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Background: 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. Methods: Multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born Jan-1997 - Aug-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. Results: 1433 children (57% male) from 67 centers in 29 countries were included. 10 and 18-years NLS rates were 54.4% and 40.3%. By 10 and 18-years, 51.5% and 66.0% of ALGS children 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% 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 novel therapies.

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

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 mu

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, 1. MD/PhD scholarship from the University of Groningen, Groningen, The Netherlands 2. ESPGHAN Networking Grant 2019 3. ChiLDReN and CTSA National Institutes of Health grants: Ann & Robert H. Lurie Children's Hospital, Chicago: U01DK062436; University of Colorado, Denver: U01DK62453, UL1 TR002535; Baylor college of Medicine, Houston: U01DK103149; Children's Hospital of Philadelphia, Philadelphia: U01DK062481, UL1TR000003; Children's Hospital of Pittsburgh, Pittsburgh: U01DK062466; University of California, San Francisco U01DK062500; University of California, San Francisco CTSI grant UL1TR001872; Riley Hospital for Children, Indianapolis: U01DK084536; Seattle Children’s Hospital, Seattle: DK084575; Children’s Hospital Los Angeles, California: U01DK084538. 4. Unrestrictive research grant from Albireo 5. Unrestrictive research grant from Mirum Pharmaceuticals. 6. C&W de Boer Stichting research grant.

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

Background: Contrast-enhanced ultrasound (CEUS) by using sulfur hexafluoride microbubbles is not licensed for use in children, but its off-label use is widespread. Purpose: To outline our experience with the off-label use of CEUS in children, specifically with regards to safety. Material and Methods: We retrieved all records of 10681 patients aged under 18 years who underwent abdominal ultrasound (US) January 2004 to December 2014. We then identified those who underwent an abdominal CEUS using sulfur hexafluoride microbubbles. Electronic patient charts were used to verify the indication for contrast agent, dose, possible adverse effects as well as information on patient height, weight, and age. Results: We identified 173 patients (mean age, 11 years; range, 0.1–18 years) who underwent a total of 287 CEUS exams. Of all exams, 46% were performed on the native liver, 31% on a transplanted liver, and 23% on other organs. The indications were “circulatory status?” (40%), “characterization of lesion?” (40%), and miscellaneous (20%). Mean contrast dose was 2.3 mL (range, 0.1–8.1 mL). No immediate adverse effects were recorded. One patient experienced itching the day after, but this was considered to be a reaction to concomitantly administered fentanyl. Conclusion: The use of intravenous ultrasound contrast seems safe in patients aged under 18 years and our results do not support the current practice to restrict the use of CEUS in children.

Objectives: The Hepatology Committee of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) aims to educate pediatric gastroenterologists, members of ESPGHAN and professionals from other specialties promoting an exchange of clinical expertise in the field of pediatric hepatology. Methods: The 2020 single topic ESPGHAN monothematic 3-day conference on pediatric liver disease, was organized in Athens, Greece and was entitled " Acute Liver Failure" (ALF). ALF is a devastating disease with high mortality and in a considerable fraction of patients, the cause remains unresolved. As knowledge in diagnosis and treatment of ALF in infants and children has increased in the past decades, the objective was to update physicians in the field with developments in medical therapy and indications for liver transplantation (LT) and to identify areas for future research in clinical and neurocognitive outcomes in ALF. Results: We recently reported the epidemiology, diagnosis, and initial intensive care management issues in separate manuscript. Herewith we report on the medical treatment, clinical lessons arising from pediatric studies, nutritional and renal replacement therapy (RRT), indications and contraindications for LT, neurocognitive outcomes, new techniques used as bridging to LT, and areas for future research. Oral presentations by experts in various fields are summarized highlighting key learning points. Conclusions: The current report summarizes the current insights in medical treatment of pediatric ALF and the directions for future research.

Our main goal with this study was to share our off-label experience with CEUS for identifying circulatory complications after liver transplantation in children. A total of 74 CEUS examinations performed on 34 pediatric patients who underwent a liver transplant were retrospectively included. About 53% of the examinations were performed on children 2 years old or younger. About 82% of the examinations were performed within 30 days from the transplant. About 62% of patients were transplanted due to a cholestatic disease, 11% due to a metabolic disease, 8% were re-transplanted due to graft failure, and 19% was due to other conditions. BA was the most common reason for transplantation and represented 38% of patients. About 38% of the transplantations were performed with whole grafts from DD, 40% with split liver grafts, and 22% with left lateral segments from LD. For diagnosing arterial circulatory complications, the PPV was 80%. For diagnosing portal vein circulatory complications, the PPV was 66.7%. NPV was 100%. In 28% of the examinations, the examiner could not visualize the normal arterial blood flow without CEUS. CEUS is a non-invasive and safe imaging technique that seems valuable in these patients and further efforts are needed to license its use in the post-transplant setting.

Introduction: Contrast-enhanced ultrasound (CEUS) is a widely used diagnostic method. In adults, it has been proven to be a useful alternative to CT and MRI for the characterisation of focal liver lesions (FLLs). However, since there is no official paediatric licensing for any ultrasound contrast agents in Europe, its use has been restricted. Purpose: To retrospectively outline our experience with CEUS as a tool for the characterisation of FLLs in paediatric patients. Methods: An eleven-year retrospective single-centre study. During this period, we identified 287 CEUS examinations performed on children, of these 36 were relevant first-time examinations with the aim of characterising a focal liver lesion. Clinical and radiological data were collected from the hospital chart. Results: The overall agreement between the CEUS diagnosis and the reference diagnosis for benign versus malignant differentiation was 75%. When analysing conclusive CEUS examinations only, the overall agreement was 96%. The specificity for correctly characterising a lesion as benign was 96%, and the negative predictive value was 100%. No side effects from CEUS were detected. Conclusions: Our study reinforces that CEUS can be useful in the medical workup for the identification and classification of focal liver lesions in children.