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Ganschow R, Richter A, Grabhorn E, Schulz A, von Hugo A, Mir TS, Broering DC, Rogiers X, Hinrichs B, Burdelski M. C2 blood concentrations of orally administered cyclosporine in pediatric liver graft recipients with a body weight below 10 kg. Pediatr Transplantation 2004: 8: 185–188. © 2004 Blackwell Munksgaard Pharmacokinetic studies in adult and pediatric liver transplant recipients have shown that the C2 monitoring is superior to the traditional determination of CsA trough levels (C0) as an estimate of CsA exposure. However, target reference values for C2 in very small infants have not been established yet. The objective of our study was to assess the distribution of C2 levels in the first week following Ltx and to analyze enteral absorption of CsA for this group of patients. We documented CsA C0 and C2 levels in 25 infants with a body weight below 10 kg (median 6.8 kg; range 3.0–9.8 kg) in the first 7 days after Ltx. The infants had a median age at transplantation of 7 months (range 0.3–20.0 months). The underlying diagnoses were biliary atresia (n = 17), acute liver failure (n = 4), metabolic disease (n = 4). All children received CsA microemulsion (NeoralTM, initial 10 mg/kg/day), prednisolone, and two single doses of basiliximab as immunosuppressive drugs. The mean C0 and C2 levels were as follows: day 1: C0 77.0 ± 39.6, C2 340.5 ± 140.0 ng/mL; day 2: C0 135.5 ± 53.2, C2 467.0 ± 168.2 ng/mL; day 3: C0 146.5 ± 70.8, C2 519.0 ± 219.1 ng/mL; day 4: C0 168.5 ± 55.1, C2 570.0 ± 163.7 ng/mL; day 5: C0 156.5 ± 38.0, C2 612.0 ± 132.4 ng/mL; day 6: C0 177.0 ± 41.1, C2 606.0 ± 149.2 ng/mL; day 7: C0 174.0 ± 27.2, C2 622.0 ± 98.8 ng/mL (r = 0.82, p < 0.05). This analysis demonstrates that there is a good enteral absorption of CsA in very small children post-Ltx in the early post-operative period. Based on the C2 levels achieved, we conclude that there is a good correlation between C0 and C2 levels even in very small infants. [ABSTRACT FROM AUTHOR]

Background: Oral cholic acid therapy is an effective therapy in children with primary bile acid synthesis deficiencies. Most reported patients with this treatment have 3β-hydroxy-Δ 5 -C 27 -steroid oxidoreductase deficiency. The aim of the study was the evaluation of cholic acid therapy in a cohort of patients with the rarer Δ 4 -3-oxosteroid 5β-reductase (Δ 4 -3-oxo-R) deficiency., Methods: Sixteen patients with Δ 4 -3-oxo-R deficiency confirmed by AKR1D1 gene sequencing who received oral cholic acid were retrospectively analyzed., Results: First symptoms were reported early in life (median 2 months of age), with 14 and 3 patients having cholestatic jaundice and severe bleeding respectively. Fifteen patients received ursodeoxycholic acid before diagnosis, with partial improvement in 8 patients. Four patients had liver failure at the time of cholic acid initiation. All 16 patients received cholic acid from a median age of 8.1 months (range 3.1-159) and serum liver tests normalized in all within 6-12 months of treatment. After a median cholic acid therapy of 4.5 years (range 1.1-24), all patients were alive with their native liver. Median daily cholic acid dose at last follow-up was 8.3 mg/kg of body weight. All patients, but one, had normal physical examination and all had normal serum liver tests. Fibrosis, evaluated using liver biopsy (n = 4) or liver elastography (n = 9), had stabilized or improved. Cholic acid therapy enabled a 12-fold decrease of 3-oxo-∆ 4 derivatives in urine. Patients had normal growth and quality of life. The treatment was well tolerated without serious adverse events and signs of hepatotoxicity., Conclusions: Oral cholic acid therapy is a safe and effective treatment for patients with Δ 4 -3-oxo-R deficiency., (© 2023. The Author(s).)

Crigler-Najjar Syndrome (CNS) with residual activity of UDP-glucuronosyltransferase 1A1 ( UGT1A1 ) and no need for daily phototherapy is called mild Crigler-Najjar Syndrome. Most of these patients need medical treatment for enzyme induction (phenobarbital) to lower blood levels of unconjugated bilirubin (UCB). Apart from this, no long-term problems have been described so far. The phenotype of patients with the homozygous pathogenic variant c.115C>G p.(His39Asp) in UGT1A1 is described as variable. Clinical observations of our patients led to the assumption that patients with variant c.115C>G have a mild CNS phenotype while having a high risk of developing progressive liver disease. For mild CNS disease, progressive liver disease has not been described so far. Therefore, we conducted a retrospective multicenter analysis of 14 patients with this particular variant, aiming for better characterization of this variant. We could confirm that patients with variant c.115C>G have a high risk of progressive liver disease (seven of fourteen), which increases with age despite having a very mild CNS phenotype. Earlier predictors and causes for an unfavorable disease course are not detectable, but close follow-up could identify patients with progressive liver disease at the beginning. In conclusion, these patients need close and specialized follow-up. Our study questions whether fibrosis in the CNS is really driven by high amounts of UCB or phototherapy.

Objectives: Protocol liver biopsies (PLBs) are part of the follow-up program at many pediatric liver transplant centers, but the impact on clinical decision-making and allograft histology following adjustments of immunosuppression (IS) after PLB has not been thoroughly analyzed., Methods: Following our previous single-center cohort study, we have now evaluated histological findings of 178 PLBs of 118 pediatric patients transplanted at our center between 1998 and 2017. In particular, we focused on the changes in allograft histology in the follow-up biopsy of a subgroup of 22 patients, in which the histologic findings led to an adjustment of immunosuppressive therapy. All biopsies of this sub-study group were reevaluated by an experienced pathologist., Results: The overall frequency and severity of fibrosis increased over time after orthotopic liver transplantation. Patients with donor-specific antibodies (DSAs) had a higher prevalence of fibrosis than DSA-negative patients. Graft inflammation decreased significantly after intensifying IS, but renal function needs to be monitored. A significant increase in fibrosis was detected in children with reduced IS., Conclusion: The adjustment of IS following PLBs has a significant impact on allograft histology. Since chronic inflammatory changes may lead to graft failure, adjustment of IS seems to be of major importance for the long-term outcome., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Liver cirrhosis in children is a rare disease with multifactorial causes that are distinct from those in adults. Underlying reasons include cholestatic, viral, autoimmune, hereditary, metabolic and cardiac disorders. Early detection of fibrosis is important as clinical stabilization or even reversal of fibrosis can be achieved in some disorders with adequate treatment. This article focuses on the longitudinal evaluation of children with chronic liver disease with noninvasive imaging tools, which play an important role in detecting cirrhosis, defining underlying causes, grading fibrosis and monitoring patients during follow-up. Ultrasound is the primary imaging modality and it is used in a multiparametric fashion. Magnetic resonance imaging and computed tomography are usually applied second line for refined tissue characterization, clarification of nodular lesions and full delineation of abdominal vessels, including portosystemic communications., (© 2022. The Author(s).)

Introduction: Combined or sequential liver and kidney transplantation (CLKT/SLKT) restores kidney function and corrects the underlying metabolic defect in children with end-stage kidney disease in primary hyperoxaluria type 1 (PH1). However, data on long-term outcome, especially in children with infantile PH1, are rare., Methods: All pediatric PH1-patients who underwent CLKT/SLKT at our center were analyzed retrospectively., Results: Eighteen patients (infantile PH1 n  = 10, juvenile PH1 n  = 8) underwent transplantation (CLKT n  = 17, SLKT n  = 1) at a median age of 5.4 years (1.5-11.8). Patient survival was 94% after a median follow-up of 9.2 years (6.4-11.0). Liver and kidney survival-rates after 1, 10, and 15 years were 90%, 85%, 85%, and 90%, 75%, 75%, respectively. Age at transplantation was significantly lower in infantile than juvenile PH1 (1.6 years (1.4-2.4) vs. 12.8 years (8.4-14.1), P  = 0.003). Median follow-up was 11.0 years (6.8-11.6) in patients with infantile PH1 vs. 6.9 years (5.7-9.9) in juvenile PH1 ( P  = 0.15). At latest follow-up kidney and/or liver graft loss and/or death showed a tendency to a higher rate in patients with infantile vs. juvenile PH1 (3/10 vs. 1/8, P  = 0.59)., Discussion: In conclusion, the overall patient survival and long-term transplant outcome of patients after CLKT/SLKT for PH1 is encouraging. However, results in infantile PH1 tended to be less optimal than in patients with juvenile PH1., Competing Interests: The following authors received support for travel, honoraria (for consultancy, lectures, and/ or board membership), and/ or grants from Alnylam: Authors SL, MJK, JO, FB. Author BH received support for travel, honoraria (for consultancy, lectures, and/ or board membership) from Dicerna Pharmaceuticals/NovoNordisk and was an employee of Dicerna Pharmaceuticals/NovoNordisk., (© 2023 Loos, Kemper, Schmaeschke, Herden, Fischer, Hoppe, Levart, Grabhorn, Schild, Oh and Brinkert.)

Introduction: Immunosuppression after pediatric liver transplantation remains a major challenge. MTOR inhibitors provide a promising therapeutic approach in combination with reduced CNI after transplantation. However, there are still few data regarding their use in children., Patients: We analyzed 37 patients with a median age of 10 years, who received Everolimus for one or more of the following indications: I = chronic graft dysfunction ( n = 22); II = progressive renal impairment ( n = 5); III = non-tolerable side effects with previous immunosuppressive medication ( n = 6); and IV = malignancies ( n = 10). The median follow-up time was 36 months., Results: Patient survival was 97%, and graft survival 84%, respectively. Stabilization of graft function was observed in 59% in subgroup 1, with 18.2% ultimately requiring retransplantation. No patient in subgroup IV developed recurrence of his primary tumor or PTLD by the endpoint of the study. Side effects were observed in 67.5% of the study patients, with infections being the most frequent ( n = 20; 54.1%). There were no relevant effects on growth and development., Conclusion: Everolimus seems to be a treatment option in selected pediatric liver graft recipients for whom other regimens are not suitable. Overall, the efficacy was good and the side effect profile appeared to be acceptable.

Background & Aims: Antibody-induced bile salt export pump deficiency (AIBD) is an acquired form of intrahepatic cholestasis, which may develop following orthotopic liver transplantation (OLT) for progressive familial intrahepatic cholestasis type 2 (PFIC-2). Approximately 8-33% of patients with PFIC-2 who underwent a transplant develop bile salt export pump (BSEP) antibodies, which trans-inhibit this bile salt transporter from the extracellular, biliary side. AIBD is diagnosed by demonstration of BSEP-reactive and BSEP-inhibitory antibodies in patient serum. We developed a cell-based test directly measuring BSEP trans-inhibition by antibodies in serum samples to confirm AIBD diagnosis., Methods: Sera from healthy controls and cholestatic non-AIBD or AIBD cases were tested (1) for anticanalicular reactivity by immunofluorescence staining of human liver cryosections, (2) for anti-BSEP reactivity by immunofluorescence staining of human embryonic kidney 293 (HEK293) cells expressing BSEP-enhanced yellow fluorescent protein (EYFP) and immunodetection of BSEP-EYFP on Western blot, and (3) for BSEP trans-inhibition using HEK293 cells stably expressing Na + /taurocholate cotransporting polypeptide (NTCP)-mCherry and BSEP-EYFP. The trans-inhibition test uses [ 3 H]-taurocholate as substrate and is divided into an uptake phase dominated by NTCP followed by BSEP-mediated export. For functional analysis, sera were bile salt depleted., Results: We found BSEP trans-inhibition by seven sera containing anti-BSEP antibodies, but not by five cholestatic or nine control sera, all lacking BSEP reactivity. Prospective screening of a patient with PFIC-2 post OLT showed seroconversion to AIBD, and the novel test method allowed monitoring of treatment response. Notably, we identified a patient with PFIC-2 post OLT with anti-BSEP antibodies yet without BSEP trans-inhibition activity, in line with asymptomatic presentation at serum sampling., Conclusions: Our cell-based assay is the first direct functional test for AIBD and allows confirmation of diagnosis as well as monitoring under therapy. We propose an updated workflow for AIBD diagnosis including this functional assay., Impact and Implications: Antibody-induced BSEP deficiency (AIBD) is a potentially serious complication that may affect patients with PFIC-2 after liver transplantation. To improve its early diagnosis and thus immediate treatment, we developed a novel functional assay to confirm AIBD diagnosis using a patient's serum and propose an updated diagnostic algorithm for AIBD., Competing Interests: EL has received honoraria for lectures from Albireo and Mirum and has served on advisory boards for both companies and on the GPGE board of directors. UB has received grants from Mirum Pharma, Albireo Pharma, and Alexion Pharma and has received consulting fees and honoraria from Mirum, Albireo, Alexion, Nestle, and Vivet. CK has received travel grant from Falk. TB has received grants, consulting fees, and/or honoraria from Abbvie, Alexion, Bayer, BMS, Gilead, GSK, Eisai, Enyo Pharma, Falk Foundation, HepaRegeniX GmbH, Humedics, Intercept, Ipsen, Janssen, Medupdate GmbH, MSD/Merck, Merz, Norgine, Novartis, Orphalan, Roche, Sequana Medical, SIRTEX, SOBI, and Shionogi. VK has received honoraria for speaker’s bureau from Falk, Albireo, CSL, Sanofi, Gilead, Abbvie, and Intercept and has served on one advisory board for Astra Zeneca. All other authors declare that there is no potential conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Authors.)

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship., Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS., Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 ( p < 0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p < 0.001)., Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment., Impact and Implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency., Competing Interests: Antonia Felzen [MD/PhD scholarship University of Groningen], Daan B.E. van Wessel [MD/PhD scholarship University of Groningen], Emmanuel M. Gonzales [Consultant for CTRS, Vivet Therapeutics, Mirum Pharmaceuticals and Albireo], Richard J. Thompson [Consultant for Shire, Albireo, Mirum Pharmaceuticals, Horizon Pharmaceuticals, Sana Biotechnology, GenerationBio, Retrophin and Qing Bile Therapeutics], Irena Jankowska [Nothing to disclose], Benjamin L. Shneider [Nothing to disclose], Etienne Sokal [Founder, board director and Chairman of the Scientific & Medical advisor board of Promethera Biosciences; consultant Johnson&Johnson], Tassos Grammatikopoulos [Consultant for Albireo], Agustina Kadaristiana [Nothing to disclose], Emmanuel Jacquemin [Consultant for CTRS and Vivet Therapeutics], Anne Spraul [Nothing to disclose], Patryk Lipiński [Nothing to disclose], Piotr Czubkowski [Nothing to disclose], Nathalie Rock [Nothing to disclose], Mohammad Shagrani [Nothing to disclose], Dieter Broering [Nothing to disclose], Emanuele Nicastro [Nothing to disclose] Deirdre Kelly [Consultant for Albireo], Gabriela Nebbia [Nothing to disclose], Henrik Arnell [Consultant for Albireo and Mirum Pharmaceuticals], Bjorn Fischler [Attended one advisory board meeting with Albireo in 2016], Jan Hulscher [Nothing to disclose], Daniele Serranti [Nothing to disclose], Cigdem Arikan [Nothing to disclose], Esra Polat [Nothing to disclose], Dominique Debray [Consultant for Alexion and Orphalan pharmaceuticals], Florence Lacaille [Nothing to disclose], Cristina Goncalves [Nothing to disclose], Loreto Hierro [Nothing to disclose], Gema Munoz Bartolo [Nothing to disclose], Yael Mozer- Glassberg [Nothing to disclose], Amer Azaz [Nothing to disclose], Jernej Brecelj [Nothing to disclose], Antal Dezsofi [Nothing to disclose], Pier Luigi Calvo [Nothing to disclose], Enke Grabhorn [Nothing to disclose], Ekkehard Sturm [Nothing to disclose] Wendy van der Woerd [Nothing to disclose], Binita Kamath [Consultant for Mirum Pharmaceuticals, Shire and DCI], Jian-She Wang [Nothing to disclose], Liting Li [Nothing to disclose], Özlem Durmaz [Nothing to disclose], Nanda Kerkar [Nothing to disclose], Marianne Hørby Jørgensen [Nothing to disclose], Ryan Fischer [Consultant for Albireo and Mirum Pharmaceuticals], Carolina Jimenez-Rivera [Nothing to disclose], Seema Alam [Nothing to disclose], Mara Cananzi [Attended one advisory board meeting with Albireo, Mirum Pharmaceuticals and Nestlè; consultant for CTRS], Noemie Laverdure [Consultant for Abbvie], Cristina Targa Ferreira [Nothing to disclose], Felipe Ordoñez Guerrero [Nothing to disclose], Heng Wang [Nothing to disclose], Valerie Sency [Nothing to disclose], Kyungmo Kim [Nothing to disclose], Huey-Ling Chen [Nothing to disclose], Elisa de Carvalho [Nothing to disclose], Alexandre Fabre [Nothing to disclose], Jesus Quintero Bernabeu [Nothing to disclose], Aglaia Zellos [Nothing to disclose], Estella M. Alonso [Nothing to disclose], Ronald J. Sokol [Consultant for Albireo and Mirum Pharmaceuticals], Frederick J. Suchy [Nothing to disclose], Kathleen M. Loomes [Consultant for Albireo, Mirum and Travere Therapeutics], Patrick J. McKiernan [Consultant for Albireo], Philip Rosenthal [Grant/Research Support by Gilead, AbbVie, Merck, Albireo, Mirum Pharmaceuticals, Arrowhead and Travere; consultant for Gilead, AbbVie, Audentes, Dicerna, Albireo, Mirum Pharmaceuticals, Travere, Takeda, Encoded, BioMarin, MedinCell and Ambys], Yumirle Turmelle [Nothing to disclose], Simon Horslen [Grant/Research support from Mirum Pharmaceuticals], Kathleen Schwarz [Grant support from Gilead, Albireo and the Global Alagille Syndrome Alliance; consultant for Mirum Pharmaceuticals, Up to Date and Sarepta], Jorge A. Bezerra [Grant support from Gilead and Albireo], Kasper Wang [Nothing to disclose], Bettina Hansen [Unrestricted grant support from Cymabay, Intercept, Calliditas, Mirum Pharmaceuticals and Albireo; consultant for Mirum Pharmaceuticals, Albireo AB, Chemomab, Calliditas, Intercept, Cyma Bay,], Henkjan J. Verkade [Consultant for Danone/Nutricia Research, Ausnutria BV, Albireo AB, Mirum Parmaceuticals, Intercept and Vivet]. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Pediatric liver transplantation (PLT) has very good results at experienced transplant centers. However, there is still an ongoing discussion about inferior outcomes, especially in young infants. The aim of this retrospective study was to evaluate outcomes of infants compared to older recipients in a single center over 20 years. We conducted a retrospective study of children who received liver transplants at our center between 1991 and 2011. Only patients without other limiting organ involvement were included and compared according to age. The inclusion criteria were fulfilled by 351 patients (173 vs. 178). The most common indication in both groups was biliary atresia (82.1% vs. 49.4%). The 1-, 5-, and 10-year patient survivals were 93.8%/91.8%/91.1% and 93%/90.8%/90.1%, and the graft survivals were 90.4%/83.5%/79.6% and 89.4%/81.8%/77.5%, respectively. Complications such as postoperative bleeding, biliary complications, or perfusion impairment occurred more often in infants. Leading indications for retransplantation (vascular complications/primary nonfunction) and leading causes of death (sepsis/multiorgan failure) were the same in both groups. Significant predictors for patient loss were decade of transplantation, retransplantation, postoperative bleeding, and infections for infants. Predictors for graft loss were bowel perforation, arterial thrombosis, and age >12 months. Children can have excellent results, independent of age at PLT., (© 2021 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Background & Aims: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date., Methods: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category., Results: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 μmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001)., Conclusions: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS., Lay Summary: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease., Competing Interests: Conflicts of interest Daan B.E. van Wessel: [nothing to disclose], Richard J. Thompson [consultancy for Shire, Albireo, Mirum, Horizon Pharmaceuticals, Sana Biotechnology, GenerationBio, Retrophin and Qing Bile Therapeutics], Emmanuel M. Gonzales [Consultant for CTRS and Mirum Pharmaceuticals], Irena Jankowska [nothing to disclose], Tassos Grammatikopoulos [nothing to disclose], Agustina Kadaristiana [nothing to disclose], Patryk Lipiński [nothing to disclose], Piotr Czubkowski [nothing to disclose], Nathalie Rock [nothing to disclose] Emmanuel Jacquemin [nothing to disclose], Anne Spraul [nothing to disclose], Etienne M. Sokal [founder and CSMO of Promethera Biosciences], Mohammad Shagrani [nothing to disclose], Dieter Broering [nothing to disclose], Talal Algoufi [nothing to disclose], Nejat Mazhar [nothing to disclose], Emanuele Nicastro [nothing to disclose] Deirdre Kelly [Consultant for Albireo], Gabriela Nebbia [nothing to disclose], Henrik Arnell [consultant for Albireo and Mirum Pharmaceuticals], Björn Fischler [has attended one advisory board meeting with Albireo in 2016], Jan Hulscher [nothing to disclose], Daniele Serranti [nothing to disclose], Cigdem Arikan [nothing to disclose], Esra Polat [nothing to disclose], Dominique Debray [consultant for Alexion pharmaceuticals], Florence Lacaille [nothing to disclose], Cristina Goncalves [nothing to disclose], Loreto Hierro [nothing to disclose], Gema Muñoz Bartolo [nothing to disclose], Yael Mozer-Glassberg [nothing to disclose], Amer Azaz [nothing to disclose], Jernej Brecelj [nothing to disclose], Antal Dezsőfi [nothing to disclose], Pier Luigi Calvo [nothing to disclose], Enke Grabhorn [nothing to disclose], Ekkehard Sturm [nothing to disclose] Wendy van der Woerd [nothing to disclose], Binita Kamath [consultant for Mirum Pharmaceuticals, Shire and DCI], Jian-She Wang [nothing to disclose], Liting Li [nothing to disclose], Özlem Durmaz [nothing to disclose], Zerrin Onal [nothing to disclose], Ton Bunt [nothing to disclose], Bettina Hansen [consultant for Mirum Pharmaceuticals, Albireo AB, Chemomab, Calliditas, Intercept, Cyma Bay, unrestricted grants from Cyma bay, Intercept, Mirum and Albireo], Henkjan J. Verkade [Consultant for Danone/Nutricia Research, Ausnutria BV, Albireo AB, GMP+Orphan, Mirum Pharmaceuticals, Intercept and Vivet]. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. All rights reserved.)