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1. 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

2. 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
2022

3. 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

4. Mitochondrial neurogastrointestinal encephalomyopathy: Clinical and biochemical impact of allogeneic stem cell transplantation in a Greek patient with one novel TYMP mutation

Author

Paisiou, A., primary, Rogalidou, M., additional, Pons, R., additional, Ioannidou, E., additional, Dimakou, K., additional, Papadopoulou, A., additional, Vaz, F.M., additional, Vessalas, G., additional, Goorden, S.M.I., additional, Roelofsen, J., additional, Zoetekouw, A., additional, Nieman, M.M., additional, Dimitriou, E., additional, Moraitou, M., additional, Peristeri, I., additional, Michelakakis, H., additional, and van Kuilenburg, A.B.P., additional

Published
2022
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7. 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

8. Helicobacter pylori Infection in Pediatric Patients Living in Europe: Results of the EuroPedHP Registry 2013 to 2016

Author

Kori, M. Le Thi, T.G. Werkstetter, K. Sustmann, A. Bontems, P. Lopes, A.I. Oleastro, M. Iwanczak, B. Kalach, N. Misak, Z. Cabral, J. Homan, M. Cilleruelo Pascual, M.L. Pehlivanoglu, E. Casswall, T. Urruzuno, P. Martinez Gomez, M.J. Papadopoulou, A. Roma, E. Dolinsek, J. Rogalidou, M. Urbonas, V. Chong, S. Kindermann, A. Miele, E. Rea, F. Cseh, Á. Koletzko, S. Helicobacter pylori Working Group of ESPGHAN

Abstract

OBJECTIVES: The aim of the study was to assess clinical presentation, endoscopic findings, antibiotic susceptibility and treatment success of Helicobacter pylori (H. pylori) infected pediatric patients. METHODS: Between 2013 and 2016, 23 pediatric hospitals from 17 countries prospectively submitted data on consecutive H. pylori-infected (culture positive) patients to the EuroPedHP-Registry. RESULTS: Of 1333 patients recruited (55.1% girls, median age 12.6 years), 1168 (87.6%) were therapy naïve (group A) and 165 (12.4%) had failed treatment (group B). Patients resided in North/Western (29.6%), Southern (34.1%) and Eastern Europe (23.0%), or Israel/Turkey (13.4%). Main indications for endoscopy were abdominal pain or dyspepsia (81.2%, 1078/1328). Antral nodularity was reported in 77.8% (1031/1326) of patients, gastric or duodenal ulcers and erosions in 5.1% and 12.8%, respectively. Primary resistance to clarithromycin (CLA) and metronidazole (MET) occurred in 25% and 21%, respectively, and increased after failed therapy. Bacterial strains were fully susceptible in 60.5% of group A, but in only 27.4% of group B. Primary CLA resistance was higher in Southern and Eastern Europe (adjusted odds ratio [ORadj] = 3.44, 95% confidence interval [CI] 2.22-5.32, P

Published
2020

11. Current treatment of Helicobacter pylori infected children and adolescents in Europe: Interim Results of the new EuroPedHp Registry

Author

Le Thi, T., Werkstetter, K., Cabral, J., Kotilea, K., Bontems, P., Cilleruelo Pascual, M., Barrio, J., Homan, M., Kori, M., Urruzuno, P., Kalach, N., Misak, Z., Lima, R., Tavares, M., Miele, E., Chiaro, A., Urbonas, V., Matusiewics, K., Krahl, A., Ugras, M. Korkut, Papadopoulou, A., Rea, F., Sykora, J., Jan de Laffolie, Klemenak, M., Rogalidou, M., Roma, E., Lopes, A., Casswall, T., Cseh, A., Banoub, H., and Koletzko, S.

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

Author

Shannon M, Vandriel, Li-Ting, Li, Huiyu, She, Jian-She, Wang, Melissa A, Gilbert, Irena, Jankowska, Piotr, Czubkowski, Dorota, Gliwicz-Miedzińska, Emmanuel M, Gonzales, Emmanuel, Jacquemin, Jérôme, Bouligand, Nancy B, Spinner, Kathleen M, Loomes, David A, Piccoli, Lorenzo, D'Antiga, Emanuele, Nicastro, Étienne, Sokal, Tanguy, Demaret, Noelle H, Ebel, Jeffrey A, Feinstein, Rima, Fawaz, Silvia, Nastasio, Florence, Lacaille, Dominique, Debray, Henrik, Arnell, Björn, Fischler, Susan, Siew, Michael, Stormon, Saul J, Karpen, Rene, Romero, Kyung Mo, Kim, Woo Yim, Baek, Winita, Hardikar, Sahana, Shankar, Amin J, Roberts, Helen M, Evans, M Kyle, Jensen, Marianne, Kavan, Shikha S, Sundaram, Alexander, Chaidez, Palaniswamy, Karthikeyan, Maria Camila, Sanchez, Maria Lorena, Cavalieri, Henkjan J, Verkade, Way Seah, Lee, James E, Squires, Christina, Hajinicolaou, Chatmanee, Lertudomphonwanit, Ryan T, Fischer, Catherine, Larson-Nath, Yael, Mozer-Glassberg, Cigdem, Arikan, Henry C, Lin, Jesus Quintero, Bernabeu, Seema, Alam, Deirdre A, Kelly, Elisa, Carvalho, Cristina Targa, Ferreira, Giuseppe, Indolfi, Ruben E, Quiros-Tejeira, Pinar, Bulut, Pier Luigi, Calvo, Zerrin, Önal, Pamela L, Valentino, Dev M, Desai, John, Eshun, Maria, Rogalidou, Antal, Dezsőfi, Sabina, Wiecek, Gabriella, Nebbia, Raquel Borges, Pinto, Victorien M, Wolters, María Legarda, Tamara, Andréanne N, Zizzo, Jennifer, Garcia, Kathleen, Schwarz, Marisa, Beretta, Thomas Damgaard, Sandahl, Carolina, Jimenez-Rivera, Nanda, Kerkar, Jernej, Brecelj, Quais, Mujawar, Nathalie, Rock, Cristina Molera, Busoms, Wikrom, Karnsakul, Eberhard, Lurz, Ermelinda, Santos-Silva, Niviann, Blondet, Luis, Bujanda, Uzma, Shah, Richard J, Thompson, Bettina E, Hansen, Binita M, Kamath, 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, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique

Subjects
Male, Cholestasis, Alagille syndrome, Bile duct atresia, Intrahepatic cholestasis, Hepatology, Hypertension, Portal/etiology, Gastroenterology and hepatology, Alagille Syndrome/epidemiology, Humans, Female, Child, Retrospective Studies
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 = 5.0 and = 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, 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, 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

13. Helicobacter pylori Infection in Pediatric Patients Living in Europe: Results of the EuroPedHP Registry 2013 to 2016

Author

Kori, Michal, Le Thi, Thu Giang, Werkstetter, Katharina, Sustmann, Andrea, Bontems, Patrick, Lopes, Ana Isabel, Oleastro, Monica, Iwanczak, Barbara, Kalach, Nicolas, Misak, Zrinjka, Cabral, José, Homan, Matjaž, Cilleruelo Pascual, Maria Luz, Pehlivanoglu, Ender, Casswall, Thomas, Urruzuno, Pedro, Martinez Gomez, Maria José, Papadopoulou, Alexandra, Roma, Eleftheria, Dolinsek, Jernej, Rogalidou, Maria, Urbonas, Vaidotas, Chong, Sonny, Kindermann, Angelika, Miele, Erasmo, Rea, Francesca, Cseh, Áron, Koletzko, Sibylle, Helicobacter pylori Working Group of ESPGHAN, İstanbul Kent Üniversitesi, Fakülteler, Sağlık Bilimleri Fakültesi, Beslenme ve Diyetetik Bölümü, Pehlivanoğlu, Ender, Kori, M., Le Thi, T. G., Werkstetter, K., Sustmann, A., Bontems, P., Lopes, A. I., Oleastro, M., Iwanczak, B., Kalach, N., Misak, Z., Cabral, J., Homan, M., Cilleruelo Pascual, M. L., Pehlivanoglu, E., Casswall, T., Urruzuno, P., Martinez Gomez, M. J., Papadopoulou, A., Roma, E., Dolinsek, J., Rogalidou, M., Urbonas, V., Chong, S., Kindermann, A., Miele, E., Rea, F., Cseh, A., Koletzko, S., Paediatric Gastroenterology, Amsterdam Gastroenterology Endocrinology Metabolism, and Amsterdam Reproduction & Development (AR&D)

Subjects
Male, HDE GAS PED, medicine.medical_specialty, Turkey, Pédiatrie, Peptic, Group B, Helicobacter Infections, 03 medical and health sciences, 0302 clinical medicine, Clarithromycin, Metronidazole, 030225 pediatrics, Internal medicine, Gastro-entérologie, Humans, Medicine, Registries, Israel, Child, Pediatric gastroenterology, Helicobacter pylori, biology, business.industry, Gastroenterology, Amoxicillin, Endoscopy, Odds ratio, biology.organism_classification, Helicobacter Pylori, Abdominal Pain, Anti-Bacterial Agents, Europe, Infecções Gastrointestinais, Pediatrics, Perinatology and Child Health, Pediatric Gastroenterology, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, business, Peptic Ulcer Disease, medicine.drug
Abstract

OBJECTIVES: The aim of the study was to assess clinical presentation, endoscopic findings, antibiotic susceptibility and treatment success of Helicobacter pylori (H. pylori) infected pediatric patients. METHODS: Between 2013 and 2016, 23 pediatric hospitals from 17 countries prospectively submitted data on consecutive H. pylori-infected (culture positive) patients to the EuroPedHP-Registry. RESULTS: Of 1333 patients recruited (55.1% girls, median age 12.6 years), 1168 (87.6%) were therapy naïve (group A) and 165 (12.4%) had failed treatment (group B). Patients resided in North/Western (29.6%), Southern (34.1%) and Eastern Europe (23.0%), or Israel/Turkey (13.4%). Main indications for endoscopy were abdominal pain or dyspepsia (81.2%, 1078/1328). Antral nodularity was reported in 77.8% (1031/1326) of patients, gastric or duodenal ulcers and erosions in 5.1% and 12.8%, respectively. Primary resistance to clarithromycin (CLA) and metronidazole (MET) occurred in 25% and 21%, respectively, and increased after failed therapy. Bacterial strains were fully susceptible in 60.5% of group A, but in only 27.4% of group B. Primary CLA resistance was higher in Southern and Eastern Europe (adjusted odds ratio [ORadj] = 3.44, 95% confidence interval [CI] 2.22-5.32, P, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2020

14. Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency

Author

Liting Li, Jian-She Wang, Ozlem Durmaz, Felipe Ordonez, Wikrom Karnsakul, Seema Alam, Cristina Targa Ferreira, Natural Course, Bettina E. Hansen, Kyung Mo Kim, Etienne Sokal, Ryan T. Fischer, Valerie Sency, Estella M. Alonso, Simon Horslen, Elisa de Carvalho, Piotr Czubkowski, Emanuele Nicastro, Nanda Kerkar, Dieter C. Broering, Björn Fischler, Dorothee Krebs-Schmitt, Kathleen M. Loomes, Dominique Debray, Marianne Hørby Jørgensen, Benjamin L. Shneider, Emmanuel Gonzales, Cigdem Arikan, Nathalie Rock, Antal Dezsőfi, Tassos Grammatikopoulos, Steffen Hartleif, Mara Cananzi, Talal Algoufi, Ronald J. Sokol, Jan B F Hulscher, Carolina Jimenez-Rivera, Emmanuel Jacquemin, Anne Spraul, Henkjan J. Verkade, Patryk Lipiński, Daan B E van Wessel, Nejat Mazhar, Maria Rogalidou, Deirdre Kelly, Alexandre Fabre, Daniele Serranti, Pier Luigi Calvo, Yael Mozer-Glassberg, Richard J. Thompson, Cristina Goncalves, Yumirle P. Turmelle, Jesus Quintero Bernabeu, Agustina Kadaristiana, Florence Lacaille, Loreto Hierro, Mohammad Shagrani, Patrick J. McKiernan, Girish S. Rao, Gema Muñoz Bartolo, Huey-Ling Chen, Wendy L. van der Woerd, Irena Jankowska, Amer Azaz, Philip J. Rosenthal, Frederick J. Suchy, Jernej Brecelj, Gabriella Nebbia, Noemie Laverdure, Henrik Arnell, Binita M. Kamath, Heng Wang, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), 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., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Center for Liver, Digestive and Metabolic Diseases (CLDM), UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique

Subjects
0301 basic medicine, Male, [SDV]Life Sciences [q-bio], CHILDREN, Compound heterozygosity, Gastroenterology, PFIC1, DISEASE, 0302 clinical medicine, Genotype, Medicine, Prospective Studies, Prospective cohort study, Child, ComputingMilieux_MISCELLANEOUS, Adenosine Triphosphatases, ATP8B1 GENE, Bile acid, Progressive familial intrahepatic cholestasis, Prognosis, Treatment Outcome, Codon, Nonsense, Child, Preschool, Cohort, 030211 gastroenterology & hepatology, Female, Original Article, EXPRESSION, medicine.medical_specialty, Adolescent, medicine.drug_class, Cholestasis, Intrahepatic, Risk Assessment, Frameshift mutation, Bile Acids and Salts, 03 medical and health sciences, Young Adult, FAMILIAL INTRAHEPATIC CHOLESTASIS, Internal medicine, Humans, ABCB11 MUTATIONS, Survival analysis, TYPE-1, ATP8B1, FIC1 deficiency, Serum bile acids, Surgical biliary diversion, Retrospective Studies, [SDV.GEN]Life Sciences [q-bio]/Genetics, Hepatology, business.industry, Infant, Original Articles, medicine.disease, Survival Analysis, Liver Transplantation, SALT EXPORT PUMP, 030104 developmental biology, Bile Ducts, Intrahepatic, Autoimmune, Cholestatic and Biliary Disease, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
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, University of Colorado; Baylor College of Medicine; Children’s Hospital of Philadelphia; Children’s Hospital of Pittsburgh; St Louis Children’s Hospital; Riley Hospital for Children; Seattle Children’s Hospital; M.D./Ph.D. Scholarship from the University of Groningen; European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Networking Grant 2019; ChilDReN National Institutes of Health Grants; Ann & Robert H. Lurie Children’s Hospital; Albireo and Mirum Pharmaceuticals

Published
2021

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

Author

Hansen BE, Vandriel SM, Vig P, Garner W, Mogul DB, Loomes KM, Piccoli DA, Rand EB, Jankowska I, Czubkowski P, Gliwicz-Miedzińska D, Gonzales EM, Jacquemin E, Bouligand J, D'Antiga L, Nicastro E, Arnell H, Fischler B, Sokal É, Demaret T, Siew S, Stormon M, Karpen SJ, Romero R, Ebel NH, Feinstein JA, Roberts AJ, Evans HM, Sundaram SS, Chaidez A, Hardikar W, Shankar S, Fischer RT, Lacaille F, Debray D, Lin HC, Jensen MK, Jaramillo C, Karthikeyan P, Indolfi G, Verkade HJ, Larson-Nath C, Quiros-Tejeira RE, Valentino PL, Rogalidou M, Dezsőfi A, Squires JE, Schwarz K, Calvo PL, Bernabeu JQ, Zizzo AN, Nebbia G, Bulut P, Santos-Silva E, Fawaz R, Nastasio S, Karnsakul W, Tamara ML, Busoms CM, Kelly DA, Sandahl TD, Jimenez-Rivera C, Banales JM, Mujawar Q, Li LT, She H, Wang JS, Kim KM, Oh SH, Sanchez MC, Cavalieri ML, Lee WS, Hajinicolaou C, Lertudomphonwanit C, Waisbourd-Zinman O, Arikan C, Alam S, Carvalho E, Melere M, Eshun J, Önal Z, Desai DM, Wiecek S, Pinto RB, Wolters VM, Garcia J, Beretta M, Kerkar N, Brecelj J, Rock N, Lurz E, Blondet N, Shah U, Thompson RJ, and Kamath BM

Subjects
Humans, Female, Male, Retrospective Studies, Child, Infant, Child, Preschool, Progression-Free Survival, Adolescent, Carrier Proteins, Membrane Glycoproteins, Alagille Syndrome complications, Alagille Syndrome drug therapy
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, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Published
2024
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16. Helicobacter pylori infection found during upper endoscopy performed for the diagnosis of celiac, inflammatory bowel diseases, and eosinophilic esophagitis: A multicenter pediatric European study.

Author

Kotilea K, Romano C, Miele E, Kindermann A, Dolstra Y, Misak Z, Urbonas V, Sykora J, Urruzuno P, Krauthammer A, Rogalidou M, Dimakou K, Zangen T, Roma E, Zellos A, Cilleruelo ML, M'Rini M, Bontems P, Sahin Y, Tavares M, Shahinyan T, Vuletic B, Kalach N, and Kori M

Subjects
Humans, Male, Female, Child, Retrospective Studies, Adolescent, Europe epidemiology, Prevalence, Endoscopy, Gastrointestinal, Child, Preschool, Helicobacter Infections diagnosis, Helicobacter Infections epidemiology, Helicobacter Infections drug therapy, Eosinophilic Esophagitis epidemiology, Eosinophilic Esophagitis diagnosis, Inflammatory Bowel Diseases epidemiology, Inflammatory Bowel Diseases diagnosis, Inflammatory Bowel Diseases microbiology, Helicobacter pylori isolation & purification, Celiac Disease diagnosis, Celiac Disease epidemiology
Abstract

Background: Helicobacter pylori may be found during upper gastrointestinal endoscopy (UGE) performed to diagnose celiac disease (CeD), inflammatory bowel disease (IBD), and eosinophilic esophagitis (EoE). We aimed to describe the frequency of H. pylori in children undergoing UGE for CeD, IBD, and EoE and the number of children receiving eradication treatment., Materials and Methods: A retrospective multicenter study from 14 countries included pediatric patients diagnosed with CeD, IBD, and EoE between January 2019 and December 2021., Data Collected: age, gender, hematologic parameters, endoscopic, histologic, and H. pylori culture results, and information on eradication treatment., Results: H. pylori was identified in 349/3890 (9%) children [167 (48%) male, median 12 years (interquartile range 8.1-14.6)]. H. pylori was present in 10% (173/1733) CeD, 8.5% (110/1292) IBD and 7.6% (66/865) EoE patients (p = NS). The prevalence differed significantly between Europe (Eastern 5.2% (28/536), Southern 3.8% (78/2032), Western 5.6% (28/513)) and the Middle East 26.6% (215/809) [odds ratio (OR) 7.96 95% confidence interval (CI) (6.31-10.1) p < 0.0001]. Eradication treatment was prescribed in 131/349 (37.5%) patients, 34.6% CeD, 35.8% IBD, and 56.1% EoE. Predictors for recommending treatment included erosions/ulcers [OR 6.45 95% CI 3.62-11.47, p < 0.0001] and nodular gastritis [OR 2.25 95% CI 1.33-3.81, p 0.003]. Treatment rates were higher in centers with a low H. pylori prevalence (<20%) [OR 3.36 95% CI 1.47-7.66 p 0.004]., Conclusions: Identifying H. pylori incidentally during UGE performed for the most common gastrointestinal diseases varies significantly among regions but not among diseases. The indications for recommending treatment are not well defined, and less than 40% of children received treatment., (© 2024 John Wiley & Sons Ltd.)

Published
2024
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17. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study.

Author

Vandriel SM, Li LT, She H, Wang JS, Gilbert MA, Jankowska I, Czubkowski P, Gliwicz-Miedzińska D, Gonzales EM, Jacquemin E, Bouligand J, Spinner NB, Loomes KM, Piccoli DA, D'Antiga L, Nicastro E, Sokal É, 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, Önal Z, Valentino PL, Desai DM, Eshun J, Rogalidou M, Dezsőfi 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

Subjects
Humans, Child, Male, Female, Retrospective Studies, Alagille Syndrome epidemiology, Cholestasis, Hypertension, Portal etiology
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., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of American Association for the Study of Liver Diseases.)

Published
2023
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18. Mitochondrial neurogastrointestinal encephalomyopathy: Clinical and biochemical impact of allogeneic stem cell transplantation in a Greek patient with one novel TYMP mutation.

Author

Paisiou A, Rogalidou M, Pons R, Ioannidou E, Dimakou K, Papadopoulou A, Vaz FM, Vessalas G, Goorden SMI, Roelofsen J, Zoetekouw A, Nieman MM, Dimitriou E, Moraitou M, Peristeri I, Michelakakis H, and van Kuilenburg ABP

Abstract

We describe the case of a Greek female patient with the Classic form of the ultra- rare and fatal autosomal recessive disorder Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and the impact of allogeneic hematopoietic stem cell transplantation on the biochemical and clinical aspects of the disease. The patient presented at the age of 15 years with severe gastrointestinal symptoms, cachexia, peripheral neuropathy and diffuse leukoencephalopathy. The diagnosis of MNGIE disease was established by the increased levels of thymidine and deoxyuridine in plasma and the complete deficiency of thymidine phosphorylase activity. The novel c.[978dup] (p.Ala327Argfs*?) variant and the previously described variant c.[417 + 1G > A] were identified in TYMP. The donor for the allogeneic hematopoietic stem cell transplantation was her fully compatible sister, a carrier of the disease. The patient had a completely uneventful post- transplant period and satisfactory PB chimerism levels. A marked and rapid decrease in thymidine and deoxyuridine plasma levels and an increase of the thymidine phosphorylase activity to the levels measured in her donor sister was observed and is still present sixteen months post-transplant. Disease symptoms stabilized and some improvement was also observed both in her neurological and gastrointestinal symptoms. Follow up studies will be essential for determining the long term impact of allogeneic hematopoietic stem cell transplantation in our patient., Competing Interests: None., (© 2021 Published by Elsevier Inc.)

Published
2021
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19. Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

Author

van Wessel DBE, Thompson RJ, Gonzales E, Jankowska I, Shneider BL, 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 JBF, Serranti D, Arikan C, 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 WL, Wang JS, Li LT, Durmaz Ö, Kerkar N, Hørby Jørgensen M, Fischer R, Jimenez-Rivera C, Alam S, Cananzi M, Laverdure N, Targa Ferreira C, Ordonez F, Wang H, Sency V, Mo Kim K, Chen HL, Carvalho E, Fabre A, Quintero Bernabeu J, Alonso EM, Sokol RJ, Suchy FJ, Loomes KM, McKiernan PJ, Rosenthal P, Turmelle Y, Rao GS, Horslen S, Kamath BM, Rogalidou M, Karnsakul WW, Hansen B, and Verkade HJ

Subjects
Adenosine Triphosphatases genetics, Adolescent, Bile Ducts, Intrahepatic surgery, Child, Child, Preschool, Cholestasis, Intrahepatic blood, Cholestasis, Intrahepatic genetics, Cholestasis, Intrahepatic surgery, Codon, Nonsense, Female, Follow-Up Studies, Humans, Infant, Liver Transplantation statistics & numerical data, Male, Prognosis, Prospective Studies, Retrospective Studies, Risk Assessment methods, Risk Assessment statistics & numerical data, Survival Analysis, Treatment Outcome, Young Adult, Adenosine Triphosphatases deficiency, Bile Acids and Salts blood, Cholestasis, Intrahepatic mortality
Abstract

Background and Aims: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. 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 insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date., Approach and Results: 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 PPTMs), 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 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. 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 < 65 μmol/L (P = 0.05) tended to be associated with improved NLS., Conclusions: Less than half of patients with FIC1 deficiency 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., (© The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Published
2021
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21. Telogen effluvium as the first symptom of Crohn's disease in a child.

Author

Rogalidou M, Tzoufi M, Katsanos K, Gaitanis G, Zioga A, Tsianos E, and Siamopoulou-Mavridou A

Abstract

Crohn's disease usually manifests gastrointestinal symptoms, however in some cases the patient presents with prominent or even exclusive extraintestinal involvement. Alopecia has been reported as a complication of therapeutic agents used in the treatment of inflammatory bowel disease, and, in a few cases of adult patients, prior to the appearance of gastrointestinal symptoms. We present a 10 year-old-child with telogen effluvium that appeared one year before the diagnosis of Crohn's disease, as the first and only symptom at that time. Other systemic causes of hair loss such as micronutrient deficiencies, endocrine imbalance or chemical exposure were excluded. Eight months later the patient presented with mild iron deficiency and signs of social retraction, while two months before the final diagnosis of Crohn's disease other more characteristic alarming symptoms (mild fever, oral apthous ulcers, weight loss) were added to the clinical picture. Alopecia improved after remission of Crohn's disease, reappeared when the patient relapsed, and finally resolved gradually when complete remission of Crohn's disease was achieved. Telogen effluvium was the first symptom of Crohn's disease in a child, and, although this is a rare association, it should be considered as an extraintestinal manifestation of Crohn's disease.

Published
2014

22. Caroli's disease: Description of a case with a benign clinical course.

Author

Tzoufi M, Rogalidou M, Drimtzia E, Sionti I, Nakou I, Argyropoulou M, Tsianos EV, and Siamopoulou-Mavridou A

Abstract

Caroli's disease is a rare congenital disorder characterized by cystic dilatation of the large in-trahepatic bile ducts. The most frequent complications due to biliary stasis are cholelithiasis, cholangitis and sepsis as well as an increased risk of cholangiocarcinoma. Patients may have a history of intermittent abdominal pain, pruritus and/or symptoms of cholangitis. It is rarely diagnosed in childhood. A 12-year-old boy with isolated Caroli's disease is described. This child presented at the age of 2 years, with 4 episodes of recurrent bacterial infections. Interestingly he remained asymptomatic for over 10 years, between the second and third episode. During the 4th episode, when he presented with fever and slight abdominal pain, the diagnosis was made on the basis of radiological findings: U/S, CT, MRI and especially with MRCP, in relation with a more typical picture, resembling cholangitis. Since then he has been followed-up systematically for ten years and remains in good clinical condition without further relapses and with unchanged radiological findings. This atypically benign course of Caroli's disease, with intermittent asymptomatic periods, without any treatment, is very rare.

Published
2011

24. Serum carnitine levels in childhood leukemia.

Author

Rogalidou M, Evangeliou A, Stiakaki E, Giahnakis E, and Kalmanti M

Subjects
Acute Disease, Adolescent, Body Mass Index, Carnitine administration & dosage, Carnitine analogs & derivatives, Child, Child, Preschool, Female, Humans, Leukemia drug therapy, Male, Muscle, Skeletal metabolism, Carnitine blood, Leukemia metabolism
Abstract

In patients with malignancies, the system of carnitine seems abnormally expressed. The serum total, free, and acyl carnitine levels in 40 children and adolescents with acute leukemia were determined using electrospray tandem mass spectrometry in 4 different phases of the disease: at the diagnosis, 1 year after the initiation of chemotherapy, at the end of treatment, and 2.4+/-1.668 years after the completion of chemotherapy. The age, sex, hemoglobin values, serum biochemistry, somatometric features of the patients, and the risk group of the disease were examined. Although the carnitine levels were found higher in patients compared with the control group from diagnosis to treatment completion, statistically significant decrease in carnitine levels was observed in patients within different phases of the disease especially during induction and consolidation treatment (phase A to B) for both free and total (P=0.023) carnitine. In addition, a statistically significant recovery in carnitine levels was observed between phase B (end of intensive chemotherapy) and D (some years after the completion of treatment) for free and total carnitine (P=0.054 and 0.035, respectively). No statistical correlation was documented between the carnitine levels and somatometric parameters or other variables studied. In conclusion, a significant transient decrease in the levels of carnitine during the treatment was observed in children with acute leukemia. Further studies are required to clarify the role of carnitine status in patients with malignancies and possibly the necessity of carnitine supplementation during chemotherapy administration.

Published
2010
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25. 3C syndrome with cryptorchidism and posterior embryotoxon.

Author

Papadopoulou E, Sifakis S, Rogalidou M, Makrigiannakis A, Giannakopoulou C, and Petersen MB

Subjects
Abnormalities, Multiple genetics, Cornea abnormalities, Dandy-Walker Syndrome diagnosis, Dandy-Walker Syndrome pathology, Diagnosis, Differential, Greece, Humans, Infant, Newborn, Karyotyping, Male, Syndrome, Abnormalities, Multiple diagnosis, Central Nervous System abnormalities, Craniofacial Abnormalities pathology, Cryptorchidism pathology, Heart Defects, Congenital pathology
Abstract

We report a case of the 3C (cranio-cerebello-cardiac) syndrome, also known as Ritscher-Schinzel syndrome, a rare autosomal recessive disorder characterized by craniofacial, cerebellar, and cardiac anomalies. In addition to features previously reported the child had Wormian bones of the skull, intra-abdominal testes, and posterior embryotoxon that have not previously been reported as part of the 3C syndrome.

Published
2005

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