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

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.

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

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.

ESPGHAN recommendations on treatment of chronic hepatitis C virus infection in adolescents and children including those living in resource-limited settings.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide, with more than three million viraemic adolescents and children. Treatment of adults with HCV infection and HCV-related liver disease has advanced considerably thanks to development and improvements in therapy. Direct-acting antiviral regimens are safe and effective. Three regimens with pangenotypic activity (glecaprevir/pibrentasvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir) and three regimens with genotype-specific activity (sofosbuvir/ribavirin, sofosbuvir/ledipasvir and elbasvir/grazoprevir) have been approved with age-specific limitation for treatment of children with chronic hepatitis C by the European Medicines Agency and the United States Food and Drug Administration. The World Health Organization has set the ambitious target to eliminate hepatitis C as a major public health threat by 2030 and based its actions against HCV on the large use of direct acting antivirals. These updated European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations on treatment of hepatitis C describe the optimal therapeutic management of adolescents and children with HCV infection including specific indications for those living in resource-limited settings.

Vaccination practices in pediatric transplantation: A survey among member centers of the European reference network TransplantChild.

BACKGROUND: There is considerable variation in vaccination practices between pediatric transplant centers. This study aims to evaluate active immunization attitudes and practices among ERN-TransplantChild centers and identify potential areas of improvement that could be addressed by shared evidence-based protocols. METHODS: A cross-sectional questionnaire of attitudes and practices toward immunization of pediatric SOT and HSCT candidates and recipients was sent to a representative member of multidisciplinary teams from 27 European centers belonging to the ERN-TransplantChild. RESULTS: A total of 28/62 SOT programs and 6/12 HSCT programs across 21 European centers participated. A quarter of centers did not have an on-site protocol for the immunizations. At the time of transplantation, pediatric candidates were fully immunized (80%-100%) in 57% and 33% of the SOT and HSCT programs. Variations in the time between vaccine administration and admission to the waiting list were reported between the centers, with 2 weeks for inactivated vaccines and variable time (2-4 weeks) for live-attenuated vaccines (LAVs). Almost all sites recommended immunization in the post-transplant period, with a time window of 4-8 months for the inactivated vaccines and 16-24 months for MMR and Varicella vaccines. Only five sites administer LAVs after transplantation, with seroconversion evaluated in 80% of cases. CONCLUSIONS: The immunization coverage of European pediatric transplant recipients is still inconsistent and far from adequate. This survey is a starting point for developing shared evidence-based immunization protocols for safe vaccination among pediatric transplant centers and generating new research studies.

Incidence and antiviral treatment of cytomegalovirus infection in infants with biliary atresia.

PURPOSE: Patients with biliary atresia (BA) and cytomegalovirus (CMV) infection may have poorer outcomes after Kasai portoenterostomy (KPE) than uninfected patients, suggesting a rationale for antiviral treatment (AVT). We aimed to describe the incidence of CMV infection and of AVT in BA patients, and to detect any differences between infected and uninfected patients to conclude if AVT is of use. METHODS: Data on BA patients who underwent KPE 2004-2020 were retrospectively collected, and the outcome was analyzed with regard to CMV status. RESULTS: Fifteen out of forty-six (33%) BA patients had signs of ongoing CMV infection. They did not differ significantly from the CMV-negative patients regarding rate of prematurity, birth weight, or biochemical markers but were slightly older at KPE. All patients received steroids postoperatively and all patients with ongoing CMV infection received AVT with very good effect on viremia and without major side effects. The AVT consisted of oral valganciclovir (10-40 (- 58) mg/kg/d) or intravenous ganciclovir (5.3-11 mg/kg/d). CONCLUSION: Ongoing CMV infection is common in this group of patients. The viremia can effectively be treated with AVT without any major side effects. Larger, randomized studies are needed to clarify the possible effect on clinical outcome.

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

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.

Proceedings of ESPGHAN Monothematic Conference 2020: "Acute Liver Failure in Children": Diagnosis and Initial Management.

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

Proceedings of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition Monothematic Conference, 2020: "Acute Liver Failure in Children": Treatment and Directions for Future Research.

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.

Pattern and Prevalence of Liver Involvement in Pediatric Acute Lymphoblastic and Myeloid Leukemia at Diagnosis.

OBJECTIVES: The prevalence and significance of liver involvement at diagnosis was studied in pediatric acute lymphoblastic (ALL) and myeloid leukemia (AML). METHODS: A population based cohort of 122 pre B-ALL, 22 T-ALL and 45 AML patients was formed from the Nordic Society of Pediatric Hematology and Oncology leukemia registries (years 2005-2017). Hepatomegaly, elevated alanine aminotransferase, high INR, hypoalbuminemia and conjugated hyperbilirubinemia at diagnosis were used as markers for liver involvement. Minimal residual disease (MRD), time to relapse and overall survival (OS) were correlated with liver involvements. RESULTS: The pattern of liver involvement was significantly different between leukemia subtypes (P = 0.025). The proportion of patients without liver abnormalities was 50.0% in AML and 44.8% in pre B-ALL and 23.5% in T-ALL patients. Hepatomegaly characterized lymphatic leukemia being present in 41.8% and 58.8% of pre B- and T-ALL patients. Liver dysfunction was most common in AML (29.5%) and least frequent in pre B-ALL (7.4%,) (P = 0.001). Conjugated hyperbilirubinemia was present in less than 5% of patients. Hepatomegaly correlated positively with age in pre B-ALL (P = 0.036) and white blood cell count (WBC) in AML (P = 0.010). Hepatic dysfunction was related with high WBC in pre B-ALL (P = 0.037) and AML (P = 0.001). Liver involvement in patients with ALL was not associated with toxicity or outcome. Patients with AML without liver involvement demonstrated superior OS. CONCLUSIONS: Liver involvement is frequent at diagnosis in pediatric leukemia and its prevalence is related with leukemia subtype, age and WBC. In AML, but not in ALL, it associates with suboptimal prognosis.

Comparison of cystatin C, creatinine, and iohexol clearance in pediatric liver transplantation-a retrospective cohort study.

Impaired renal function after pediatric (LT) is a recognized problem. Accurate monitoring of (GFR) is imperative to detect declining renal function. GFR can be estimated via s-creatinine and/or p-cystatin C or measured by inulin and or/iohexol clearances. We retrospectively compared eGFRcrea and eGFRcyst, to mGFRiohex after LT. Data from 91 children with 312 concomitant measurements of s-creatinine, p-cystatin C, and iohexol clearance, obtained between 2007 and 2015, were analyzed. eGFR was calculated by using the p-cystatin C-based CAPA and CKD-EPI formulas, and the s-creatinine-based Schwartz-LYON, FAS, revised Schwartz and MDRD formulas. Also, the arithmetic means of cystatin C-based and creatinine-based equations were used. Every calculated eGFR was compared to mGFRiohex in statistical correlation, accuracy, precision, bias, and misclassifications. Among the different equations, p-cystatin C-based formulas (CAPA and CKD-EPI) as well as the s-creatinine-based Schwartz-LYON formula showed the most correct estimates regarding accuracy (84-87.5%), bias (0.19-4.0 ml/min/1.73 m2 ), and misclassification rate (24.7-25%). In patients with renal function <75 ml/min/1.73 m2 , cystatin C-based formulas were significantly more accurate and less biased than creatinine-based formulas. In conclusion, S-creatinine could be used in a clinical setting on a regular basis in liver transplanted pediatric patients, with reliable results, if eGFR is calculated by the Schwartz-LYON formula. When suspected renal dysfunction, cystatin C-based eGFR should be calculated, since it gives more accurate and less biased estimates than creatinine-based eGFR, and should be confirmed by mGFR (iohexol).

Cholestasis after very preterm birth was associated with adverse neonatal outcomes but no significant long-term liver disease: A population-based study.

AIM: To describe outcome linked to neonatal cholestasis in a defined cohort of very preterm infants. METHODS: Population-based retrospective case-control study of preterm infants, gestational age <30 weeks, surviving for 28 days, in Stockholm County. Cholestasis was defined as conjugated bilirubin ≥30 µmol/L exceeding 20% of total level at least twice and graded as high if exceeding 100 µmol/L. Cholestatic cases were matched on gestational week with two non-cholestatic controls. RESULTS: The incidence rate of cholestasis was 37/250 (14.8%), with increasing rates in lower gestational weeks. Perinatal factors associated with cholestasis were pre-eclampsia and being born small for gestational age. Cholestatic infants had three times more bronchopulmonary dysplasia and eight times more retinopathy of prematurity. The mortality was 13.5% in cholestatic infants versus 2.7% in controls (P = .040). All deceased cholestatic infants had high-grade cholestasis. No surviving infants developed chronic liver disease by 10 years of age. CONCLUSION: Cholestasis was common in very preterm infants and linked to disease severity and adverse outcome. Cholestasis may be an independent risk factor for bronchopulmonary dysplasia and retinopathy of prematurity and more severe cholestasis associated with increased mortality. Cholestasis was not associated with chronic liver disease later in childhood.

Evidence for B cell maturation but not trained immunity in uninfected infants exposed to hepatitis C virus.

OBJECTIVES: Vertical transmission of hepatitis C virus (HCV) is rare compared with other chronic viral infections, despite that newborns have an immature, and possibly more susceptible, immune system. It further remains unclear to what extent prenatal and perinatal exposure to HCV affects immune system development in neonates. DESIGN: To address this, we studied B cells, innate immune cells and soluble factors in a cohort of 62 children that were either unexposed, exposed uninfected or infected with HCV. Forty of these infants were followed longitudinally from birth up until 18 months of age. RESULTS: As expected, evidence for B cell maturation was observed with increased age in children, whereas few age-related changes were noticed among innate immune cells. HCV-infected children had a high frequency of HCV-specific IgG-secreting B cells. Such a response was also detected in some exposed but uninfected children but not in uninfected controls. Consistent with this, both HCV-exposed uninfected and HCV-infected infants had evidence of early B cell immune maturation with an increased proportion of IgA-positive plasma cells and upregulated CD40 expression. In contrast, actual HCV viraemia, but not mere exposure, led to alterations within myeloid immune cell populations, natural killer (NK) cells and a distinct soluble factor profile with increased levels of inflammatory cytokines and chemokines. CONCLUSION: Our data reveal that exposure to, and infection with, HCV causes disparate effects on adaptive B cells and innate immune cell such as myeloid cells and NK cells in infants.

Pediatric transplantation in Europe during the COVID-19 pandemic: Early impact on activity and healthcare.

The current pandemic SARS-CoV-2 has required an unusual allocation of resources that can negatively impact chronically ill patients and high-complexity procedures. Across the European Reference Network on Pediatric Transplantation (ERN TransplantChild), we conducted a survey to investigate the impact of the COVID-19 outbreak on pediatric transplant activity and healthcare practices in both solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). The replies of 30 professionals from 18 centers in Europe were collected. Twelve of 18 centers (67%) showed a reduction in their usual transplant activity. Additionally, outpatient visits have been modified and restricted to selected ones, and the use of telemedicine tools has increased. Additionally, a total of 14 COVID-19 pediatric transplanted patients were identified at the time of the survey, including eight transplant recipients and six candidates for transplantation. Only two moderate-severe cases were reported, both in HSCT setting. These survey results demonstrate the limitations in healthcare resources for pediatric transplantation patients during early stages of this pandemic. COVID-19 disease is a major worldwide challenge for the field of pediatric transplantation, where there will be a need for systematic data collection, encouraging regular discussions to address the long-term consequences for pediatric transplantation candidates, recipients, and their families.

Systematic Review and Meta-analysis: Partial External Biliary Diversion in Progressive Familial Intrahepatic Cholestasis.

OBJECTIVES: We assessed available data on impact of partial external biliary diversion (PEBD) surgery on clinical outcomes in patients with progressive familial intrahepatic cholestasis (PFIC). METHODS: We performed a systematic literature review (PubMed) and meta-analysis to evaluate relationships between liver biochemistry parameters (serum bile acids, bilirubin, and alanine aminotransferase [ALT]) and early response (pruritus improvement) or long-term outcomes (need for liver transplant) in patients with PFIC who underwent PEBD. RESULTS: Searches identified 175 publications before September 2018; 16 met inclusion criteria. Receiver operating characteristic (ROC) analysis examined ability of liver biochemistry parameters to discriminate patients who demonstrated early and long-term response to PEBD from those who did not. Regarding pruritus improvement in 155 included patients in aggregate, 104 (67%) were responders, 14 (9%) had partial response, and 37 (24%) were nonresponders. In ROC analyses of individual patient data, post-PEBD serum concentration of bile acids, in particular, could discriminate responders from nonresponders for pruritus improvement (area under the curve, 0.99; P < 0.0001; n = 42); to a lesser extent, this was also true for bilirubin (0.87; P = 0.003; n = 31), whereas ALT could not discriminate responders from nonresponders for pruritus improvement (0.74; P = 0.06; n = 28). Reductions from pre-PEBD values in serum bile acid concentration (0.89; P = 0.0003; n = 32) and bilirubin (0.98; P = 0.002; n = 18) but not ALT (0.62; P = 0.46; n = 18) significantly discriminated decreased aggregate need for liver transplant. CONCLUSION: Changes in bile acids seem particularly useful in discriminating early and long-term post-PEBD outcomes and may be potential biomarkers of response to interruption of enterohepatic circulation in patients with PFIC.

Comparison of Recommendations for Treatment of Chronic Hepatitis C Virus Infection in Children and Adolescents: A Position Paper of the Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition.

OBJECTIVE: This position paper written by the Hepatitis Expert Team of the Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition aimed to systematically evaluate clinical practice guidelines (CPGs), medical consensus, and position papers on the use of direct-acting antivirals (DAA) to treat chronic hepatitis C virus (HCV) infection in adolescents and children in order to compare recommendations and provide the basis for developing a unified position statement. METHODS: MEDLINE, Cochrane-Library, National Guideline Clearinghouse and select websites of relevant societies/organizations were used to identify CPGs, medical consensus and position papers between 2011-2019. RESULTS: A total of 5 documents were analysed: 3 CPGs, 1 medical consensus, and 1 position paper. All publications were consistent in recommending DAA treatment for adolescents (12-17 years old) with chronic HCV infection. Similarly, all of these publications consistently recommended deferring therapy for children between 3 and 11 years of age until DAA became available as standard of care. Finally, none of the included publications recommended treating children younger than 3 years old. By contrast, there was significant discrepancy across the retrieved documents regarding specific DAA regimens and treatment strategies. CONCLUSIONS: There is strong consensus on treating all adolescents with chronic HCV infection with DAA and on delaying therapy in younger children until these agents are approved for them. Interferon-based therapies should be avoided. Specific recommendations regarding which DAA regimen to use and treatment duration varied significantly. Key stakeholders need to convene to standardize therapeutic strategies at a global level if we are to eradicate HCV in children.

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

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

Mouse Model of Alagille Syndrome and Mechanisms of Jagged1 Missense Mutations.

BACKGROUND & AIMS: Alagille syndrome is a genetic disorder characterized by cholestasis, ocular abnormalities, characteristic facial features, heart defects, and vertebral malformations. Most cases are associated with mutations in JAGGED1 (JAG1), which encodes a Notch ligand, although it is not clear how these contribute to disease development. We aimed to develop a mouse model of Alagille syndrome to elucidate these mechanisms. METHODS: Mice with a missense mutation (H268Q) in Jag1 (Jag1+/Ndr mice) were outbred to a C3H/C57bl6 background to generate a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice). Liver tissues were collected at different timepoints during development, analyzed by histology, and liver organoids were cultured and analyzed. We performed transcriptome analysis of Jag1Ndr/Ndr livers and livers from patients with Alagille syndrome, cross-referenced to the Human Protein Atlas, to identify commonly dysregulated pathways and biliary markers. We used species-specific transcriptome separation and ligand-receptor interaction assays to measure Notch signaling and the ability of JAG1Ndr to bind or activate Notch receptors. We studied signaling of JAG1 and JAG1Ndr via NOTCH 1, NOTCH2, and NOTCH3 and resulting gene expression patterns in parental and NOTCH1-expressing C2C12 cell lines. RESULTS: Jag1Ndr/Ndr mice had many features of Alagille syndrome, including eye, heart, and liver defects. Bile duct differentiation, morphogenesis, and function were dysregulated in newborn Jag1Ndr/Ndr mice, with aberrations in cholangiocyte polarity, but these defects improved in adult mice. Jag1Ndr/Ndr liver organoids collapsed in culture, indicating structural instability. Whole-transcriptome sequence analyses of liver tissues from mice and patients with Alagille syndrome identified dysregulated genes encoding proteins enriched at the apical side of cholangiocytes, including CFTR and SLC5A1, as well as reduced expression of IGF1. Exposure of Notch-expressing cells to JAG1Ndr, compared with JAG1, led to hypomorphic Notch signaling, based on transcriptome analysis. JAG1-expressing cells, but not JAG1Ndr-expressing cells, bound soluble Notch1 extracellular domain, quantified by flow cytometry. However, JAG1 and JAG1Ndr cells each bound NOTCH2, and signaling from NOTCH2 signaling was reduced but not completely inhibited, in response to JAG1Ndr compared with JAG1. CONCLUSIONS: In mice, expression of a missense mutant of Jag1 (Jag1Ndr) disrupts bile duct development and recapitulates Alagille syndrome phenotypes in heart, eye, and craniofacial dysmorphology. JAG1Ndr does not bind NOTCH1, but binds NOTCH2, and elicits hypomorphic signaling. This mouse model can be used to study other features of Alagille syndrome and organ development.

Prevalence of chronic hepatitis C virus infection among childhood cancer survivors in Stockholm, Sweden.

Background: Childhood cancer survivors treated before 1992, when blood donor screening for hepatitis C virus (HCV) infection was introduced, are at risk of transfusion-transmitted HCV infection. A national HCV screening campaign targeting blood transfusion recipients was launched in Sweden in 2007-2010. The aims of this study were to, among adult childhood cancer survivors in Stockholm County, investigate the prevalence of HCV infection, the natural course of infection, treatment outcome and anti-HCV testing frequency before, during and after the screening campaign and finally to actively screen the untested ones. Material and Methods: This was a combined retrospective register based and prospective screening study of adult childhood cancer survivors (n = 686) treated for malignancy in Stockholm before 1992. In the first part, we investigated the prevalence of HCV infection and previous anti-HCV testing, and in the second part, we actively traced and HCV-screened the remaining untested cohort living in Stockholm. Analysis of previous documented anti-HCV tests in medical records, laboratory records, and the national communicable disease registry was performed. In the second part, 231 presumably untested individuals were contacted by mail and offered an anti-HCV test. The natural course of HCV infection and treatment outcome was analyzed for those found to be chronically infected. Results: In total, 235 patients were tested and 11 were HCV-RNA positive. The overall prevalence of chronic HCV infection among the tested childhood cancer survivors was thus 4.7% (95% CI = 2.6-8.2%), which is almost 10 times higher than the national prevalence of 0.5%. Only 12% of the Stockholm cohort were tested during the screening campaign in 2007-2010, while the test uptake using active tracing screening within this study was 40% (p < .001). Conclusion: With today's effective treatment options, active tracing and HCV screening of childhood cancer survivors are recommended.

Contrast-Enhanced Ultrasound for identifying circulatory complications after liver transplants in children.

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.

Survey of Impediments to Prevention of Mother-to-infant Transmission of Hepatitis B Virus by International Societies.

OBJECTIVE: Mother-to-infant transmission (MIT) is the leading cause of hepatitis B virus (HBV) infections globally. The aim of this international study was to assess the impediments to prevention of (MIT) of HBV. METHODS: A cross-sectional survey was developed by the Federation of the International Societies for Pediatric Gastroenterology, Hepatology and Nutrition. (FISPGHAN) The survey was sent to HBV experts of the 5-member societies of FISPGHAN, and 63 of 91 countries/regions responded. Main outcome measures include percentage of countries having vaccine programs, timing of the first dose of HBV vaccine, availability of HBV vaccine for outborn neonates, payment of HBV vaccine and hepatitis B immune globulin, screening HBV markers during pregnancy, and antivirals to highly infectious pregnant mothers. RESULTS: Among the participating countries/regions, 11% did not implement infant HBV immunization programs. The first dose of vaccine was given >24 hours in 36% of the total countries and 100% of African countries. The recommended birth dose was unavailable for outborn neonates in 45% of the total countries, including 92% of African and 50% of Latin American countries/regions. During pregnancy, 44% countries do not screen maternal viral markers, and 46% do not provide third trimester antiviral therapy for highly viremic pregnant mothers. CONCLUSIONS: Our study demonstrated multiple obstacles to achieving the goal of preventing MIT of HBV. Comprehensive public health programs to enhance vaccine coverage rate, supply HBV vaccine for out-born neonates, screening maternal HBV markers, treating highly viremic pregnant mothers are proposed to overcome these obstacles and achieve the goal of preventing MIT of HBV.