, Beuers, Ulrich, Vujasinovic, Miroslav, Alvaro, Domenico, Frokjaer, Jens Brondum, Buttgereit, Frank, Capurso, Gabriele, Culver, Emma L., De-Madaria, Enrique, Della-Torre, Emanuel, Detlefsen, Sonke, Dominguez-Munoz, Enrique, Czubkowski, Piotr, Ewald, Nils, Frulloni, Luca, Gubergrits, Natalya, Duman, Deniz Guney, Hackert, Thilo, Iglesias-Garcia, Julio, Kartalis, Nikolaos, Laghi, Andrea, Lammert, Frank, Lindgren, Fredrik, Okhlobystin, Alexey, Oracz, Grzegorz, Parniczky, Andrea, Mucelli, Raffaella Maria Pozzi, Rebours, Vinciane, Rosendahl, Jonas, Schleinitz, Nicolas, Schneider, Alexander, van Bommel, Eric F. H., Verbeke, Caroline Sophie, Vullierme, Marie Pierre, Witt, Heiko, Besselink, Marc G., Bruno, Marco J., Czako, Laszlo, del Chiaro, Marco, Filippova, Oleksandra, Fukuda, Akihisa, Gaujoux, Sebastien, Hart, Phil A., Hegyi, Peter, Jonas, Eduard, Kahraman, Alisan, Kleger, Alexander, Kuryata, Olexander, Laukkarinen, Johanna, Lerch, Markus M., Marchegiani, Giovanni, Marschal, Hanns-Ulrich, Matos, Celso, Molad, Yair, Oguz, Dilek, Pukitis, Aldis, Satoi, Sohei, Stone, John H., Verheij, Joanne, de Vries, Niek, KKÜ, Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Löhr, Jm, Beuers, U, Vujasinovic, M, Alvaro, D, Frøkjær, Jb, Buttgereit, F, Capurso, G, Culver, El, de-Madaria, E, DELLA TORRE, E, Detlefsen, S, Dominguez-Muñoz, E, Czubkowski, P, Ewald, N, Frulloni, L, Gubergrits, N, Duman, Dg, Hackert, T, Iglesias-Garcia, J, Kartalis, N, Laghi, A, Lammert, F, Lindgren, F, Okhlobystin, A, Oracz, G, Parniczky, A, Mucelli, Rmp, Rebours, V, Rosendahl, J, Schleinitz, N, Schneider, A, van Bommel, Ef, Verbeke, C, Vullierme, Mp, Witt, H, and UEG guideline working, Group.

Subjects
Abdominal pain, IMMUNOGLOBULIN G4-RELATED DISEASE, SERUM IGG4 LEVELS, Medizin, Disease, RC799-869, Severity of Illness Index, immune-related cholangitis, Serology, 0302 clinical medicine, LONG-TERM OUTCOMES, Prednisone, Drug Dosage Calculations, Child, other organ involvement, STEROID-THERAPY, INTERNATIONAL-CONSENSUS, Evidence-Based Medicine, glucocorticoids, Gastroenterology, Induction Chemotherapy, IgG4-related, Diseases of the digestive system. Gastroenterology, PRIMARY SCLEROSING CHOLANGITIS, TYPE-1 AUTOIMMUNE PANCREATITIS, CONSENSUS DIAGNOSTIC-CRITERIA, Europe, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, diabetes mellitus, 030211 gastroenterology & hepatology, medicine.symptom, digestive, autoimmune pancreatitis type 1, Glucocorticoid, Immunosuppressive Agents, medicine.drug, Adult, medicine.medical_specialty, Digestive System Diseases, biomarkers, cancer, disease, Maintenance Chemotherapy, 03 medical and health sciences, Internal medicine, Diabetes mellitus, medicine, Humans, FINE-NEEDLE-ASPIRATION, Dose-Response Relationship, Drug, business.industry, EMISSION TOMOGRAPHY/COMPUTED TOMOGRAPHY, Body Weight, Editorials, Cancer, Guideline, medicine.disease, business
Abstract

Frulloni, Luca/0000-0001-7417-2655; Hart, Phil/0000-0003-4346-6196; Capurso, Gabriele/0000-0002-0019-8753; de-Madaria, Enrique/0000-0002-2412-9541; Lohr, Matthias/0000-0002-7647-198X; Frokjaer, Jens Brondum/0000-0001-8722-0070 WOS:000542363500001 PubMed: 32552502 The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6-0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2-4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added. National Societies Committee of the United European Gastroenterology (UEG) We gratefully acknowledge the support from the National Societies Committee of the United European Gastroenterology (UEG) for the conduct of these guidelines independent from other sources. No other funding was received.

Published
2020

27. 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

28. Maralixibat-treated patients with Alagille syndrome (ALGS) demonstrate improved event-free survival in a natural history comparison with patients from the GALA database: application of real-world evidence analytics.

Author

Hansen, B. E., Vandriel, S. M., Vig, P., Garner, W., Li, L.-T., She, H., Wang, J.-S., Gilbert, M. A., Jankowska, I., Czubkowski, P., Gliwicz-Miedzińska, D., Gonzales, E. M., Jacquemin, E., Bouligand, J., Spinner, N. B., Loomes, K. M., Piccoli, D. A., D'Antiga, L., Nicastro, E., and Sokal, É.

Published
2022
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29. Phenotypic divergence of Jagged I and NOTCH 2 associated Algille syndrome: results from the international multicenter GALA study group.

Author

UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Vandriel S, Li, L., She, H., Wang, JS., Gilbert, MA, Spinner, NB, Loomes, K.M., Piccoli, D.A., d'Antiga, L., Nicastro, E, Luigi Calvo, P., Hardikar, W., Shankar, S., Fawaz, RL., Nastasio, S., Bulut P., Jankowska, I, Czubkowski, P., Gliwicz-Miedzinska, D, Sokal, Etienne, Demaret, Tanguy, The Liver Meeting Digital Experience - AASLD, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, Vandriel S, Li, L., She, H., Wang, JS., Gilbert, MA, Spinner, NB, Loomes, K.M., Piccoli, D.A., d'Antiga, L., Nicastro, E, Luigi Calvo, P., Hardikar, W., Shankar, S., Fawaz, RL., Nastasio, S., Bulut P., Jankowska, I, Czubkowski, P., Gliwicz-Miedzinska, D, Sokal, Etienne, Demaret, Tanguy, and The Liver Meeting Digital Experience - AASLD

Published
2020

32. Acute Hepatitis of Unknown Etiology Among Young Children

Author

Indolfi, Giuseppe, Czubkowski, Piotr, Fitzpatrick, Emer, Gonzales, Emmanuel, Gupte, Girish, Mancell, Sara, Mozer-Glassberg, Yael, Nicastro, Emanuele, Norman, Junge, Stephenne, Xavier, Zellos, Aglaia, and Samyn, Marianne

Abstract

In April 2022, an increased incidence of acute hepatitis cases of unknown etiology among previously healthy children across the United Kingdom was described. Since, more than 270 cases from the United Kingdom and hundreds more from all across the world have been reported. The majority of affected children were younger than 6 years of age. The clinical presentation was nonspecific with diarrhea and vomiting usually preceding the appearance of jaundice, abdominal pain, nausea, and malaise. Approximately 5% have required liver transplantation. An infectious etiology has been considered likely given the epidemiological and clinical features of the reported cases. Between 50 and 60% of the children tested were diagnosed with adenovirus infection although a clear etiological connection has still to be demonstrated. No link with SARS-CoV-2 infection and COVID-19 vaccine was found. What is not clear to date is whether the high number of acute hepatitis cases reported is related to a true increase in incidence or heightened awareness following on from the initial reports from the United Kingdom. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) developed a paper on the current outbreak of acute hepatitis of unknown etiology recognizing its importance and the need of approaching the current situation with a scientifically rigorous approach. The aims of the article are to summarize the current knowledge and to identify the most pertinent issues regarding the diagnosis and management of this condition and the research questions raised.

Published
2022
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33. Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial

Author

Thompson, Richard J, Arnell, Henrik, Artan, Reha, Baumann, Ulrich, Calvo, Pier Luigi, Czubkowski, Piotr, Dalgic, Buket, D'Antiga, Lorenzo, Durmaz, Özlem, Fischler, Björn, Gonzalès, Emmanuel, Grammatikopoulos, Tassos, Gupte, Girish, Hardikar, Winita, Houwen, Roderick H J, Kamath, Binita M, Karpen, Saul J, Kjems, Lise, Lacaille, Florence, Lachaux, Alain, Lainka, Elke, Mack, Cara L, Mattsson, Jan P, McKiernan, Patrick, Özen, Hasan, Rajwal, Sanjay R, Roquelaure, Bertrand, Shagrani, Mohammad, Shteyer, Eyal, Soufi, Nisreen, Sturm, Ekkehard, Tessier, Mary Elizabeth, Verkade, Henkjan J, and Horn, Patrick

Abstract

Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC.

Published
2022
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35. Proceedings of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition Monothematic Conference, 2020

Author

Zellos, Aglaia, Debray, Dominique, Indolfi, Giuseppe, Czubkowski, Piotr, Samyn, Marianne, Hadzic, Nedim, Gupte, Girish, Fischler, Björn, Smets, Françoise, Clément de Cléty, Stéphan, Grenda, Ryszard, Mozer, Yael, Mancell, Sara, Jahnel, Jörg, Auzinger, Georg, Worth, Austen, Lisman, Ton, Staufner, Christian, Baumann, Ulrich, Dhawan, Anil, Alonso, Estelle, Squires, Robert H., and Verkade, Henkjan J.

Abstract

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. The 2020 single topic ESPGHAN monothematic 3-day conference on pediatric liver disease, was organized in Athens, Greece and was entitled “ Acute Liver Failure” (ALF). ALF is a devastating disease with high mortality and in a considerable fraction of patients, the cause remains unresolved. 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 developments in medical therapy and indications for liver transplantation (LT) and to identify areas for future research in clinical and neurocognitive outcomes in ALF. We recently reported the epidemiology, diagnosis, and initial intensive care management issues in separate manuscript. Herewith we report on the medical treatment, clinical lessons arising from pediatric studies, nutritional and renal replacement therapy (RRT), indications and contraindications for LT, neurocognitive outcomes, new techniques used as bridging to LT, and areas for future research. Oral presentations by experts in various fields are summarized highlighting key learning points. The current report summarizes the current insights in medical treatment of pediatric ALF and the directions for future research.

Published
2022
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36. Proceedings of ESPGHAN Monothematic Conference 2020

Author

Zellos, Aglaia, Debray, Dominique, Indolfi, Giuseppe, Czubkowski, Piotr, Samyn, Marianne, Hadzic, Nedim, Gupte, Girish, Fischler, Björn, Smets, Françoise, Cléty, Stéphan Clément, Grenda, Ryszard, Mozer, Yael, Mancell, Sara, Jahnel, Jörg, Auzinger, Georg, Worth, Austen, Lisman, Ton, Staufner, Christian, Baumann, Ulrich, Dhawan, Anil, Alonso, Estelle, Squires, Robert H., and Verkade, Henkjan J.

Abstract

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. 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. 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. 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.

Published
2022
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38. Analysis of quality of life, hepatic biochemical markers, and sleep in patients with progressive familial intrahepatic cholestasis who had a pruritus response with odevixibat treatment.

Author

Gupte, G., Thompson, R. J., D’Antiga, L., Grammatikopoulos, T., Gonzalès, E., Lacaille, F., Lachaux, A., Roquelaure, B., Baumann, U., Lainka, E., Sturm, E., Shteyer, E., Czubkowski, P., Artan, R., Dalgic, B., Özen, H., Loomes, K. M., Vittorio, J. M., Karpen, S. J., and McKiernan, P.

Published
2022
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39. The Impact of Severe Acute Respiratory Syndrome Coronavirus Type 2 on Children With Liver Diseases

Author

Nicastro, Emanuele, Ebel, Noelle H., Kehar, Mohit, Czubkowski, Piotr, Ng, Vicky L., Michaels, Marian G., Lobritto, Steven J., Martinez, Mercedes, and Indolfi, Giuseppe

Abstract

Children are seldom affected by severe forms of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2) infection; however, the impact of comorbidities in the clinical presentation and outcome of SARS-CoV2 in children is poorly characterized including that of chronic liver disease (CLD) and those taking immunosuppressive medications for autoimmune liver disease or following liver transplantation (LT). Although not the main target organ, a spectrum of liver involvement has been described in children infected with SARS-CoV2 and those presenting with Multisystem Inflammatory Syndrome in Children (MIS-C). The Hepatology Committee of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the Society of Pediatric Liver Transplantation (SPLIT) present an evidence-based position paper on liver involvement in children with SARS-CoV2 infection and its impact on those with CLD as well as LT recipients. All children may exhibit acute liver injury from SARS-CoV2 infection, and those with CLD and may experience hepatic decompensation. Preventative and therapeutic measures are discussed.

Published
2022
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41. 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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42. Cholestasis Due to USP53 Deficiency

Author

Bull, Laura N., Ellmers, Rebecca, Foskett, Pierre, Strautnieks, Sandra, Sambrotta, Melissa, Czubkowski, Piotr, Jankowska, Irena, Wagner, Bart, Deheragoda, Maesha, and Thompson, Richard J.

Abstract

Although a number of genetic forms of cholestasis have been identified, the genetic etiology of disease remains unidentified in a subset of cholestasis patients. Whole exome sequencing (WES) was performed in DNA from patients diagnosed with cholestasis, at different points on the continuum from progressive familial intrahepatic cholestasis to benign recurrent intrahepatic cholestasis, in whom no disease mutations in known cholestasis genes had been identified. Candidate genes were then assessed in a larger patient sample, by targeted next-generation sequencing (NGS). Disease features at presentation and follow-up were collected from available medical records. By WES, we identified 3 patients with homozygous mutations in USP53. Screening of USP53in a larger set of patients identified 4 additional patients with homozygous mutations in USP53. Six of the 7 patients had deletion mutations, and 1 had a missense mutation; 3 of the patients were siblings, all bearing a deletion that also disrupted neighboring MYOZ2. Age of onset ranged from early infancy to adolescence. Cholestasis tended to be biochemically mild and intermittent, and responsive to medication. Liver fibrosis was, however, present in all 4 patients who were biopsied, and splenomegaly was apparent in 5 of 7 at last ultrasound. Two groups recently identified patients with liver disease and mutation in USP53. We have now identified biallelic mutation in USP53in 7 further patients with cholestasis, from 5 families. Most individuals had evidence of chronic liver disease, and long-term follow-up is recommended.

Published
2021
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46. Management of Hepatitis B Virus Infection and Prevention of Hepatitis B Virus Reactivation in Children With Acquired Immunodeficiencies or Undergoing Immune Suppressive, Cytotoxic, or Biological Modifier Therapies

Author

Indolfi, Giuseppe, Abdel-Hady, Mona, Bansal, Sanjay, Debray, Dominique, Smets, Françoise, Czubkowski, Piotr, Woerd, Wendy, Samyn, Marianne, Jahnel, Jörg, Gupte, Girish, Zellos, Aglaia, Mozer-Glassberg, Yael, Verkade, Henkjan J., Sokal, Etienne, and Fischler, Björn

Abstract

Reactivation of hepatitis B virus (HBV) is a known complication of immune-suppressive, cytotoxic, and biological modifier therapies in patients currently infected with HBV or who have had past exposure to HBV. Nowadays, newer and emerging forms of targeted biologic therapies are available for the management of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions and solid-organ, bone marrow, or haematologic stem cell transplant but there is currently a lack of a systematic approach to the care of patients with or at risk of HBV reactivation. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) together with a working group of ESPGHAN members with clinical and research expertise in viral hepatitis developed an evidence-based position paper on reactivation of HBV infection in children identifying pertinent issues addressing the diagnosis, prevention, and treatment of this condition. Relevant clinical questions were formulated and agreed upon by all the members of the working group. Questions were answered and positions were based on evidence resulting from a systematic literature search on PubMed and Embase from their inception to July 1, 2019. A document was produced and the working group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique. A recommendation was accepted provided upon agreement by at least 75% of the working group members. This position paper provides a comprehensive update on the diagnosis, prevention and treatment of HBV reactivation in children.

Published
2020
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47. Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Author

Miethke, Alexander G, Moukarzel, Adib, Porta, Gilda, Covarrubias Esquer, Joshue, Czubkowski, Piotr, Ordonez, Felipe, Mosca, Antonella, Aqul, Amal A, Squires, Robert H, Sokal, Etienne, D'Agostino, Daniel, Baumann, Ulrich, D'Antiga, Lorenzo, Kasi, Nagraj, Laborde, Nolwenn, Arikan, Cigdem, Lin, Chuan-Hao, Gilmour, Susan, Mittal, Naveen, Chiou, Fang Kuan, Horslen, Simon P, Huber, Wolf-Dietrich, Jaecklin, Thomas, Nunes, Tiago, Lascau, Anamaria, Longpre, Lara, Mogul, Douglas B, Garner, Will, Vig, Pamela, Hupertz, Vera F, Gonzalez-Peralta, Regino P, Ekong, Udeme, Hartley, Jane, Laverdure, Noemie, Ovchinsky, Nadia, and Thompson, Richard J

Abstract

Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat—an ileal bile acid transporter inhibitor—in participants with all types of PFIC.

Published
2024
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49. SAT-048 - 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., Thompson, R., Grammatikopoulos, T., Kadaristiana, A., Jankowska, I., Lipiński, P., Czubkowski, P., Gonzales, E., Jacquemin, E., Spraul, A., Sokal, E., Shagrani, M.A., Broering, D.C., Algoufi, T., Mazhar, N., Nicastro, E., Kelly, D., Nebbia, G., Arnell, H., Fischler, B., Sankaranarayanan, S., Hulscher, J., Serranti, D., Arikan, C., Polat, E., Debray, D., Lacaille, F., Goncalves, C., Hierro, L., Bartolo, G.M., Mozer-Glassberg, Y., Azaz, A., Brecelj, J., Dezsőfi, A., Calvo, P.L., Pizzol, A., Schmitt, D., Sturm, E., van der Woerd, W., Hansen, B., and Verkade, H.

Published
2018
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50. PEG 3350 Versus Lactulose for Treatment of Functional Constipation in Children

Author

Jarzebicka, Dorota, Sieczkowska-Golub, Joanna, Kierkus, Jaroslaw, Czubkowski, Piotr, Kowalczuk-Kryston, Monika, Pelc, Maciej, Lebensztejn, Dariusz, Korczowski, Bartosz, Socha, Piotr, and Oracz, Grzegorz

Abstract

The aim of this study was to compare the clinical efficacy and tolerance of polyethylene glycol 3350 (PEG) and lactulose for the treatment of functional constipation in infants and children. This randomized, multicenter study covered 12 weeks of treatment and 4 weeks of follow-up of patients with functional constipation. Patients were randomized (central randomization) to receive either PEG or lactulose. The primary end points were the number of defecations per week after 12 weeks of treatment and improvement in stool consistency of at least 2 points in the Bristol scale. The secondary end point was the presence of adverse events. Bowel movements =3 per week and stool consistency =2 (Bristol scale) were considered as successful treatment. We enrolled 102 patients (M 57, F 45) aged 3.62 ± 1.42 years and 88 completed the study. At week 12, good clinical outcome was achieved in 98% (PEG) and 90% (lactulose). The PEG group had more defecations per week compared with the lactulose group (7.9 ± 0.6 vs 5.7 ± 0.5, P= 0.008) and both groups had similar frequency of defecation with pain (5% vs 5%, P= 0.9), stool retention (7% vs 10%, P= 057), large volume of stools (30% vs 31%, P= 0.9) and hard stools (7% vs 13%, P= 0.58). There were more patients with side effects in the lactulose group (15 vs 23, P= 0.02), mostly bloating and abdominal pain. PEG 3350 is more effective and causes fewer side effects than lactulose in the treatment of constipation in infants and children.

Published
2019
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