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Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in children. We hypothesized environmental toxins could drive progression to metabolic dysfunction-associated steatohepatitis (MASH), and assayed serum toxins and metabolites in children with histologically characterized MASLD/MASH., Methods: Environmental chemicals, common in household items, perfluoroalkyl substances (PFAS), brominated flame retardants (PBDEs), and metabolic profiles were assayed in children enrolled in the multicenter NASH Clinical Research Network Pediatric Database 2. Mixture models, using repeated holdout weighted quantile sum regression (WQSrh) were run in addition to single chemical/metabolite logistic regression. For metabolomic analyses, random subset version of WQSrh was used for the large number of predictors versus participants. Nominal and false discovery rate (FDR) p-values (two-sided) were computed., Results: Four hundred and thirty-five children distributed across MASH (n = 293) and MASLD (n = 142), with 304 (69.9%) males. Mean (standard deviation) for Nonalcoholic Steatohepatitis Score (NAS) and alanine aminotransferase (ALT) for MASLD were 3.1 (1.0), 67.9 (43.4), and for MASH 4.2 (1.4), 144 (121). There was an inverse association between PFAS/PBDE mixture and MASH versus MASLD, lobular inflammation (p = 0.026), NAS (p = 0.009, FDR p = 0.04), and log-transformed ALT (p = 0.005, FDR p = 0.025) driven by perfluorohexane sulfonate (PFHxS). Metabolites from positive hydrophilic interaction liquid chromatography mode, biliverdin (p = 0.002) and 1-methylhistidine (associated with meat ingestion, p = 0.02) and reverse phase negative mode, hippuric acid (solvent exposure, p = 0.022) significantly associated with MASH., Conclusions: Significant negative PFAS/PBDE mixture effect and odds of MASH were dominated by PHFXS. Several metabolites are significantly associated with MASH which inform mechanistic pathways and could drive key therapeutic and diagnostic strategies in children., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome., Methods: The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 μg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0-4) from baseline to weeks 21-24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed., Findings: Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 μmol/L [SD 115] with odevixibat vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change -90 μmol/L [95% CI -133 to -48] with odevixibat vs 22 μmol/L [-35 to 80] with placebo; difference in LS mean change -113 μmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths., Interpretation: Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study., Funding: Albireo Pharma, an Ipsen company., Competing Interests: Declaration of interests NO has received research support to their institution from Albireo Pharma (an Ipsen company) and Mirum, and consulting fees from Albireo Pharma (an Ipsen company). UB has received grants or contracts and consulting fees from Mirum, Albireo Pharma (an Ipsen company), and Alexion. PB has received an unrestricted research grant from Albireo Pharma (an Ipsen company) and payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Mirum; and has participated on a data safety monitoring or advisory board for Albireo Pharma (an Ipsen company) and Mirum. MC has received payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Albireo Pharma (an Ipsen company) and has participated on a data safety monitoring or advisory board for Albireo Pharma (an Ipsen company) and Mirum. RF has received payments or honoraria for lectures, presentations, speakers bureaus, or educational events from Albireo Pharma (an Ipsen company) and Mirum, and has participated on a data safety monitoring or advisory board for Albireo Pharma (an Ipsen company). GI has participated on a data safety monitoring or advisory board for Albireo Pharma (an Ipsen company), Mirum, and Kedrion Pharma. PR has received research support to their institution from Albireo Pharma (an Ipsen company); grants or contracts from AbbVie, Arrowhead, Gilead, Merck, Mirum, Takeda, and Travere; consulting fees from Albireo Pharma (an Ipsen company), Ambys, Audentes, BioMarin, Dicerna, Encoded, Gilead, MedinCell, Mirum, RNAV8, Takeda, and Travere; and payment or honoraria for speakers bureaus from Mirum. MR has received consulting fees from Albireo Pharma (an Ipsen company), Grifols, Mirum, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Mirum and Takeda; and support for attending meetings or travel, or both, from Mirum and Albireo Pharma (an Ipsen company). ESt has received unrestricted grants from Albireo Pharma (an Ipsen company) and Mirum; consulting fees from Albireo Pharma (an Ipsen company) and Mirum; and payment or honoraria to their institution for lectures, presentations, speakers bureaus, or educational events from Albireo Pharma (an Ipsen company) and Mirum. WvdW has received consulting fees from Mirum. HJV has received grants or contracts to their institution from Albireo Pharma (an Ipsen company), Mirum, and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition; and consulting fees paid to their institution from Albireo Pharma (an Ipsen company) and Mirum. AW has received research support from Albireo Pharma (an Ipsen company), and has participated on a data safety monitoring or advisory board for Mirum. QY was previously employed at Albireo Pharma (an Ipsen company). CC, JPM, and SM were previously employed at Albireo Pharma (an Ipsen company) and received salary and stock options. JPM also held patents with and received support for attending meetings or travel, or both, from Albireo Pharma (an Ipsen company). QN and JR are current employees of Ipsen and receive salary or stock options (or both). MA, PC, ÖD, WSL, AB, WWK, FL, GM, and ESo declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: High levels of serum matrix metalloproteinase-7 (MMP-7) have been linked to biliary atresia (BA), with wide variation in concentration cutoffs. We investigated the accuracy of serum MMP-7 as a diagnostic biomarker in a large North American cohort., Approach and Results: MMP-7 was measured in serum samples of 399 infants with cholestasis in the Prospective Database of Infants with Cholestasis study of the Childhood Liver Disease Research Network, 201 infants with BA and 198 with non-BA cholestasis (age median: 64 and 59 days, p = 0.94). MMP-7 was assayed on antibody-bead fluorescence (single-plex) and time resolved fluorescence energy transfer assays. The discriminative performance of MMP-7 was compared with other clinical markers. On the single-plex assay, MMP-7 generated an AUROC of 0.90 (CI: 0.87-0.94). At cutoff 52.8 ng/mL, it produced sensitivity = 94.03%, specificity = 77.78%, positive predictive value = 64.46%, and negative predictive value = 96.82% for BA. AUROC for gamma-glutamyl transferase = 0.81 (CI: 0.77-0.86), stool color = 0.68 (CI: 0.63-0.73), and pathology = 0.84 (CI: 0.76-0.91). Logistic regression models of MMP-7 with other clinical variables individually or combined showed an increase for MMP-7+gamma-glutamyl transferase AUROC to 0.91 (CI: 0.88-0.95). Serum concentrations produced by time resolved fluorescence energy transfer differed from single-plex, with an optimal cutoff of 18.2 ng/mL. Results were consistent within each assay technology and generated similar AUROCs., Conclusions: Serum MMP-7 has high discriminative properties to differentiate BA from other forms of neonatal cholestasis. MMP-7 cutoff values vary according to assay technology. Using MMP-7 in the evaluation of infants with cholestasis may simplify diagnostic algorithms and shorten the time to hepatoportoenterostomy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The safety and efficacy of sofosbuvir-velpatasvir in children aged 3-17 years with chronic hepatitis C virus (HCV) infection of any genotype were evaluated., Methods: In this Phase 2, multicenter, open-label study, patients received once daily for 12 weeks either sofosbuvir-velpatasvir 400/100 mg tablet (12-17 years), 200/50 mg low dose tablet or oral granules (3-11 years and ≥17 kg), or 150/37.5 mg oral granules (3-5 years and <17 kg). The efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Dose appropriateness was confirmed by intensive pharmacokinetics in each age group., Findings: Among 216 patients treated, 76% had HCV genotype 1% and 12% had genotype 3. Rates of SVR12 were 83% (34/41) among 3-5-year-olds, 93% (68/73) among 6-11-year-olds, and 95% (97/102) among 12-17-year-olds. Only two patients experienced virologic failure. The most common adverse events were headache, fatigue, and nausea in 12-17-year-olds; vomiting, cough, and headache in 6-11-year-olds; and vomiting in 3-5-year-olds. Three patients discontinued treatment because of adverse events. Four patients had serious adverse events; all except auditory hallucination (n = 1) were considered unrelated to study drug. Exposures of sofosbuvir, its metabolite GS-331007, and velpatasvir were comparable to those in adults in prior Phase 2/3 studies. Population pharmacokinetic simulations supported weight-based dosing for children in this age range., Interpretation: The pangenotypic regimen of sofosbuvir-velpatasvir is highly effective and safe in treating children 3-17 years with chronic HCV infection., (© 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease among US children. Studies have associated food insecurity with MASLD in adults, but there are few studies of pediatric MASLD, particularly in high-risk populations. We assessed the impact of household food insecurity at 4 years of age on MASLD in Latinx children., Methods: Using a prospective cohort design, Latina mothers were recruited during pregnancy and followed with their children until early to mid-childhood. Our primary exposure was household food insecurity at 4 years of age measured using the validated US Household Food Security Food Module. Our primary outcome, MASLD, was defined as alanine transaminase (ALT) ≥95th% for age/gender plus body mass index (BMI) ≥85% at time of ALT measurement (assessed between ages 5-12). We used multivariable logistic regression models to test for independent associations between household food insecurity and pediatric MASLD., Results: Among 136 children, 28.7% reported household food insecurity at 4 years of age and 27.2% had MASLD in early to middle childhood. Approximately 49% of children with MASLD and 21% of children without MASLD were food insecure (p < 0.01). Exposure to household food insecurity at age 4 was independently associated with a 3.7-fold higher odds of MASLD later in childhood (95% CI: 1.5-9.0, p < 0.01)., Conclusions: Exposure to household food insecurity at 4 years of age was associated with increased risk for MASLD later in childhood. Further studies are needed to explore mechanism(s) and impact of reducing food insecurity on risk for MASLD., (© 2024 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Objective: Maralixibat, an ileal bile acid transporter inhibitor, is the first drug approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients aged ≥3 months with Alagille syndrome (ALGS). Approval was based on reductions in pruritus from the pivotal ICONIC trial, information from two additional trials (ITCH and IMAGO), and long-term extension studies. Although participants in these trials met strict inclusion and exclusion criteria, patients have received maralixibat under broader circumstances as part of an expanded access program or commercially. The expanded access and postapproval settings inform a real-world understanding of effectiveness and safety. The objective was to report on the use of maralixibat in the real-world setting in eight patients who otherwise would not have met entrance criteria for the clinical trials, providing unique insights into its effectiveness in the management of ALGS., Methods: We reviewed records of patients with ALGS who received maralixibat but would have been excluded from trials due to surgical biliary diversion, reduction of antipruritic/cholestatic concomitant medications, administration of medication through a gastrostomy or nasogastric tube, or use in patients under consideration for transplantation., Results: Maralixibat appeared to be effective with reductions in pruritus compared to baseline. Consistent with clinical trials, maralixibat was well tolerated without appreciable gastrointestinal complications. Liver enzyme elevations were observed but were interpreted as consistent with normal fluctuations observed in ALGS, with no increases in bilirubin., Conclusion: Maralixibat may be effective and well tolerated in patients with ALGS in broader clinical contexts than previously reported., (© 2024 The Authors. Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Mitochondrial hepatopathies (MHs) are primary mitochondrial genetic disorders that can present as childhood liver disease. No recognized biomarkers discriminate MH from other childhood liver diseases. The protein biomarkers growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) differentiate mitochondrial myopathies from other myopathies. We evaluated these biomarkers to determine if they discriminate MH from other liver diseases in children., Methods: Serum biomarkers were measured in 36 children with MH (17 had a genetic diagnosis); 38 each with biliary atresia, α1-antitrypsin deficiency, and Alagille syndrome; 20 with NASH; and 186 controls., Results: GDF15 levels compared to controls were mildly elevated in patients with α1-antitrypsin deficiency, Alagille syndrome, and biliary atresia-young subgroup, but markedly elevated in MH (p<0.001). FGF21 levels were mildly elevated in NASH and markedly elevated in MH (p<0.001). Both biomarkers were higher in patients with MH with a known genetic cause but were similar in acute and chronic presentations. Both markers had a strong performance to identify MH with a molecular diagnosis with the AUC for GDF15 0.93±0.04 and for FGF21 0.90±0.06. Simultaneous elevation of both markers >98th percentile of controls identified genetically confirmed MH with a sensitivity of 88% and specificity of 96%. In MH, independent predictors of survival without requiring liver transplantation were international normalized ratio and either GDF15 or FGF21 levels, with levels <2000 ng/L predicting survival without liver transplantation (p<0.01)., Conclusions: GDF15 and FGF21 are significantly higher in children with MH compared to other childhood liver diseases and controls and, when combined, were predictive of MH and had prognostic implications., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Alagille syndrome and progressive familial intrahepatic cholestasis are conditions that can affect multiple organs. Advancements in molecular testing have aided in the diagnosis of both. The impairment of normal bile flow and secretion leads to the various hepatic manifestations of these diseases. Medical management of Alagille syndrome and progressive familial intrahepatic cholestasis remains mostly targeted on supportive care focusing on quality of life, cholestasis, and fat-soluble vitamin deficiency. The most difficult therapeutic issue is typically related to pruritus, which can be managed by various medications such as ursodeoxycholic acid, rifampin, cholestyramine, and antihistamines. Surgical operations were previously used to disrupt enterohepatic recirculation, but recent medical advancements in the use of ileal bile acid transport inhibitors have shown great efficacy for the treatment of pruritus in both Alagille syndrome and progressive familial intrahepatic cholestasis., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Pediatric metabolic-associated fatty liver disease (MAFLD) is a global health problem, with lifestyle modification as its major therapeutic strategy. Rigorous characterization of dietary content on MAFLD in children is lacking. We hypothesized an objectively measured healthier diet would positively modulate MAFLD., Methods: Diet was assessed using the Nutrition Data System for Research in children enrolled from 10 tertiary clinical centers to determine the Healthy Eating Index (HEI, 0-100) and individual food components., Results: In all, 119 children were included (13.3 ± 2.7 y), 80 (67%) male, 67 (18%) White, and 90 (76%) Hispanic, with an average body mass index Z-score of 2.2 ± 0.5. Diet was classified as low HEI < 47.94 (n = 39), mid HEI ≥ 47.94 and < 58.89 (n = 41), or high HEI ≥ 58.89 (n=39). Children with high HEI (healthier diet) had lower body weight (p = 0.005) and more favorable lipids. Mean serum triglycerides for low, mid, and high HEI were 163, 148, and 120 mg/dL, respectively; p = 0.04 mid versus high, p = 0.01 low versus high. Mean HDL was 38, 41 and 43 mg/dL; p = 0.02 low vs high. Less severe steatosis was noted with added sugar ≤ 10% of calories (p = 0.03). Higher lobular inflammation is associated with a higher percentage of calories from fat (OR (95% CI) = 0.95 (0.91-1.00), p = 0.04)., Conclusions: In children with MAFLD, high HEI is associated with lower body weight and more favorable lipids, while added sugar and fat intake has individual histologic features. Differential consumption of major dietary components may modify both metabolic risk factors and histologic liver injury, highlighting the importance of objective diet assessments in children with MAFLD., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Our objective was to better understand the natural history and disease modifiers of Alpha-1-antitrypsin deficiency (AATD), a common genetic liver disease causing hepatitis and cirrhosis in adults and children. The clinical course is highly variable. Some infants present with neonatal cholestasis, which can resolve spontaneously or progress to cirrhosis; others are well in infancy, only to develop portal hypertension later in childhood., Methods: The Childhood Liver Disease Research Network has been enrolling AATD participants into longitudinal, observational studies at North American tertiary centers since 2004. We examined the clinical courses of 2 subgroups of participants from the several hundred enrolled; first, those presenting with neonatal cholestasis captured by a unique study, enrolled because of neonatal cholestasis but before specific diagnosis, then followed longitudinally (n=46); second, separately, all participants who progressed to liver transplant (n=119)., Results: We found male predominance for neonatal cholestasis in AATD (65% male, p=0.04), an association of neonatal gamma-glutamyl transpeptidase elevation to more severe disease, and a higher rate of neonatal cholestasis progression to portal hypertension than previously reported (41%) occurring at median age of 5 months. Participants with and without preceding neonatal cholestasis were at risk of progression to transplant. Participants who progressed to liver transplant following neonatal cholestasis were significantly younger at transplant than those without neonatal cholestasis (4.1 vs. 7.8 years, p=0.04, overall range 0.3-17 years). Neonatal cholestasis had a negative impact on growth parameters. Coagulopathy and varices were common before transplant, but gastrointestinal bleeding was not., Conclusions: Patients with AATD and neonatal cholestasis are at risk of early progression to severe liver disease, but the risk of severe disease extends throughout childhood. Careful attention to nutrition and growth is needed., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Greater hepatitis-related symptomology is associated with lower health-related quality-of-life (HRQoL) among untreated youth with chronic hepatitis B (CHB). How HRQoL changes over time in this population is unknown., Methods: Children from 7 hepatology centers in North America positive for hepatitis B surface antigen, not taking anti-viral therapy, were enrolled in the Hepatitis B Research Network. A validated self-report HRQoL measure, the Child Health Questionnaire Child Report (CHQ-CF87), was completed annually by participants 10-17 years, with demographic variables, liver disease symptoms, and laboratory tests. Linear mixed-effects models were used to evaluate the 10 CHQ-CF87 subscale scores over 5 years among participants who completed the CHQ-CF87 at least twice., Results: Participants (N = 174) completed the CHQ-CF87 a median of 4 times. Median age was 12 years (interquartile range: 10-14) at baseline; 60% were female, 79% Asian, and 47% adopted. The CHQ-CF87 subscale scores were high at baseline (median range: 75.4-100) and did not differ by time point, except for the Family Activities subscale (mean [95% CI]: 82.3 [79.8-84.8] at baseline; 90.8 [86.1-94.6] week 240). Most subscale scores lacked sufficient individual-level variability in change over time to evaluate predictors. Being White versus Asian predicted a more favorable change in Behavior (6.5 [95% CI: 2.0-11.0]). Older age predicted less favorable change in Mental Health (-0.8 [95% CI: -1.36 to -0.23] per year). Changes in liver enzymes and hepatitis B antigens, DNA, or symptom count were not related to changes in these subscale scores., Conclusion: HRQoL was generally good and consistent across 5 years in youth with CHB., Competing Interests: Dr Schwarzenberg consults for Mirum, Renexxion, and UpToDate; Dr Schwarz has research and consulting funds from Gilead, research funding from Albireo, consulting for Mirum, Sarepta, and UpToDate, and is on the editorial board of JPGN Reports ; Dr Rosenthal has research support from AbbVie, Albireo, Arrowhead, Gilead, Merck, Mirum, Takeda, Travere, and is a consultant for Albireo, Audentes, BioMarin, Dicerna, Encoded, Gilead, MedinCell, Mirum, RNAV8, Takeda, Taysha, and Travere; Dr Murray consults and is on the DSMB of Albireo and Gilead and the Board of Director of Improve Care Now; Dr Mogul is Senior Director for Scientific Affairs and Engagement for Mirum, Inc. Dr Ling has research support from AbbVie. The remaining 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.)

Background: Sarcopenia occurs in pediatric chronic liver disease, although the prevalence and contributing factors in genetic intrahepatic cholestasis are not well-described. The objective of this study was to measure muscle mass in school-aged children with genetic intrahepatic cholestasis and assess relationships between sarcopenia, clinical variables, and outcomes., Methods: Estimated skeletal muscle mass (eSMM) was calculated on dual-energy x-ray absorptiometry obtained in a Childhood Liver Disease Research Network study of children with bile acid synthesis disorders(BASD) alpha-1 antitrypsin deficiency (a1ATd), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Relationships between eSMM, liver disease, and transplant-free survival were assessed., Results: eSMM was calculated in 127 participants (5-18 y): 12 BASD, 41 a1ATd, 33 CIC, and 41 ALGS. eSMM z-score was lower in CIC (-1.6 ± 1.3) and ALGS (-2.1 ± 1.0) than BASD (-0.1 ± 1.1) and a1ATd (-0.5 ± 0.8, p < 0.001). Sarcopenia (defined as eSMM z-score ≤- 2) was present in 33.3% of CIC and 41.5% of ALGS participants. eSMM correlated with bone mineral density in the 4 disease groups (r=0.52-0.55, p < 0.001-0.07), but not serum bile acids, bilirubin, aspartate aminotransferase/platelet ratio index, or clinically evident portal hypertension. Of the 2 patients who died (1 with sarcopenia) and 18 who underwent liver transplant (LT, 4 with sarcopenia), eSMM z-score did not predict transplant-free survival. eSMM z-score correlated with the Physical Pediatric Quality of Life Inventory score (r=0.38-0.53, p = 0.007-0.04) in CIC and a1ATd., Conclusion: Severe sarcopenia occurs in some children with ALGS and CIC. The lack of correlation between eSMM and biochemical cholestasis suggests mechanisms beyond cholestasis contribute to sarcopenia. While sarcopenia did not predict transplant-free survival, LT and death were infrequent events. Future studies may define mechanisms of sarcopenia in genetic intrahepatic cholestasis., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Children with rare cholestatic liver diseases, such as Alagille syndrome, progressive familial intrahepatic cholestasis, and biliary atresia typically require liver transplantation (LT). The objective of this analysis was to assess the economic burden of LT on these patients. Health care resource utilization and costs associated with pediatric LT were retrospectively assessed using insurance claims data from the US IBM MarketScan Commercial and Medicaid databases collected between October 2015 and December 2019. Inclusion criteria were as follows: ≥1 procedure code for LT, <18 years old at transplant, and ≥6 months of insurance eligibility at baseline. A cholestatic liver disease population who received LT was selected in the absence of specific diagnosis codes by excluding other severe liver conditions (ie, acute liver failure, malignancy) and by excluding severely decompensated individuals requiring ICU admission before LT. Annualized rates were reported. Over a mean study duration of 1.8 years, 53 commercially insured and 100 Medicaid-insured children received LT, with mean (SD) ages at baseline of 6.9 (6.0) and 5.7 (5.4) years, respectively. During this period, commercially insured and Medicaid-insured patients had annualized means of 65.3 and 52.8 medical visits, respectively. Most were outpatient visits, although the burden of inpatient visits was also high, with mean inpatient stays (inclusive of LT stay) of 37.2 and 31.6 days per year, respectively. Commercially insured and Medicaid-insured patients averaged US$512,124 and $211,863 in medical costs and $26,998 and $15,704 in pharmacy costs, respectively. These costs remained substantial throughout the first year after transplant. Overall, pediatric LT resulted in substantial health care resource utilization and cost burden in both commercially- and Medicaid-insured patients. Novel targeted medications that negate the need for pediatric LT could decrease the associated morbidity and costs., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of American Association for the Study of Liver Diseases.)

Background: Alterations in both mitochondrial DNA (mtDNA) and nuclear DNA genes affect mitochondria function, causing a range of liver-based conditions termed mitochondrial hepatopathies (MH), which are subcategorized as mtDNA depletion, RNA translation, mtDNA deletion, and enzymatic disorders. We aim to enhance the understanding of pathogenesis and natural history of MH., Methods: We analyzed data from patients with MH phenotypes to identify genetic causes, characterize the spectrum of clinical presentation, and determine outcomes., Results: Three enrollment phenotypes, that is, acute liver failure (ALF, n = 37), chronic liver disease (Chronic, n = 40), and post-liver transplant (n = 9), were analyzed. Patients with ALF were younger [median 0.8 y (range, 0.0, 9.4) vs 3.4 y (0.2, 18.6), p < 0.001] with fewer neurodevelopmental delays (40.0% vs 81.3%, p < 0.001) versus Chronic. Comprehensive testing was performed more often in Chronic than ALF (90.0% vs 43.2%); however, etiology was identified more often in ALF (81.3% vs 61.1%) with mtDNA depletion being most common (ALF: 77% vs Chronic: 41%). Of the sequenced cohort (n = 60), 63% had an identified mitochondrial disorder. Cluster analysis identified a subset without an underlying genetic etiology, despite comprehensive testing. Liver transplant-free survival was 40% at 2 years (ALF vs Chronic, 16% vs 65%, p < 0.001). Eighteen (21%) underwent transplantation. With 33 patient-years of follow-up after the transplant, 3 deaths were reported., Conclusions: Differences between ALF and Chronic MH phenotypes included age at diagnosis, systemic involvement, transplant-free survival, and genetic etiology, underscoring the need for ultra-rapid sequencing in the appropriate clinical setting. Cluster analysis revealed a group meeting enrollment criteria but without an identified genetic or enzymatic diagnosis, highlighting the need to identify other etiologies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Prospective data regarding the safety and yield of liver biopsy in both adults and children with chronic hepatitis B are limited. The aim of this study is to report safety, yield, and complication rates among adults and children with chronic hepatitis B undergoing percutaneous liver biopsy., Methods: Data on the indication for procedural characteristics and complication rate for liver biopsies performed as part of the Hepatitis B Research Network were prospectively recorded on a study case report form and analyzed in aggregate., Results: Among 2506 adult and pediatric subjects enrolled in the Hepatitis B Research Network between 2011 and 2018, 465 (19%) underwent 491 liver biopsies for clinical or research reasons. Adequate liver tissue was obtained in 98% of the procedures. In total, there were 32 complications reported for 24 biopsies: 23 biopsies with 30 complications in adults and 1 biopsy with 2 complications in children. Pain (n=19) and vasovagal reaction (n=6) were the most common complications. There were 7 serious adverse events, including an arterioportal venous fistula, a pneumothorax, 4 cases of bleeding, and severe pain with no associated condition. There were no deaths., Conclusions: These data demonstrate that percutaneous liver biopsy is associated with a high yield of tissue (98%) and a rate of serious complications of 1.4% in both children and adults with chronic HBV. These results support the focused use of liver biopsy in the evaluation of novel treatments in development for chronic hepatitis B., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Leukocyte telomere length (LTL) gets shorter with each cell division and is also sensitive to reactive oxygen species damage and inflammatory processes. Studies in adults with non-alcoholic fatty liver disease (NAFLD) have found that increased fibrosis but not ALT levels are associated with shorter LTL. Few pediatric studies have been conducted; as such, we sought to evaluate potential associations between LTL and liver disease and liver disease progression in pediatric patients. Using data from the Treatment of NAFLD in Children (TONIC) randomized controlled trial, we assessed the potential predictive relationship between LTL and liver disease progression based on two successive liver biopsies over 96 weeks. We assessed the potential relationship between LTL and child age, sex, and race/ethnicity and features of liver disease including components of histology. We subsequently evaluated predictors for improvement in non-alcoholic steatohepatitis (NASH) at 96 weeks including LTL. We also assessed predictors of lobular inflammation improvement at 96 weeks using multivariable models. Mean LTL at baseline was 1.33 ± 0.23 T/S. Increasing lobular and portal inflammation were associated with longer LTL. In multivariable models, greater lobular inflammation at baseline was associated with longer LTL (Coeff 0.03, 95% CI 0.006-0.13; p = 0.03). Longer LTL at baseline was associated with worsening lobular inflammation at 96 weeks (Coeff 2.41, 95% CI 0.78-4.04; p < 0.01). There was no association between liver fibrosis and LTL. The association between LTL and pediatric NASH does not parallel adults with no association between fibrosis stage and NASH. Conversely, longer LTL was associated with more lobular inflammation at baseline and increased lobular inflammation over the 96-week period. Longer LTL in children may indicate greater risk for future complications from NASH., (© 2023. The Author(s).)

Background and Aims: In biliary atresia, serum bilirubin is commonly used to predict outcomes after Kasai portoenterostomy (KP). Infants with persistently high levels invariably need liver transplant, but those achieving normalized levels have a less certain disease course. We hypothesized that serum bile acid levels could help predict outcomes in the latter group., Approach and Results: Participants with biliary atresia from the Childhood Liver Disease Research Network were included if they had normalized bilirubin levels 6 months after KP and stored serum samples from the 6-month post-KP clinic visit ( n  = 137). Bile acids were measured from the stored serum samples and used to divide participants into ≤40 μmol/L ( n  = 43) or >40 μmol/L ( n  = 94) groups. At 2 years of age, the ≤40 μmol/L compared with >40 μmol/L group had significantly lower total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, bile acids, and spleen size, as well as significantly higher albumin and platelet counts. Furthermore, during 734 person-years of follow-up, those in the ≤40 μmol/L group were significantly less likely to develop splenomegaly, ascites, gastrointestinal bleeding, or clinically evident portal hypertension. The ≤40 μmol/L group had a 10-year cumulative incidence of liver transplant/death of 8.5% (95% CI: 1.1%-26.1%), compared with 42.9% (95% CI: 28.6%-56.4%) for the >40 μmol/L group ( p  = 0.001)., Conclusions: Serum bile acid levels may be a useful prognostic biomarker for infants achieving normalized bilirubin levels after KP., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of American Association for the Study of Liver Diseases.)

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.)

Background and Aims: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis., Approach and Results: A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p < 0.001) and MMP-7 ( p < 0.001) in participants with BA. The best prediction model for LSM in BA using clinical and lab measurements had an R2 = 0.437; adding IL-8 and MMP-7 improved R2 to 0.523 and 0.526 (both p < 0.0001). In participants with A1AT, CTGF and LSM were negatively correlated ( p = 0.004); adding CTGF to an LSM prediction model improved R2 from 0.524 to 0.577 ( p = 0.0033). Biomarkers did not correlate with LSM in ALGS. A significant number of biomarker/lab correlations were found in participants with BA but not those with A1AT or ALGS., Conclusions: Endoglin, IL-8, and MMP-7 significantly correlate with increased LSM in children with BA, whereas CTGF inversely correlates with LSM in participants with A1AT; these biomarkers appear to enhance prediction of LSM beyond clinical tests. Future disease-specific investigations of change in these biomarkers over time and as predictors of clinical outcomes will be important., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Objective: To assess and characterize health care resource utilization (HRU) in children with the rare, genetic, multisystem disorder, Alagille syndrome., Study Design: This retrospective analysis reviewed commercially insured and Medicaid-insured claims from October 1, 2015 to December 31, 2019 to assess HRU in patients with Alagille syndrome. As there is no specific International Classification ofDiseases-10 code for Alagille syndrome, patients were identified using the following algorithm: ≥1 claim with diagnosis code Q44.7 (other congenital malformations of the liver); <18 years of age, with no history of biliary atresia (International Classification ofDiseases-10 code: Q44.2); and ≥6 months of insurance eligibility prior to diagnosis. HRU was summarized per patient per year over all available claims postdiagnosis., Results: A total of 171 commercially insured and 215 Medicaid-insured patients with Alagille syndrome were available for analysis. Annually, commercially insured and Medicaid-insured patients averaged 31 medical visits (range, 1.5-237) and 48 medical visits (range, 0.7-690), respectively. The most common visits were outpatient with the majority encompassing lab/imaging and primary care visits (commercially insured: 21 [range, 0.0-183]; Medicaid-insured: 26 [range, 0.0-609]). Inpatient visits were the highest driver of costs in both the commercial and Medicaid populations., Conclusions: Patients with Alagille syndrome have a substantial HRU burden driven largely by numerous outpatient visits and costly inpatient stays. Given the complexity and variability of Alagille syndrome presentation, patients may benefit from multidisciplinary and subspecialized care., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Autoantibody seroconversion has been extensively studied in the context of COVID-19 infection but data regarding post-vaccination autoantibody production is lacking. Here we aimed to determine the incidence of common autoantibody formation following mRNA COVID-19 vaccines in patients with inflammatory arthritis (IA) and in healthy controls., Methods: Autoantibody seroconversion was measured by serum ELISA in a longitudinal cohort of IA participants and healthy controls before and after COVID-19 mRNA-based immunization., Results: Overall, there was a significantly lower incidence of ANA seroconversion in participants who did not contract COVID-19 prior to vaccination compared with those who been previously infected (7.4% vs 24.1%, P = 0.014). Incidence of de novo anti-CCP seroconversion in all participants was low at 4.9%. Autoantibody levels were typically of low titre, transient, and not associated with increase in IA flares., Conclusions: In both health and inflammatory arthritis, the risk of autoantibody seroconversion is lower following mRNA-based immunization than following natural SARS-CoV-2 infection. Importantly, seroconversion does not correlate with self-reported IA disease flare risk, further supporting the encouragement of mRNA-based COVID-19 immunization in the IA population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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).)

Background and Aims: Treatment of immune-tolerant (IT) children and adults with combined peginterferon alfa-2a and entecavir results in a decline in serum HBeAg and HBsAg concentrations but rarely results in loss of HBeAg or sustained off-treatment response. Factors associated with declines in these viral antigens during treatment remain unexplored., Approach and Results: We investigated the pattern of virologic and biochemical response in 86 participants (59 children, 27 adults) by serial quantitative measurement of HBsAg (qHBsAg), quantitative HBeAg (qHBeAg), HBV RNA, interferon-inducible protein (IP-10), IL-18, and alanine aminotransferase (ALT). Each individual had previously been treated with 8 weeks of entecavir followed by 40 weeks of combined peginteferon and entecavir. We defined the interrelationships between these parameters and virologic response measured as nadir declines from baseline for HBeAg and HBsAg. The patterns of HBsAg and HBeAg decline were similar in pediatric and adult participants. Higher levels of IP-10 were observed during treatment in participants with greater ALT elevations and greater reductions of qHBsAg and qHBeAg. Individuals with peak ALT values exceeding three times the upper limit of normal were significantly more likely to have >1 log 10 decline in both viral antigens. HBV DNA became undetectable in 21 of 86 (24%) and HBV RNA in 4 of 77 (5%) during therapy, but both markers remained negative only in those who became HBsAg negative, all of whom also had ALT elevations., Conclusions: Induction of IP-10 during peginterferon treatment in adults and children in the IT phase of chronic HBV infection is associated with ALT elevations and decline in viral antigens, suggesting a degree of interferon-inducible viral control., (© 2022 American Association for the Study of Liver Diseases.)

Background and Aims: The natural history of gastroesophageal variceal hemorrhage (VH) in biliary atresia (BA) is not well characterized. We analyzed risk factors, incidence, and outcomes of VH in a longitudinal multicenter study., Approach and Results: Participants enrolled in either an incident (Prospective Database of Infants with Cholestasis [PROBE]) or prevalent (Biliary Atresia Study of Infants and Children [BASIC]) cohort of BA were included. Variceal hemorrhage (VH) was defined based on gastrointestinal bleeding in the presence of varices accompanied by endoscopic or nontransplant surgical intervention. Cumulative incidence of VH and transplant-free survival was compared based on features of portal hypertension (e.g., splenomegaly, thrombocytopenia) and clinical parameters at baseline in each cohort (PROBE: 1.5 to 4.5 months after hepatoportoenterostomy [HPE]; BASIC: at enrollment > 3 years of age). Analyses were conducted on 869 children with BA enrolled between June 2004 and December 2020 (521 in PROBE [262 (51%) with a functioning HPE] and 348 in BASIC). The overall incidence of first observed VH at 5 years was 9.4% (95% CI: 7.0-12.4) in PROBE and 8.0% (5.2-11.5) in BASIC. Features of portal hypertension, platelet count, total bilirubin, aspartate aminotransferase (AST), albumin, and AST-to-platelet ratio index at baseline were associated with an increased risk of subsequent VH in both cohorts. Transplant-free survival at 5 years was 45.1% (40.5-49.6) in PROBE and 79.2% (74.1-83.4) in BASIC. Two (2.5%) of 80 participants who had VH died, whereas 10 (12.5%) underwent transplant within 6 weeks of VH., Conclusions: The low risk of VH and associated mortality in children with BA needs to be considered in decisions related to screening for varices and primary prophylaxis of VH., (© 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

There is growing interest in, but limited data about, intestinal bile acid transport inhibitors as treatment for cholestatic liver disease. The current analyses combine two similar randomized placebo-controlled trials with subsequent extension phases investigating the impact of maralixibat in children with severe cholestasis secondary to Alagille Syndrome (n = 57). The primary outcomes were measures of pruritus (ItchRO[Obs]) and clinician scratch scale (CSS), both increasing in severity from 0 to 4) and quality of life (QoL) (Parent PedsQL and Multidimensional Fatigue Scale module [MFS] scaled 0-100 with increased QoL) at week 48 of the extension phase relative to the baseline of the placebo-controlled trials (week 13). Secondary assessments included other clinical and biochemical parameters assessed in participants at week 72 or end of treatment (after week 48). At week 48, statistically and clinically significant least square mean (95% CI) improvements in pruritus and QoL were observed (ItchRO[Obs] -1.59 [-1.81, -1.36], CSS -1.36 [-1.67, -1.05], PedsQL +10.17 [4.48, 15.86], and multidimension fatigue [MFS] +13.97 [7.85, 20.08]). At week 48, serum bile acids, platelet count, and cholesterol decreased, whereas alanine aminotransferase (ALT) increased and total bilirubin (TB) and albumin were stable. Changes were durable at week 72 and end of treatment. There were no deaths; 2 participants underwent liver transplantation. Study drug was discontinued in 9 participants after treatment-emergent adverse events, 6 of which were events of increased ALT or TB. Conclusion: Maralixibat administration was associated with marked improvement in pruritus and QoL. Interpretation of these findings is complicated by the complex natural history of severe cholestasis in Alagille syndrome., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

The conduct of long-term conventional randomized clinical trials in rare diseases is very difficult, making evidenced-based drug development problematic. As a result, real-world data/evidence are being used more frequently to assess new therapeutic approaches in orphan diseases. In this investigation, inclusion and exclusion criteria from a published trial of maralixibat in Alagille syndrome (ALGS, ITCH NCT02057692) were applied to a prospective longitudinal cohort of children with cholestasis (LOGIC NCT00571272) to derive contextual comparator data for evolving clinical trials of intestinal bile acid transport inhibitors in ALGS. A natural history/clinical care cohort of 59 participants who met adapted inclusion and exclusion criteria of ITCH was identified from 252 LOGIC participants with ALGS with their native liver. Frequency weighting was used to match the age distribution of ITCH and yielded a cohort (Alagille Syndrome Natural History [ALGS NH]) that was very similar to the baseline status of ITCH participants. During a 2-year prospective follow-up there was a significant reduction in pruritus in the weighted ALGS NH cohort as assessed by the clinician scratch score (-1.43 [0.28] -1.99, -0.87; mean [SEM] 95% confidence interval). During the same time period, the total bilirubin, albumin, and alanine aminotransferase levels were unchanged, whereas platelet count dropped significantly (-65.2 [16.2] -98.3, -32.1). Weighted survival with native liver was 91% at 2 years in the ALGS NH. These investigations provide valuable real-world data that can serve as contextual comparators to current clinical trials, especially those without control populations, and highlight the value and importance of funded multicenter, prospective, natural history studies., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Although transplant outcomes for biliary atresia (BA) have improved, there are few data to predict the risk of specific posttransplant complications. We therefore defined the impact of comorbidities in BA on posttransplant outcomes. Patients enrolled in the Society of Pediatric Liver Transplantation registry from 2011 to 2019 (n = 1034) were grouped by comorbidities of >1.0% incidence: any supplemental feeding, dialysis, other abdominal surgery (not Kasai portoenterostomy [KPE]), hepatopulmonary syndrome, and cardiac disease requiring intervention. Demographic and outcome data were compared using the Kruskal-Wallis, chi-square, and log-rank tests. Cox proportional hazards models and binary logistic regression were performed for modeling. Patients with BA with comorbidities comprised 77% (n = 799) of our cohort and had evidence of greater medical acuity, including higher calculated Pediatric End-Stage Liver Disease scores and hospitalizations in the intensive care unit before transplant (P < 0.001 for both) versus those without comorbidities. After transplant, patients with BA with comorbidities had more graft loss (P = 0.02), longer initial hospitalization and intubation (P < 0.001 for both), and increased rates of reoperation (P = 0.001) and culture-proven infection (P < 0.001) within 30 days after transplant. Only patients with BA with comorbidities on supplemental feed had increased rates of patient death (P = 0.02). Multivariate analysis identified lower z weight and higher creatinine as risk factors for graft and patient loss in patients with BA with comorbidities. Prior KPE was protective against culture-proven infection and vascular complications within 30 and 90 days, respectively. Patients with BA with comorbidities have evidence of higher medical acuity at transplant and reduced graft survival; however, they overall did not experience greater incidence of patient death. Our data provide organ-system-specific data to risk-stratify patients with BA and posttransplant outcomes., (© 2021 by the American Association for the Study of Liver Diseases.)

Competing Interests: Disclosures: S.L. receives research support from Abbvie and Gilead. K.M. serves as a consultant for Gilead and Albireo. P.R. receives research support from Abbvie, Gilead, Bristol Myers Squibb, Roche/Genentech, Merck, Travere and consults for Gilead, Abbvie, Intercept, Travere, Albireo, Audentes, Dicerna, and Mirum. N.R.-B. receives research support from Gilead. S.S. receives research support from the Cystic Fibrosis Therapeutic Disease Network, the Cystic Fibrosis Foundation, and Gilead and serves as a consultant for UpToDate. J.T. receives research support from Gilead, Alnylam Inc, Arrowhead Pharmaceuticals, and Dicerna Inc, and serves as a consultant for BioMarin, Editas, Proteostasis, and Retrophin. K.S. receives research support from Gilead, Bristol-Myers Squibb, Roche/Genentech, and serves as a consultant for Gilead, Roche/Genentech, and UptoDate. The other authors declare no conflicts of interest.

Background and Aims: Achieving HBsAg loss is an important landmark in the natural history of chronic hepatitis B (CHB). A more personalized approach to prediction of HBsAg loss is relevant in counseling patients. This study sought to develop and validate a prediction model for HBsAg loss based on quantitative HBsAg levels (qHBsAg) and other baseline characteristics., Methods: The Hepatitis B Research Network (HBRN) is a prospective cohort including 1240 untreated HBeAg-negative patients (1150 adults, 90 children) with median follow-up of 5.5 years. Incidence rates of HBsAg loss and hepatitis B surface antibody (anti-HBs) acquisition were determined, and a predictor score of HBsAg loss using readily available variables was developed and externally validated., Results: Crude incidence rates of HBsAg loss and anti-HBs acquisition were 1.6 and 1.1 per 100 person-years (PY); 67 achieved sustained HBsAg loss for an incidence rate of 1.2 per 100 PY. Increased HBsAg loss was significantly associated with older age, non-Asian race, HBV phenotype (inactive CHB vs. others), HBV genotype A, lower HBV-DNA levels, and lower and greater change in qHBsAg. The HBRN-SQuARe (sex,∆quantHBsAg, age, race) score predicted HBsAg loss over time with area under the receiver operating characteristic curve (AUROC) (95% CIs) at 1 and 3 years of 0.99 (95% CI: 0.987-1.00) and 0.95 (95% CI 0.91-1.00), respectively. In validation in another cohort of 1253 HBeAg-negative patients with median follow-up of 3.1 years, HBRN SQuARe predicted HBsAg loss at 1 and 3 years with AUROC values of 0.99 (0.98-1.00) and 0.88 (0.77-0.99), respectively., Conclusion: HBsAg loss in predominantly untreated patients with HBeAg-negative CHB can be accurately predicted over a 3-year horizon using a simple validated score (HBRN SQuARe). This prognostication tool can be used to support patient care and counseling., (© 2021 American Association for the Study of Liver Diseases.)

Liver damage in hepatitis B is immune driven and correlates with inflammatory markers in patient serum. There is no comparison of these markers to determine if inflammatory profiles are distinct to different types of liver damage across patients at different stages of disease. We measured 25 inflammatory markers in patients with acute hepatitis B and chronic hepatitis B with hepatitis B e antigen seroconversion and chronic patients stopping nucleoside analogue therapy. Myeloid markers dominated the inflammatory profile in all stages of hepatitis B. More inflammatory markers were detectable in chronic patients, including elevated concentrations of cytotoxic effectors Fas ligand, TRAIL, and TNF-α., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: To evaluate neurodevelopmental status among children with inherited cholestatic liver diseases with native liver and variables predictive of impairment., Methods: Participants with Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), and alpha 1 antitrypsin deficiency (A1AT) enrolled in a longitudinal, multicenter study and completed the Wechsler Preschool and Primary Scale of Intelligence-III or Intelligence Scale for Children-IV. Full Scale Intelligence Quotient (FSIQ) was analyzed continuously and categorically (>100, 85-99, 70-84, <70). Univariate linear regression was performed to study association between FSIQ and risk factors, stratified by disease., Results: Two hundred and fifteen completed testing (ALGS n = 70, PFIC n = 43, A1AT n = 102); median age was 7.6 years (3.0-16.9). Mean FSIQ in ALGS was lower than A1AT (94 vs 101, P = 0.01). Frequency of FSIQ < 85 (>1 standard deviation [SD] below average) was highest in ALGS (29%) versus 18.6% in PFIC and 12.8% in A1AT, and was greater than expected in ALGS based on normal distribution (29% vs 15.9%, P = 0.003). ALGS scored significantly lower than test norms in almost all Wechsler composites; A1AT scored lower on Working Memory and Processing Speed; PFIC was not different from test norms. Total bilirubin, alkaline phosphatase, albumin, hemoglobin, and parental education were significantly associated with FSIQ., Conclusions: Patients with ALGS are at increased risk of lower FSIQ, whereas our data suggest A1AT and PFIC are not. A1AT and ALGS appear vulnerable to working memory and processing speed deficits suggestive of attention/executive function impairment. Malnutrition, liver disease severity, and sociodemographic factors appear related to FSIQ deficits, potentially identifying targets for early interventions., Competing Interests: Conflicts of Interest: D.H.L. reports grant/research support from Abbvie, Gilead, and CF Foundation; he also serves on advisory panels for Merck and Gilead. B.M.K. is a consultant for Mirum, Albireo and Audentes; she has unrestricted educational grants from Mirum and Albireo. V.L.N. is a consultant for Albireo. P.R. reports grants from Gilead, Merck, BMS, AbbVie, Travere Therapeutics, Albireo, and Mirum, Arrowhead; and serving as a consultant for Gilead, Mirum, Albireo, Audentes, and Vertex. R.J.S. reports consulting for Albireo, Mirum/Shire, and Retrophin (all <$10,000 per year). K.M.L. reports consulting for Albireo, Mirum and Retrophin (now known as Travere Therapeutics). The remaining authors report no conflicts of interest. The study sponsors did not have a role in study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the paper for publication., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Nutritional status is known to strongly predict health outcomes in people with cystic fibrosis (CF), but the prevalence of and consequences for CF children with growth failure and underweight CF adults on the liver transplant (LT) waitlist has not been delineated. We utilized UNOS registry data from 2003 to 2017 to investigate the impact of growth failure and underweight on outcomes in liver transplant candidates with CF. Almost 1 in 3 children and adults with CF had growth failure or were underweight, respectively, at listing. Body mass index under-estimated growth failure compared to height and weight z-scores for children. In multivariate analysis of children, growth failure (HR 2.1, 95% CI 1.7-2.6), and CF (HR 2.7, 95% CI 1.6-4.6, vs. Non-CF) were independent risk factors for waitlist death among children; having both increased death risk almost fourfold (SHR 3.88, 95% CI 1.42-10.58). However, among children who did receive a LT, CF was not associated with death within 1-year post-LT. Underweight adult CF candidates were less likely to receive LT, again suggesting the importance of nutritional evaluation and early intervention in this at-risk cohort., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objectives: The aim of the study was to determine the frequency and natural history of infantile idiopathic cholestasis (IC) in a large, prospective, multicenter cohort of infants., Methods: We studied 94 cholestatic infants enrolled up to 6 months of age in the NIDDK ChiLDReN (Childhood Liver Disease Research Network) "PROBE" protocol with a final diagnosis of IC; they were followed up to 30 months of age., Results: Male sex (66/94; 70%), preterm birth (22/90 with data; 24% born at < 37 weeks' gestational age), and low birth weight (25/89; 28% born at <2500 g) were frequent, with no significant differences between outcomes. Clinical outcomes included death (n = 1), liver transplant (n = 1), biochemical resolution (total bilirubin [TB] ≤1 mg/dL and ALT < 35 U/L; n = 51), partial resolution (TB > 1 mg/dL and/or ALT > 35 U/L; n = 7), and exited healthy (resolved disease per study site report but without documented biochemical resolution; n = 34). Biochemical resolution occurred at median of 9 months of age. GGT was <100 U/L at baseline in 34 of 83 participants (41%)., Conclusions: Frequency of IC and of death or liver transplant was less common in this cohort than in previously published cohorts, likely because of recent discovery and diagnosis of genetic etiologies of severe/persistent cholestasis that previously were labeled as idiopathic. Preterm birth and other factors associated with increased vulnerability in neonates are relatively frequent and may contribute to IC. Overall outcome in IC is excellent. Low/normal GGT was common, possibly indicating a role for variants in genes associated with low-GGT cholestasis-this warrants further study., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objective: To investigate the humoral and cellular immune response to messenger RNA (mRNA) COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment., Methods: Established patients at New York University Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunisation. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analysed for humoral response. Cellular immune response to SARS-CoV-2 was further analysed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany, were also analysed for humoral immune response., Results: Although healthy subjects (n=208) and patients with IMID on biologic treatments (mostly on tumour necrosis factor blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, patients with IMID on methotrexate do not demonstrate an increase in CD8+ T-cell activation after vaccination., Conclusions: In two independent cohorts of patients with IMID, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut-offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunisation efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines., Competing Interests: Competing interests: JUS declares that he has served as a consultant for Janssen, Novartis, Pfizer, Sanofi, UCB and Abbvie and has received funding for investigator-initiated studies from Novartis, Sanofi and Janssen. GS has served as a consultant for Abbvie, BMS, Eli Lilly, Gilead, GSK Novartis, Janssen and Roche and has received funding for investigator-initiated studies from BMS, Eli Lilly, GSK, Novartis and UCB. MM declares grants from Eli Lilly, Pfizer and Sanofi and personal fees from Meissa Vaccines. PI has received consulting fees from GSK. RHH has received consulting from Janssen. SA reports grant support from Johnson and Johnson. GS declares consulting fees from AbbVie., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine the outcomes of chronic hepatitis B virus (HBV) infection in a large, prospectively studied cohort of children in the US and Canada., Study Design: This was a prospective, observational study of children with chronic HBV enrolled in 7 clinical centers and evaluated at baseline, weeks 24 and 48, and annually thereafter, with analysis of demographic, clinical, physical examination, and blood test data., Results: Among 362 children followed for a median of 4.2 years, elevated alanine aminotransferase (ALT) levels (>1 upper limit of normal) were present in 72% at last evaluation, including in 60% of children with loss of hepatitis B e antigen during follow-up and 70% of those who were hepatitis B e antigen negative at baseline. Significant ALT flares (male patients ≥400 U/L, female patients ≥350 U/L) occurred in 13 children. Of 129 children who fulfilled the American Association for the Study of Liver Diseases treatment criteria during follow-up, anti-HBV treatment was initiated in only 25. One child died (unrelated to liver disease), 1 developed cirrhosis, but no episodes of cirrhotic decompensation or hepatocellular carcinoma were observed. Decline in platelet count was inversely associated with ALT elevations., Conclusions: In a cohort of children with chronic HBV infection in the US and Canada, many children remained at risk of progressive liver disease due to active hepatitis, but major clinical outcomes such as cirrhosis, cancer, and death were rare. Many children who met criteria for treatment remained untreated., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: To evaluate the efficacy of percutaneous and endoscopic therapeutic interventions for biliary strictures and leaks following LT in children., Methods: Retrospective analysis of 49 consecutive pediatric liver transplant recipients (27 girls, 22 boys, mean age at transplant 3.9 years) treated at our institution from 1989 to 2019 for biliary leak and/or biliary stricture was performed. Minimally invasive approach was considered clinically successful if it resulted in patency of the narrowed biliary segment and/or correction of the biliary leak., Results: Forty-two patients had a stricture at the biliary anastomosis; seven had a biliary leak. After an average 13.8 years of follow-up, long-term clinical success with minimally invasive treatment (no surgery or re-transplant) was achieved for 24 children (57%) with biliary stricture and 4 (57%) with biliary leaks. Eight patients required re-transplant; however, only one was due to failure of both percutaneous and surgical management. For biliary strictures, failure of non-surgical management was associated with younger age at stricture diagnosis (p < .02)., Conclusions: Percutaneous and endoscopic management of biliary strictures and leaks after LT in children is associated with a durable result in >50% of children., (© 2021 Wiley Periodicals LLC.)

Over the course of history, mining and metallurgical activities have influenced the socioeconomic development of human populations. However, these past and current activities can also lead to substantial environmental contamination by various metals. Here, we used an interdisciplinary approach (incorporating archaeology, mineralogy, environmental chemistry and ecotoxicology) to investigate the origin, fate and potential ecotoxicity of anomalous manganese (Mn) concentrations detected in the ancient mining district of Berthelange (medieval period, eastern France). Mineralogical investigations of slag samples showed that smelting temperature conditions in medieval bloomeries led to the production of slags mainly composed of Fe- and Mn-rich olivine, i.e., fayalites. Further mineralogical analyses of bulk soil and clay fractions allowed us to identify the presence of serpentine. This evidence of olivine weathering can account for the release of Mn from slags into the soil. In addition, chemical analyses of total and available (exchangeable and reducible) Mn concentrations in soil samples clearly showed the contribution of slags deposited 1000 years ago to soil contamination. A complementary ecotoxicity bioassay performed on soils from a slag heap using the land snail Cantareus aspersus confirmed that a significant fraction of the Mn detected in soils remains available for partitioning with the soil solution and transfer to soil organisms. Although no growth inhibition of snails was observed after 28 days of exposure, the animals accumulated quite elevated Mn concentrations in their tissues. Our study emphasizes the environmental availability and bioavailability of Mn from ancient metallurgical wastes to soil-dwelling invertebrates, i.e., snails, even one millennium after their deposition. Hence, as for more recent industrial sites, past mining ecosystems must be a cause of concern for the scientific community and public authorities., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Fatty liver disease (FLD) influences liver disease progression and liver cancer risk. We investigated the impact of FLD on liver disease severity in a large North American cohort with chronic hepatitis B virus (HBV)., Methods: Liver biopsies from 420 hepatitis B surface antigen-positive adults enrolled in the Hepatitis B Research Network and who were not on HBV therapy in the previous month were evaluated for inflammation and fibrosis. Steatohepatitis was based on steatosis, hepatocyte ballooning ± Mallory-Denk bodies, and perisinusoidal fibrosis. Models evaluated factors associated with steatohepatitis, and the associations of steatohepatitis with fibrosis, and longitudinal alanine aminotransferase, aspartate aminotransferase, and Fibrosis-4., Results: The median age was 42 years, 62.5% were male, and 79.5% were Asian. One hundred thirty-two (31.4%) patients had FLD (77 [18.3%] steatosis only, 55 [13.1%] steatohepatitis). Older age, overweight/obesity, and diabetes were associated with steatohepatitis. Steatohepatitis (vs no FLD) was associated with 1.68 times higher risk of advanced fibrosis at baseline (95% confidence interval, 1.12-2.51), and there was an indication of higher incident cirrhosis rate during follow-up. Steatohepatitis vs no FLD was also independently associated with, on average, 1.39 times higher alanine aminotransferase (P < 0.01) and 1.25 times higher Fibrosis-4 (P = 0.04) across 4 years., Discussion: Coexisting steatosis occurred in nearly a third of adults (13% had steatohepatitis) with chronic HBV in this North American cohort who underwent liver biopsies. Steatohepatitis was associated with advanced fibrosis and higher biochemical measures of hepatic inflammation over time. Therefore, in addition to viral suppression, screening for and managing metabolic abnormalities is important to prevent disease progression in HBV., (Copyright © 2021 by The American College of Gastroenterology.)

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., (© The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Objective: Although oral methotrexate (MTX) remains the anchor drug for rheumatoid arthritis (RA), up to 50% of patients do not achieve a clinically adequate outcome. In addition, there is a lack of prognostic tools for treatment response prior to drug initiation. This study was undertaken to investigate whether interindividual differences in the human gut microbiome can aid in the prediction of MTX efficacy in new-onset RA., Methods: We performed 16S ribosomal RNA gene and shotgun metagenomic sequencing on the baseline gut microbiomes of drug-naive patients with new-onset RA (n = 26). Results were validated in an additional independent cohort (n = 21). To gain insight into potential microbial mechanisms, we conducted ex vivo experiments coupled with metabolomics analysis to evaluate the association between microbiome-driven MTX depletion and clinical response., Results: Our analysis revealed significant associations of the abundance of gut bacterial taxa and their genes with future clinical response (q < 0.05), including orthologs related to purine and MTX metabolism. Machine learning techniques were applied to the metagenomic data, resulting in a microbiome-based model that predicted lack of response to MTX in an independent group of patients. Finally, MTX levels remaining after ex vivo incubation with distal gut samples from pretreatment RA patients significantly correlated with the magnitude of future clinical response, suggesting a possible direct effect of the gut microbiome on MTX metabolism and treatment outcomes., Conclusion: Taken together, these findings are the first step toward predicting lack of response to oral MTX in patients with new-onset RA and support the value of the gut microbiome as a possible prognostic tool and as a potential target in RA therapeutics., (© 2020, American College of Rheumatology.)

Background: Hepatocelluar carcinoma typically occurs with underlying cirrhosis. However roughly 20% of cases arise in a non-cirrhotic liver. There is limited literature that addresses the long-term survival of the narrow subgroup who received transplantation. For such patients we sought to calculate life expectancies both at time of transplant and several years later, stratified by key risk factors, and to determine if survival has improved in recent years. Such information can be helpful in making treatment decisions., Methods: Data on 4,373 non-cirrhotic HCC patients who underwent liver transplantation in the MELD era (2002-2018) from the United States OPTN database were analyzed using the Cox proportional hazards regression model and life table methods., Results: Demographic and past medical history factors related to survival were patient age, donor age over 20, and the presence of ascites or severe hepatic encephalopathy. Survival did not vary by race or sex. HCC-specific factors significantly related to survival were the total number of tumors, extrahepatic spread, lymph node involvement, satellite lesions, micro- or macrovascular invasion, tumor differentiation (grade), and pre-transplant treatment. Survival improved over the study period, at 4% per calendar year during the first 5 years post transplant and 1% per year thereafter., Conclusions: Life expectancy in non-cirrhotic HCC transplant patients is much reduced from normal, and varies according to age and tumor-related factors. Survival improved modestly over the study period.

Objectives: Cholestasis is caused by a wide variety of etiologies, often genetic in origin. Broad overlap in clinical presentations, particularly in newborns, renders prioritizing diagnostic investigations challenging. In this setting, a timely, comprehensive assessment using a multigene panel by a clinical diagnostic laboratory would likely prove useful. We summarize initial findings from a testing program designed to discover genetic causes of cholestasis., Methods: A neonatal/adult sequencing panel containing 66 genes (originally 57; nine added March 2017) relevant to cholestasis was used. A broad range of eligible patients were enrolled with current/history of cholestasis without an identified cause, or unexplained chronic liver disease. DNA sequencing utilized a custom-designed capture library, and variants were classified and reported as benign, likely benign, variant of unknown significance (VOUS), likely pathogenic (LP), or pathogenic (P), according to the clinical interpretation workflow at EGL Genetics (Tucker, GA)., Results: A total of 2433 samples were submitted between February 2016 and December 2017; 2171 results were reported. Median turnaround time was 21 days. Results from the 2171 subjects (57% <1 year old) included 583 P variants, 79 LP variants, and 3117 VOUS; 166 P/LP variants and 415 VOUS were novel. The panel's overall diagnostic yield was 12% (n = 265/2171) representing 32 genes. The top five genetic diagnoses for the group, in order: JAG1 + NOTCH2 (Alagille syndrome), ABCB11, SERPINA1, ABCB4, and POLG., Conclusions: These findings support the utility of comprehensive rapid multigene testing in diagnosing cholestasis and highlight the evolving understanding of genetic variants contributing to the pathogenesis of cholestasis., Competing Interests: Conflicts of Interest: S.J.K.: Consultant for Albireo, Logic Bio, Intercept, Mirum, and Retrophin, Inc. B.M.K.: Consultant for Albireo, Retrophin, Inc., Shire, Mirum, DCI. J.J.A.: During the course of this study was a consultant for Retrophin, Inc and laboratory director at Emory/EGL. I.I.: During the course of this study was a full-time employee of Retrophin, Inc. P.R.: Consultant for Albireo, Alexion, Alnylam, Audentes, Intercept, and Retrophin, Inc. R.S.: Consultant for Albireo, Alexion, Shire, Mirum, and Retrophin, Inc. S.D.: Full-time employee of Retrophin, Inc. R.T.: Consultant for Retrophin, Inc, Shire, Mirum Albireo, Alnylam, Horizon Pharma, Sana Biotechnology, Qing Bile Therapeutics, and GenerationBio, and has stock options at Qing Bile Therapeutics and GenerationBio. J.E.H.: Equity interest in Asklepion, and consultant for Retrophin, Inc, Shire, Alnylam, Friesland Campina, Mirum, and Nordmark., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

ORM1-like 3 (ORMDL3) has strong genetic linkage to childhood onset asthma. To determine whether ORMDL3 selective expression in airway smooth muscle (ASM) influences ASM function, we used Cre-loxP techniques to generate transgenic mice (hORMDL3Myh11eGFP-cre), which express human ORMDL3 selectively in smooth muscle cells. In vitro studies of ASM cells isolated from the bronchi of hORMDL3Myh11eGFP-cre mice demonstrated that they developed hypertrophy (quantitated by FACS and image analysis), developed hyperplasia (assessed by BrdU incorporation), and expressed increased levels of tropomysin proteins TPM1 and TPM4. siRNA knockdown of TPM1 or TPM4 demonstrated their importance to ORMDL3-mediated ASM proliferation but not hypertrophy. In addition, ASM derived from hORMDL3Myh11eGFP-cre mice had increased contractility to histamine in vitro, which was associated with increased levels of intracellular Ca2+; increased cell surface membrane Orai1 Ca2+ channels, which mediate influx of Ca2+ into the cytoplasm; and increased expression of ASM contractile genes sarco/endoplasmic reticulum Ca2+ ATPase 2b and smooth muscle 22. In vivo studies of hORMDL3Myh11eGFP-cre mice demonstrated that they had a spontaneous increase in ASM and airway hyperreactivity (AHR). ORMDL3 expression in ASM thus induces changes in ASM (hypertrophy, hyperplasia, increased contractility), which may explain the contribution of ORMDL3 to the development of AHR in childhood onset asthma, which is highly linked to ORMDL3 on chromosome 17q12-21.

Studies of human hepatitis B virus (HBV) immune pathogenesis are hampered by limited access to liver tissues and technologies for detailed analyses. Here, utilizing imaging mass cytometry (IMC) to simultaneously detect 30 immune, viral, and structural markers in liver biopsies from patients with hepatitis B e antigen+ (HBeAg+) chronic hepatitis B, we provide potentially novel comprehensive visualization, quantitation, and phenotypic characterizations of hepatic adaptive and innate immune subsets that correlated with hepatocellular injury, histological fibrosis, and age. We further show marked correlations between adaptive and innate immune cell frequencies and phenotype, highlighting complex immune interactions within the hepatic microenvironment with relevance to HBV pathogenesis.

The Peierls-Nabarro barrier is a discrete effect that frequently occurs in discrete nonlinear systems. A signature of the barrier is the slowing and eventual stopping of discrete solitary waves. This work examines intense electromagnetic waves propagating through a periodic honeycomb lattice of helically driven waveguides, which serves as a paradigmatic Floquet topological insulator. Here it is shown that discrete topologically protected edge modes do not suffer from the typical slowdown associated with the Peierls-Nabarro barrier. Instead, as a result of their topological nature, the modes always move forward and redistribute their energy: a narrow (discrete) mode transforms into a wide effectively continuous mode. On the other hand, a discrete edge mode that is not topologically protected does eventually slow down and stop propagating. Topological modes that are initially narrow naturally tend to wide envelope states that are described by a generalized nonlinear Schrödinger equation. These results provide insight into the nature of nonlinear topological insulators and their application.

Although beneficial effects of an early goal directed therapy (EGDT) after cardiac arrest and successful return of spontaneous circulation (ROSC) have been described, clinical implementation in this period seems rather difficult. The aim of the present study was to investigate the feasibility and the impact of EGDT on myocardial damage and function after cardiac resuscitation. A translational pig model which has been carefully adapted to the clinical setting was employed. After 8 min of cardiac arrest and successful ROSC, pigs were randomized to receive either EGDT (EGDT group) or therapy by random computer-controlled hemodynamic thresholds (noEGDT group). Therapeutic algorithms included blood gas analysis, conductance catheter method, thermodilution cardiac output and transesophageal echocardiography. Twenty-one animals achieved successful ROSC of which 13 pigs survived the whole experimental period and could be included into final analysis. cTnT and LDH concentrations were lower in the EGDT group without reaching statistical significance. Comparison of lactate concentrations between 1 and 8 h after ROSC exhibited a decrease to nearly baseline levels within the EGDT group (1 h vs 8 h: 7.9 vs. 1.7 mmol/l, P < 0.01), while in the noEGDT group lactate concentrations did not significantly decrease. The EGDT group revealed a higher initial need for fluids (P < 0.05) and less epinephrine administration (P < 0.05) post ROSC. Conductance method determined significant higher values for preload recruitable stroke work, ejection fraction and maximum rate of pressure change in the ventricle for the EGDT group. EGDT after cardiac arrest is associated with a significant decrease of lactate levels to nearly baseline and is able to improve systolic myocardial function. Although the results of our study suggest that implementation of an EGDT algorithm for post cardiac arrest care seems feasible, the impact and implementation of EGDT algorithms after cardiac arrest need to be further investigated.