Browsing by Subject "Intrahepatic bile ducts"

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    Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency
    (Wolters Kluwer, 2021-08) van Wessel, Daan B.E.; Thompson, Richard J.; Gonzales, Emmanuel; Jankowska, Irena; Shneider, Benjamin L.; Sokal, Etienne; Grammatikopoulos, Tassos; Kadaristiana, Agustina; Jacquemin, Emmanuel; Spraul, Anne; Lipiński, Patryk; Czubkowski, Piotr; Rock, Nathalie; Shagrani, Mohammad; Broering, Dieter; Algoufi, Talal; Mazhar, Nejat; Nicastro, Emanuele; Kelly, Deirdre; Nebbia, Gabriella; Arnell, Henrik; Fischler, Björn; Hulscher, Jan B.F.; Serranti, Daniele; Arikan, Cigdem; Debray, Dominique; Lacaille, Florence; Goncalves, Cristina; Hierro, Loreto; Muñoz Bartolo, Gema; Mozer-Glassberg, Yael; Azaz, Amer; Brecelj, Jernej; Dezsőfi, Antal; Calvo, Pier Luigi; Krebs-Schmitt, Dorothee; Hartleif, Steffen; van der Woerd, Wendy L.; Wang, Jian-She; Li, Li-ting; Durmaz, Özlem; Kerkar, Nanda; Hørby Jørgensen, Marianne; Fischer, Ryan; Jimenez-Rivera, Carolina; Alam, Seema; Cananzi, Mara; Laverdure, Noémie; Targa Ferreira, Cristina; Ordonez, Felipe; Wang, Heng; Sency, Valerie; Kim, Kyung Mo; Chen, Huey-Ling; Carvalho, Elisa; Fabre, Alexandre; Bernabeu, Jesus Quintero; Alonso, Estella M.; Sokol, Ronald J.; Suchy, Frederick J.; Loomes, Kathleen M.; McKiernan, Patrick J.; Rosenthal, Philip; Turmelle, Yumirle; Rao, Girish S.; Horslen, Simon; Kamath, Binita M.; Rogalidou, Maria; Karnsakul, Wikrom W.; Hansen, Bettina; Verkade, Henkjan J.; Pediatrics, School of Medicine
    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.
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    Organoids and Spheroids as Models for Studying Cholestatic Liver Injury and Cholangiocarcinoma
    (Wolters Kluwer, 2021) Sato, Keisaku; Zhang, Wenjun; Safarikia, Samira; Isidan, Abdulkadir; Chen, Angela M.; Li, Ping; Francis, Heather; Kennedy, Lindsey; Baiocchi, Leonardo; Alvaro, Domenico; Glaser, Shannon; Ekser, Burcin; Alpini, Gianfranco; Medicine, School of Medicine
    Cholangiopathies, such as primary sclerosing cholangitis, biliary atresia, and cholangiocarcinoma, have limited experimental models. Not only cholangiocytes but also other hepatic cells including hepatic stellate cells and macrophages are involved in the pathophysiology of cholangiopathies, and these hepatic cells orchestrate the coordinated response against diseased conditions. Classic two-dimensional monolayer cell cultures do not resemble intercellular cell-to-cell interaction and communication; however, three-dimensional cell culture systems, such as organoids and spheroids, can mimic cellular interaction and architecture between hepatic cells. Previous studies have demonstrated the generation of hepatic or biliary organoids/spheroids using various cell sources including pluripotent stem cells, hepatic progenitor cells, primary cells from liver biopsies, and immortalized cell lines. Gene manipulation, such as transfection and transduction can be performed in organoids, and established organoids have functional characteristics which can be suitable for drug screening. This review summarizes current methodologies for organoid/spheroid formation and a potential for three-dimensional hepatic cell cultures as in vitro models of cholangiopathies.