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Gastric distension activates a cerebral network including brainstem, thalamus, insula, perigenual anterior cingulate, cerebellum, ventrolateral prefrontal cortex and potentially somatosensory regions. Cortical deactivations during gastric distension have hardly been reported. To describe brain areas of decreased activity during gastric fundus distension compared to baseline, using data from our previously published study (Gastroenterology, 128, 2005 and 564). H215O-brain positron emission tomography was performed in 11 healthy volunteers during five conditions (random order): (C1) no distension (baseline); isobaric distension to individual thresholds for (C2) first, (C3) marked, (C4) unpleasant sensation and (C5) sham distension. Subtraction analyses were performed (in SPM2) to determine deactivated areas during distension compared to baseline, with a threshold of Puncorrected_voxel_level < 0.001 and Pcorrected_cluster_level < 0.05. Baseline–maximal distension (C1–C4) yielded significant deactivations in: (i) bilateral occipital, lateral parietal and temporal cortex as well as medial parietal lobe (posterior cingulate and precuneus) and medial temporal lobe (hippocampus and amygdala), (ii) right dorsolateral and dorso- and ventromedial PFC, (iii) left subgenual ACC and bilateral caudate head. Intragastric pressure and epigastric sensation score correlated negatively with brain activity in similar regions. The right hippocampus/amygdala deactivation was specific to sham. Gastric fundus distension in health is associated with extensive cortical deactivations, besides the activations described before. Whether this represents task-independent suspension of ‘default mode’ activity (as described in various cognitive tasks) or an visceral pain/interoception-specific process remains to be elucidated. [ABSTRACT FROM AUTHOR]

Unlabelled: The aim of the study was to investigate the clinical aspects of neonatal cholestasis. The medical records of 85 cholestatic infants were retrospectively reviewed. A majority of the patients were referred from other parts of the country. The most common diagnoses were extrahepatic biliary atresia (n = 30 patients), alpha1-antitrypsin deficiency (n = 11) and progressive familial intrahepatic cholestasis (n = 11). On presentation, the biliary atresia group had higher mean serum values of bilirubin, G-GT and cholesterol than the patients with intrahepatic cholestasis, with no significant differences noticed for any other biochemical parameter. A lack of excretion on hepatobiliary scintigraphy was noticed in all investigated patients with biliary atresia, but also in 9 of 34 patients with intrahepatic neonatal cholestasis. There was no statistical correlation between the age at portoenterostomy and the outcome in patients with biliary atresia. However, both the detection of a partial flow on perioperative cholangiogram and the establishment of a non-icteric phase within 6 mo after the portoenterostomy correlated to a good outcome. Eight of 11 patients with progressive familial intrahepatic cholestasis were treated with a biliary diversion procedure, five of eight experienced a sustained cholestatic remission.Conclusions: Progressive familial intrahepatic cholestasis may be a more common cause of neonatal cholestasis in Sweden than reported elsewhere and that the experience with biliary diversion is positive. While early referral in patients with extrahepatic biliary atresia remains important, a portoenterostomy should be attempted also in patients referred after 3 mo of age. [ABSTRACT FROM AUTHOR]

Mother-to-infant transmission of hepatitis G virus (HGV [or GBV-C]) was studied in sera from 42 mothers at high risk for bloodborne infections and from their 45 infants (3 twin pairs). Seven (17%) of the mothers had HGV RNA in serum by a polymerase chain reaction assay. One of the 8 (12.5%) infants born to HGV-infected mothers became positive for HGV at 3 months of age. He remained HGV-infected throughout the study (42 months), with no signs of liver disease. His twin sister remained HGV-negative despite the presence of serum and salivary HGV in both the mother and the brother. Analysis of HGV sequences from the infected mother and the infected child confirmed a genetic link between the virus of the mother and the infected child. Thus, mother-to-infant transmission of HGV, presumably occurring at partus, may cause persistent HGV viremia. [ABSTRACT FROM AUTHOR]

Introduction: Selective serotonin reuptake inhibitors (SSRIs) are frequently used in the treatment of irritable bowel syndrome (IBS) although evidence of their efficacy is scarce. Aim: Twenty three non-depressed IBS patients were recruited from a tertiary care centre and included in a crossover trial comparing six weeks of treatment with the SSRI citalopram (20 mg for three weeks, 40 mg for three weeks) with placebo. IBS symptom severity was the primary outcome measure, and depression and anxiety scores were also measured. The effect of acute administration of citalopram on colonic sensitivity and on colonic response to feeding was investigated as a putative predictor of symptomatic response to the drug. Results: After three and six weeks of treatment, citalopram significantly improved abdominal pain, bloating, impact of symptoms on daily life, and overall well being compared with placebo. There was only a modest effect on stool pattern. Changes in depression or anxiety scores were not related to symptom improvement. The effect of acute administration of citalopram during a colonic barostat study did not predict clinical outcome. Analysis of the first treatment period as a double blind parallel arm study confirmed the benefit of citalopram over placebo. Conclusions: The SSRI citalopram significantly improves IBS symptoms, including abdominal pain, compared with placebo. The therapeutic effect is independent of effects on anxiety, depression, and colonic sensorimotor function. [ABSTRACT FROM AUTHOR]

Background: Fibroblast growth factor 19 (FGF19) is produced in the small intestine and is involved in suppression of hepatic bile acid (BA) synthesis. FGF19 is also expressed in the liver and serum levels are elevated in adults with cholestatic liver disease. This may reflect a rescue mechanism to dampen liver injury caused by increased intrahepatic BAs.Objectives: To examine circulating FGF19 at early stages of biliary atresia and at short-term follow-up post-Kasai portoenterostomy (KPE) in relation to noncholestatic infants. The relationship between FGF19, BAs and markers for BA synthesis and hepatic gene expression of factors involved in BA metabolism were also evaluated.Methods: Liver tissue, portal and peripheral blood samples were obtained from fifteen patients at KPE; additional blood was collected 4-6 months after surgery. Two control groups were included; to examine possible changes related to surgery and to compare FGF19 in biliary atresia to noncholestatic infants.Results: Circulating FGF19 levels correlated to its hepatic gene expression at time of KPE in biliary atresia and levels were elevated compared to noncholestatic infants. At follow-up, FGF19 levels were markedly reduced, and the decline coincided with reductions in bilirubin and conjugated chenodeoxycholic acid and with increased levels of the BA synthesis marker C4.Conclusion: Elevated circulating FGF19 in biliary atresia is of hepatic origin and reduced following KPE. Changes in serum FGF19 may reflect the level of restoration of the enterohepatic circulation, and this warrants further long-term studies on the role of FGF19 in the cholestatic liver. [ABSTRACT FROM AUTHOR]

Biliary atresia ( BA) is the most common indication for LT in children. We investigated whether this diagnosis per se, compared to other chronic liver diseases ( OCLD), had an influence on patient survival. Data from 421 Scandinavian children, 194 with BA and 227 with OCLD, listed for LT between 1990 and 2010 were analyzed. The intention-to-treat survival and influencing risk factors were studied. Patients with BA had higher risk of death after listing than patients with OCLD. The youngest (<1 year) and smallest (<10 kg) children with the highest bilirubin (>510 μmol/L), highest INR (>1.6), and highest PELD score (>20) listed during 1990s had the worst outcome. Given the same PELD score, patients with BA had higher risk of death than patients with OCLD. For adolescents, low weight/ BMI was the only prognostic marker. Impaired intention-to-treat survival in patients with BA was mainly explained by more advanced liver disease in younger ages and higher proportion of young children in the BA group rather than diagnosis per se. PELD score predicted death, but seemed to underestimate the severity of liver disease in patients with BA. Poor nutritional status and severe cholestasis had negative impact on survival, supporting the 'sickest children first' allocation policy and correction of malnutrition before surgery. [ABSTRACT FROM AUTHOR]

Inherited metabolic diseases of the liver are characterized by deficiency of a hepatic enzyme or protein often resulting in life-threatening disease. The remaining liver function is usually normal. For most patients, treatment consists of supportive therapy, and the only curative option is liver transplantation. Hepatocyte transplantation is a promising therapy for patients with inherited metabolic liver diseases, which offers a less invasive and fully reversible approach. Procedure-related complications are rare. Here, we review the experience of hepatocyte transplantation for metabolic liver diseases and discuss the major obstacles that need to be overcome to establish hepatocyte transplantation as a reliable treatment option in the clinic. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infection, which mostly causes a subclinical infection early in life, has important clinical consequences in certain patient groups. CMV is the most common congenital infection and can cause permanent disabilities such as hearing loss and motor- and cognitive deficits in affected infants. In allogeneic haematopoietic stem cell and solid organ transplant recipients, CMV still is an important infectious complication with a risk for life-threatening disease. The previous Swedish recommendations for the management of CMV infections were updated by an expert group under the guidance of The Swedish Reference Group for Antiviral Treatment (RAV) and published at the website of RAV in August 2023 (https://www.sls.se/rav/rekommendationer/cytomegalovirus/). We here provide a translation of the updated recommendations, with minor modifications regarding diagnosis of CMV pneumonia. In the present recommendations, we discuss aspects of old and new CMV antivirals, including dosing for different age groups, and cover the management of congenital infections and CMV in immunocompromised patients. The recommendations are evidence-graded in accordance with the Oxford Centre for Evidence-Based Medicine.

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.)

Objectives: Patients with biliary atresia (BA) and ongoing cytomegalovirus (CMV) infection may have poorer outcomes after Kasai portoenterostomy than uninfected patients. Still, there is no consensus on the usefulness of viral testing and antiviral treatment (AVT). This study aims to explore the need for future research on AVT for CMV infection by assessing how CMV infection in BA patients is managed in different centers., Methods: An online questionnaire with 10 questions was offered to participants at an international congress on BA, organized in collaboration with the European Reference Network for rare liver diseases in 2022. Answers to questions were either dichotomic or multiple choices of different numeric intervals. Ongoing CMV infection was defined by detecting cytomegalovirus-immunoglobulin M (CMV-IgM) in serum or cytomegalovirus-deoxyribonucleic acid (CMV-DNA) by polymerase chain reaction in blood or urine., Results: There were 43 respondents from 36 centers in 26 countries. The total number of BA patients per year was between 208 and 380 from centers with 0-5 to >20 BA patients yearly (median 6-10). CMV infection was tested in 27 centers (75%), of which 18 (67%) use AVT. The rate of CMV infection varied between 0%-5% and 40%-50% (median 5%-10%). Willingness to treat the infection did not differ between centers with low and high rates of CMV infection., Conclusions: Most centers test for CMV infection, and a considerable proportion use AVT despite the lack of evidence of its benefits. A future randomized study on treating CMV infection in BA patients is necessary and feasible., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. JPGN Reports Published by Wiley Periodicals LLC. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

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., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

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).)

Background: The histological prevalence of allograft fibrosis in asymptomatic children after liver transplantation (LT) is well documented. However, long-term graft and patient survival remain unclear. This retrospective multicenter study aims to determine the prevalence of allograft fibrosis and analyze the long-term outcome for patients transplanted in childhood., Methods: We reviewed clinical data of children who had undergone 10-y protocol liver biopsies. We excluded patients with autoimmune hepatitis, primary sclerosing cholangitis, hepatitis B or C, and retransplantation. In total, 494 patients transplanted in childhood across 12 international transplant centers were included. We evaluated the development of fibrosis by comparing the results with biopsies obtained 5 and 15 y post-LT. Histological findings were correlated with graft and patient survival up to 20 y post-LT., Results: In the 10-y biopsies, periportal or pericentral fibrosis was observed in 253 patients (51%), 87 (18%) had bridging fibrosis, 30 (6%) had cirrhosis, and 124 (25%) had no fibrosis. The prevalence and stage of graft fibrosis significantly progressed from 5 to 10 y. At 10 y, the severity of fibrosis correlated significantly with inflammation. Patients with graft cirrhosis in the 10-y biopsy were more likely to die or require retransplantation subsequently ( P = 0.027)., Conclusions: At 10 y post-LT, most patients transplanted in childhood developed fibrosis, based on the protocol liver biopsies. Although mild-to-moderate graft fibrosis did not largely affect patient or graft survival up to 20 y post-LT, this progressive fibrosis finding has substantial implications for developing cirrhosis and portal hypertension in adult care., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2023 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation., Competing Interests: MC has received grant support unrelated to this study from Genetics spa, PSC Pediatric Foundation, AMAF, EpaC and AIRCS. He also received speakers/consultancy/advisory fees for GlaxoSmithKline, Dr. Falk Pharma, Cymabay, Advanz Pharma, Albireo, Ipsen, Mayoly Spindler, Perspectum, Echosens, Kowa, and Mirun. PT receives institutional support from Birmingham NIHR BRC. Unrelated to this study PT has received grant support from the Wellcome Trust, Innovate UK, the Medical Research Foundation, GlaxoSmithKline (GSK), Guts UK, PSC Support, LifeArc, NIHR, Intercept Pharma, Dr. Falk Pharma, Gilead Sciences, and Bristol Myers Squibb. He has also received speaker fees from Intercept and Dr. Falk, and advisory board/consultancy fees from Intercept, Cymabay, Pliant Pharma, Dr. Falk, Albireo, Ipsen and GlaxoSmithKine. HNH consultancies for Arrowhead, Takeda, GLG, Albireo, Alnylam and Mirum. LC received speakers fee from Advanz and Echosens. LD’A received consultancy fees from: Albireo, Mirum, Alexion, Astra Zeneca, Selecta, Vivet, Spark, Genespire, and Tome, in fields unrelated to the current topic. DD received consultancy fees from: Mirum, Vertex, Orphalan, Univar, Alexion, in fields unrelated to this study. UB received consultancy fees or grant support from: Mirum, Albireo, Alexion, Nestle and Vivet in fields unrelated to this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Carbone, Della Penna, Mazzarelli, De Martin, Villard, Bergquist, Line, Neuberger, Al-Shakhshir, Trivedi, Baumann, Cristoferi, Hov, Fischler, Hadzic, Debray, D’Antiga, Selzner, Belli and Nadalin.)

Background: Approximately 3.5 million children and adolescents worldwide are chronically infected with HCV. This study uses pharmacokinetic modeling to identify pediatric doses of elbasvir/grazoprevir (EBR/GZR) that achieve plasma concentrations similar to those seen in adults receiving the approved fixed-dose combination regimen of EBR/GZR., Patients and Methods: We conducted a nonrandomized, single-arm, multicenter, open-label phase 2b trial in children and adolescents aged 3 to <18 years with chronic HCV genotype 1 or 4 infection (NCT03379506). Pharmacokinetic data were used to bridge efficacy and safety data from adults to children in a stepwise (oldest to youngest) manner. A total of 57 participants were enrolled: cohort 1 (aged 12 to <18 y), n=22; cohort 2 (aged 7 to <12 y), n=17; and cohort 3 (aged 3 to <7 y), n=18., Results: Steady-state plasma exposures were achieved by week 4 for EBR and GZR in all cohorts and daily dosing achieved geometric mean steady-state area under the concentration-time curve at 0-24 hours that fell within comparability bounds established for adults. All participants achieved sustained virologic response 12 weeks after completing treatment (ie, undetectable HCV RNA 12 wk following completion of treatment). Headache (n=4), fatigue (n=4), and nausea (n=2) were the most common treatment-related adverse events (all mild or moderate); no participant discontinued because of an adverse event., Conclusions: Pediatric EBR/GZR pharmacokinetic models were successfully developed based on complex adult population pharmacokinetic models. At appropriate age-related doses, EBR/GZR is safe and effective in pediatric and adolescent participants with HCV infection., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.)

Background: Biliary atresia (BA) is a rare cholangiopathy where one of the proposed aetiological mechanisms is an infectious viral trigger. Coronavirus disease-19 (COVID) lockdown restrictions were implemented to reduce the transmission of infections. Strictness of lockdown varied across European countries. This study aimed to investigate if there was an association between strictness of lockdown and change in isolated BA (IBA) incidence in Europe., Methods: We approached European centres involved in the European Reference Network RARE-LIVER. We included IBA patients born between 2015 and June 2020. We calculated the number of IBA patients born per centre per month. The Stringency Index (SI) was used as lockdown strictness indicator. The association between percentage change of mean number of IBA patients born per month and the SI was assessed., Results: We included 412 IBA patients from thirteen different centres. The median number of patients per month did not change: 6 (1-15) pre-lockdown and 7 (6-9) during lockdown ( p = 0.34). There was an inverse association between SI and percentage change in IBA (B = -0.73, p = 0.03). Median age at Kasai portoenterostomy (days) did not differ between time periods (51 (9-179) vs. 53 (19-126), p = 0.73)., Conclusion: In this European study, a stricter COVID-lockdown was seemingly accompanied by a simultaneous larger decrease in the number of IBA patients born per month in the lockdown. Results should be interpreted with caution due to the assumptions and limitations of the analysis.

Spontaneous bleeds are a leading cause of death in the pediatric JAG1-related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in bleeding events in patients, whether Jag1 Ndr/Ndr mice display bleeds or vascular defects, and whether discovered vascular pathology can be confirmed in patients non-invasively. We performed a systematic review of patients with ALGS and vascular events following PRISMA guidelines, in the context of patient sex, and found significantly more girls than boys reported with spontaneous intracranial hemorrhage. We investigated vascular development, homeostasis, and bleeding in Jag1 Ndr/Ndr mice, using retina as a model. Jag1 Ndr/Ndr mice displayed sporadic brain bleeds, a thin skull, tortuous blood vessels, sparse arterial smooth muscle cell coverage in multiple organs, which could be aggravated by hypertension, and sex-specific venous defects. Importantly, we demonstrated that retinographs from patients display similar characteristics with significantly increased vascular tortuosity. In conclusion, there are clinically important sex differences in vascular disease in ALGS, and retinography allows non-invasive vascular analysis in patients. Finally, Jag1 Ndr/Ndr mice represent a new model for vascular compromise in ALGS., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)