Search

Background: Intestinal transplantation (IT) is a complex procedure that requires nuanced immunosuppressive strategies to optimize patient outcomes. Despite advancements, significant variability remains in immunosuppressive protocols across transplant centers due to a lack of consensus on the optimal approaches for induction, maintenance, and clinical testing. This variability complicates standardization and identification of best practices for IT recipients., Methods: A descriptive survey study was conducted to characterize immunosuppressive and testing strategies in IT at major transplant centers in the United States. Ten centers known to have performed over 10 ITs since 2015 were selected from the Scientific Registry of Transplant Recipients database. A 22-question survey was distributed to surgical directors, collecting data on pre-, peri-, and post-transplant immunological testing, desensitization strategies, immunosuppressive regimens, and management of antibody-mediated rejection (AMR) and acute cellular rejection (ACR)., Results: Nine centers (90%) responded. All centers conducted pretransplant human leukocyte antigen (HLA) and donor-specific antibody (DSA) testing, with varying frequencies and methodologies. Desensitization was reported by 44% of centers for isolated IT and by 22% for multivisceral transplants. Induction therapy predominantly involved antithymocyte globulin (89%) and rituximab (44%). Tacrolimus was universally used for maintenance, with varying trough level targets across centers. Post-transplant DSA testing was performed by all centers, and protocol-driven endoscopic bowel biopsies were routine at 67% of centers. AMR was diagnosed at 89% of centers, with plasmapheresis and IVIG being the most common treatments. Variability was noted in desensitization practices and AMR management., Conclusion: This survey highlights considerable consistency in pre- and post-transplant testing and immunosuppressive regimens for IT recipients, while significant variability exists in desensitization strategies and AMR management. Further research is needed to standardize these practices to improve patient outcomes across transplant centers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Background: The immune heterogeneity of biliary atresia (BA) presents a challenge for development of prognostic biomarkers. This study aimed to identify early immune signatures associated with biliary drainage after Kasai Portoenterostomy (KPE)., Methods: Serum samples, liver slides, and clinical data were obtained from patients enrolled in the NIDDK-supported Childhood Liver Disease Research Network. Serum cytokines and hepatic immune cell subsets were measured at diagnosis and compared among 3 groups: 38 infants with BA (20 with evidence of bile flow after KPE; 18 without) and 17 non-BA cholestatic infants., Results: BA participants had lower numbers of lipid associated macrophages (LAM), and increased serum levels of Eotaxin-3, interleukin (IL) 12p70, and IL-8 versus non-BA groups (p < 0.05 for all). Among BA participants, monocyte like macrophages and serum levels of granulocyte-macrophage colony stimulating factor (GM-CSF) were increased in BA participants with good biliary drainage (p = 0.004 and p < 0.001 respectively). Levels of GM-CSF, IL-16, c-reactive protein, TNF-β predicted successful biliary drainage with an area under the receiver operating curve of 0.84 (p < 0.001)., Conclusion: These findings suggest that distinct macrophage-associated immune networks at diagnosis may impact biliary drainage after KPE. Identification of early prognostic immune-modulatory markers has potential to improve patient stratification for medical and surgical therapies., Impact Statement: We identify serum cytokines, particularly GM-CSF, that are associated with future biliary drainage in patients with biliary atresia. Characterization of macrophage-associated immune networks provides novel insight into early disease mechanism that may impact patient outcomes. Early prognostic biomarkers markers in biliary atresia can help in patient stratification for medical and surgical therapies., Competing Interests: Competing interests: SAT serves as a consultant for Ipsen and Mirum Pharma. SH serves on the Data Safety Monitoring Board coordinated by Syneos Health for a therapeutic drug trial for biliary atresia. KML serves as a consultant for Ipsen and Mirum Pharma. PV serves on the Speaker’s Bureau for Mirum and is a consultant for Grifols. SJK serves as a consultant for Ipsen, Hemoshear, Intercept, Mirum, and Vertex. RJS serves as consultant for Ipsen and Mirum Pharma. All remaining coauthors declare no conflicts of interest for this manuscript. Consent statement: Written informed consent was obtained for all participants. Institutional review board approval was obtained for the study and conformed to the ethical guidelines of the 1975 Declaration of Helsinki., (© 2025. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background and Aims: Biliary atresia (BA) entails an inflammatory sclerosing lesion of the biliary tree, with prominent fibrosis in infancy. Previous studies revealed that neutrophil-activating IL-8 and neutrophil extracellular traps (NETs) positively correlated with bilirubin and the risk of liver transplant. The aims of this study were to determine the mechanism of NET formation (NETosis) in BA and whether NETs induce stellate cell activation., Approach and Results: BA and other liver disease control plasma and tissue were obtained at diagnosis and transplant. Elastase, NETs, and IL-8 were quantified by ELISA for plasma and by immunohistochemistry for liver tissue. FACS analysis of neutrophils co-cultured with BA or control plasma measured BA-specific NETosis. Stellate cell activation from co-culture studies of stellate cells with NETs was measured by real-time quantitative PCR, ELISA, and FACS. Liver neutrophils and NETs, and plasma elastase, NETs, and IL-8, were significantly increased in BA at diagnosis and transplant. Normal neutrophils co-cultured with BA plasma had increased NETosis and activation of CXCR2, an IL-8 receptor; CXCR2 inhibition decreased NET production. Immunohistochemistry identified increased NET expression of profibrogenic tissue factor and IL-17. NETs co-cultured with stellate cells resulted in stellate cell activation based on increased ACTA2 and COL1A1 mRNA, collagen protein, and cell surface expression of actin, collagen1A, and platelet-derived growth factor receptor-beta., Conclusions: Patients with BA have persistent IL-8-CXCR2-mediated NETosis that correlates with biomarkers of injury and fibrosis, and NETs induce stellate cell activation, suggesting a role for NETs in the immunopathogenesis of disease. Future investigations should focus on therapeutic agents that inhibit NETs in BA., (Copyright © 2024 American Association for the Study of Liver Diseases.)

There is currently no clear consensus on screening techniques to evaluate the presence or severity of Fontan-associated liver disease (FALD). Cardiac MRI (CMR) is used routinely for post-Fontan surveillance, but CMR-derived measures that relate to the severity of FALD are not yet defined. This was a cross-sectional single-center study of post-Fontan patients who underwent a CMR. CMR exams were re-analyzed by a single pediatric cardiologist. Surrogates of FALD included Gamma-Glutamyl Transferase (GGT), Fibrosis-4 laboratory score (FIB-4), and imaging findings. Findings consistent with cirrhosis on liver ultrasound included increased liver echogenicity and/or nodularity. Statistical analyses were performed to investigate potential relationships between CMR parameters and markers of FALD. Sixty-one patients were included. A larger inferior vena cava cross-sectional area (IVC-CSA) indexed to height was significantly associated with a higher FIB-4 score (Spearman's ρ = 0.28, p = 0.04), a higher GGT level (Spearman's ρ = 0.40, p = 0.02), and findings consistent with cirrhosis on liver ultrasound (OR 1.17, 95% CI: (1.01, 1.35), p = 0.04). None of the other CMR parameters were associated with markers of FALD. A larger indexed IVC-CSA was associated with higher systemic ventricle end-diastolic pressure (EDP) on cardiac catheterization (Spearman's ρ = 0.39, p = 0.018) as well as older age (Spearman's ρ = 0.46, p =  < 0.001). Indexed IVC-CSA was the only CMR parameter that was associated with markers of FALD. This measure has the potential to serve as an additional non-invasive tool to improve screening strategies for FALD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Enhanced B-cell presentation of donor alloantigen relative to presentation of HLA-mismatched reference alloantigen is associated with acute cellular rejection (ACR), when expressed as a ratio called the antigen presenting index (API) in an exploratory cohort of liver and intestine transplant (LT and IT) recipients., Methods: To test clinical performance, we measured the API using the previously described 6-h assay in 84 LT and 54 IT recipients with median age 3.3 y (0.05-23.96). Recipients experiencing ACR within 60 d after testing were termed rejectors., Results: We first confirmed that B-cell uptake and presentation of alloantigen induced and thus reflected the alloresponse of T-helper cells, which were incubated without and with cytochalasin and primaquine to inhibit antigen uptake and presentation, respectively. Transplant recipients included 76 males and 62 females. Rejectors were tested at median 3.6 d before diagnosis. The API was higher among rejectors compared with nonrejectors (2.2 ± 0.2 versus 0.6 ± 0.04, P value = 1.7E-09). In logistic regression and receiver-operating-characteristic analysis, API ≥1.1 achieved sensitivity, specificity, and positive and negative predictive values for predicting ACR in 99 training set samples. Corresponding metrics ranged from 80% to 88% in 32 independent posttransplant samples, and 73% to 100% in 20 independent pretransplant samples. In time-to-event analysis, API ≥1.1 predicted higher incidence of late donor-specific anti-HLA antibodies after API measurements in LT recipients ( P = 0.011) and graft loss in IT recipients ( P = 0.008), compared with recipients with API <1.1, respectively., Conclusions: Enhanced donor antigen presentation by circulating B cells predicts rejection after liver or intestine transplantation as well as higher incidence of DSA and graft loss late after transplantation., Competing Interests: The antigen presenting test is based on US Patent 10222374, inventors: R.S. and C.A., Assignee: University of Pittsburgh of the Commonwealth System of Higher Education, Pittsburgh, PA, and licensed to Plexision, Inc., Pittsburgh 15224, in which the University and R.S. holds equity. C.A. is a consultant to licensee without other financial relationships. Disclosed conflicts of interest have been managed in accordance with the University of Pittsburgh’s policies and procedures. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. All other authors have nothing to disclose. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

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.)

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 & Aims: Biliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA., Methods: We performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls. Whole-genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models., Results: A GWAS of common single nucleotide polymorphisms (SNPs), i.e. allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p = 3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p = 1.34E-7), both supported by credible peaks of neighboring SNPs. Like other previously reported BA-associated genes, AFAP1 and TUSC3 are ciliogenesis and planar polarity effectors (CPLANE). In gene-set-based GWAS, BA was associated with 6,005 SNPs in 102 CPLANE genes (p = 5.84E-15). Compared with non-CPLANE genes, more CPLANE genes harbored rare variants (allele frequency <1%) that were assigned Human Phenotype Ontology terms related to hepatobiliary anomalies by predictive algorithms, 87% vs. 40%, p <0.0001. Rare variants were present in multiple genes distinct from those with BA-associated common variants in most BA cases. AFAP1 and TUSC3 knockdown blocked ciliogenesis in mouse tracheal cells. Inhibition of ciliogenesis caused biliary dysgenesis in zebrafish. AFAP1 and TUSC3 were expressed in fetal liver organoids, as well as fetal and BA livers, but not in normal or disease-control livers. Integrative analysis of BA-associated variants and liver transcripts revealed abnormal vasculogenesis and epithelial tube formation, explaining portal vein anomalies that co-exist with BA., Conclusions: BA is associated with polygenic susceptibility in CPLANE genes. Rare variants contribute to polygenic risk in vulnerable pathways via unique genes., Impact and Implications: Liver transplantation is needed to cure most children born with biliary atresia, a poorly understood rare disease. Transplant immunosuppression increases the likelihood of life-threatening infections and cancers. To improve care by preventing this disease and its progression to transplantation, we examined its genetic basis. We find that this disease is associated with both common and rare mutations in highly specialized genes which maintain normal communication and movement of cells, and their organization into bile ducts and blood vessels during early development of the human embryo. Because defects in these genes also cause other birth defects, our findings could lead to preventive strategies to lower the incidence of biliary atresia and potentially other birth defects., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To describe the worldwide experience with living donation (LD) in intestinal transplantation (ITx) and compare short-term and long-term outcomes to a propensity-matched cohort of deceased donors., Background: ITx is a rare life-saving procedure for patients with complicated intestinal failure (IF). Living donation (LD)-ITx has been performed with success, but no direct comparison with deceased donation (DD) has been performed. The Intestinal Transplant Registry (ITR) was created in 1985 by the Intestinal Transplant Association to capture the worldwide activity and promote center's collaborations., Methods: Based on the ITR, 4156 ITx were performed between January 1987 and April 2019, of which 76 (1.8%) were LD, including 5 combined liver-ITx, 7 ITx-colon, and 64 isolated ITx. They were matched with 186 DD-ITx for recipient age/sex, weight, region, IF-cause, retransplant, pretransplant status, ABO compatibility, immunosuppression, and transplant date. Primary endpoints were acute rejection and 1-/5-year patient/graft survival., Results: Most LDs were performed in North America (61%), followed by Asia (29%). The mean recipient age was: 22 years; body mass index: 19kg/m²; and female/male ratio: 1/1.4. Volvulus (N=17) and ischemia (N=17) were the most frequent IF-causes. Fifty-two percent of patients were at home at the time of transplant. One-/5-year patient survival for LD and DD was 74.2/49.8% versus 80.3/48.1%, respectively ( P =0.826). One-/5-year graft survival was 60.3/40.6% versus 69.2/36.1%, respectively ( P =0.956). Acute rejection was diagnosed in 47% of LD versus 51% of DD ( P =0.723)., Conclusion: Worldwide, LD-ITx has been rarely performed. This retrospective matched ITR analysis revealed no difference in rejection and in patient/graft survival between LD and DD-ITx., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The purpose of the study was to investigate outcome after pediatric transjugular intrahepatic portosystemic shunt (TIPS) with respect to survival MATERIAL AND METHODS: After searching for studies on TIPS in children in Ovid, Medline, Embase, Scopus and Cochrane published between 2000 and 2022, individual patient data were retrieved from five retrospective cohorts. Overall survival (OS) and transplant-free survival (TFS) were calculated using Kaplan-Meier analysis and log-rank test and compared to the indication (ascites vs. variceal bleeding) as well as to the level of obstruction (pre-hepatic vs. hepatic vs. post-hepatic). Additionally, TIPS patency was analyzed., Results: n = 135 pediatric patients were included in the final analysis. Indication for pediatric TIPS creation was heterogeneous among the included studies. TIPS patency decreased from 6 to 24 months, subsequent pediatric liver transplantation was performed in 22/135 (16.3%) of cases. The presence of ascites was related with poorer TFS (HR 2.3, p = 0.023), while variceal bleeding was not associated with impaired survival. Analysis of the level of obstruction (pre-hepatic, hepatic and post-hepatic) failed to prove significantly reduced OS for post-hepatic obstruction (HR 3.2, p = 0.092) and TFS (HR 1.3, p = 0.057). There was no difference in OS and TFS according to age at time of TIPS placement., Conclusions: The presence of ascites associates with impaired survival after TIPS in children, with no differences in survival according to the age of the child. Interventional shunt procedures can be considered feasible for all ages., Level of Evidence: Level 2a., (© 2023. The Author(s).)

Competing Interests: The authors declare no conflicts of interest.

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 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: Organ transplantation is a known risk factor for Clostridioides difficile infection (CDI). There is limited published data on the impact of CDI in the intestinal transplant population., Methods: We utilized the National Readmission Database (2010-2017) to study the outcomes of CDI in patients having a history of intestinal transplantation. Association of CDI with readmission and hospital resource utilization was computed in multivariable models adjusted for demographics and comorbidities., Results: During 2010-2017, 8442 hospitalizations with the history of intestinal transplantation had indexed hospital admissions. Of these, 320 (3.8%) had CDI. CDI hospitalization in intestine transplant patients was associated with higher median cost $54 430 (IQR: 27 231, 109 980) as compared to patients who did not have CDI $48 888 (IQR: 22 578, 112 777), (β: 71 814 95% confidence intervals [CI]: 676-142 953, p = .048). The median length of stay was also longer for patients with CDI 7 (IQR: 4, 13) days as compared to 5 (IQR: 3, 11) days in non-CDI (β: 5.51 95% CI: 0.73-10.29, p = .02). The mortality rate, intestinal transplant complications, presence of malnutrition, acute kidney injury, ICU admissions, and sepsis were similar in both groups. CDI was the top cause of 30-day readmission in the intestinal transplant recipients with CDI during the index admission; the number of 30-day readmissions also increased from 2010 to 2017., Conclusion: CDI hospitalization in post-intestine transplant patients occurs commonly and is associated with a longer length of stay and higher costs during hospitalization. The CDI was the most common cause of readmission after the index admission of CDI in these patients., (© 2023 Wiley Periodicals LLC.)

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: 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.)

Competing Interests: The authors declare no funding or conflicts of interest.

Congenital cytomegalovirus infection is the most common congenital infection. Although most infants with congenital cytomegalovirus infection are asymptomatic at birth, a subset will have readily apparent clinical and/or laboratory manifestations including hepatitis; progression to hepatic failure has not previously been described in term infants who initiated antiviral treatment shortly after birth. We present 2 term infants with congenital cytomegalovirus infection and hepatitis who progressed to hepatic failure despite initial laboratory improvement on therapy., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Recurrent primary sclerosing cholangitis (rPSC) following liver transplant (LT) has a negative impact on graft and patient survival; little is known about risk factors for rPSC or disease course in children., Approach and Results: We retrospectively evaluated risk factors for rPSC in 140 children from the Pediatric PSC Consortium, a multicenter international registry. Recipients underwent LT for PSC and had >90 days of follow-up. The primary outcome, rPSC, was defined using Graziadei criteria. Median follow-up after LT was 3 years (interquartile range 1.1-6.1). rPSC occurred in 36 children, representing 10% and 27% of the subjects at 2 years and 5 years following LT, respectively. Subjects with rPSC were younger at LT (12.9 vs. 16.2 years), had faster progression from PSC diagnosis to LT (2.5 vs. 4.1 years), and had higher alanine aminotransferase (112 vs. 66 IU/L) at LT (all P < 0.01). Inflammatory bowel disease was more prevalent in the rPSC group (86% vs. 66%; P = 0.025). After LT, rPSC subjects had more episodes of biopsy-proved acute rejection (mean 3 vs. 1; P < 0.001), and higher prevalence of steroid-refractory rejection (41% vs. 20%; P = 0.04). In those with rPSC, 43% developed complications of portal hypertension, were relisted for LT, or died within 2 years of the diagnosis. Mortality was higher in the rPSC group (11.1% vs. 2.9%; P = 0.05)., Conclusions: The incidence of rPSC in this cohort was higher than previously reported, and was associated with increased morbidity and mortality. Patients with rPSC appeared to have a more aggressive, immune-reactive phenotype. These findings underscore the need to understand the immune mechanisms of rPSC, to lay the foundation for developing new therapies and improve outcomes in this challenging population., (© 2021 by the American Association for the Study of Liver Diseases.)

Background: This analysis assessed combined safety data from 4 clinical studies of teduglutide in pediatric patients with short-bowel syndrome-associated intestinal failure (SBS-IF)., Methods: Safety data from teduglutide-treated patients in 4 clinical trials were pooled. The completed 12-week and 24-week phase 3 core studies (NCT01952080/EudraCT 2013-004588-30 and NCT02682381/EudraCT 2015-002252-27) enrolled children aged 1-17 years with SBS-IF. Patients could elect to enroll in ongoing open-label extensions (NCT02949362/EudraCT 2016-000863-17 and NCT02954458/EudraCT 2016-000849-30). Interim data from ongoing studies were included., Results: Safety data are reported for 89 pediatric patients treated with teduglutide for a median (range) of 51.7 (5.0-94.7) weeks. Adverse events (AEs) were reported in all patients; the most common were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), and cough (33.7%). Thirty-five patients (39.3%) had AEs considered related to teduglutide treatment; abdominal pain and vomiting were most frequent (5.6% each). Three serious AEs in 3 patients (3.4%) were considered related to teduglutide treatment: ileus, d-lactic acidosis, and gastrointestinal obstruction due to hard stools. All 3 events resolved. One cecal polyp was detected, which was not biopsied or found on repeat colonoscopy. No cases of neoplasia occurred., Conclusion: Based on integrated data from 4 clinical studies, including long-term follow-up for ≤161 weeks, teduglutide had a safety profile consistent with the individual core pediatric studies and as expected for pediatric patients with SBS-IF who never received teduglutide. The most frequent AEs reflected treatment with teduglutide, complications of the underlying disease, and typical childhood illnesses., (© 2020 American Society for Parenteral and Enteral Nutrition.)

Objective: We sought to (1) determine the prevalence of cardiac changes in patients with ESLD awaiting OLT (2) determine relationship between nutritional indices and cardiac changes., Methods: Retrospective review of transthoracic ECHO, clinical and nutritional information of pediatric patients evaluated for OLT. ECHO was analyzed for LVH, defined as LVMI > 95 g/m 2.7 and/or RWT > 0.42. These findings were correlated with age, ESLD etiology, growth and nutritional parameters as well as pre- and post-OLT., Results: Sixty-five patients were included, all had normal left ventricular systolic function. Nine patients (14%) had LVMI > 95 g/m 2.7 , five patients (8%) had RWT > 0.42, none met both criteria. None had thickened interventricular septal wall. Fourteen patients (20%) had significant left ventricular dilation. Nutritional deprivation was modestly present-weight under third percentile in 22%, length under third percentile in 24%, and both weight and length under third percentile in 17%. There were 12 patients (17%) with MUAC below two standard deviations for age; of these one had an elevated LVMI and another had an RWT > 0.42., Conclusions: In this contemporary cross-sectional evaluation, a smaller proportion of patients with ESLD had LVH in contrast to prior studies. Despite a comparable disease burden, our cohort had better nutritional status. Though there was a trend between nutritional and LVH indices, this correlation may be better assessed prospectively in a larger cohort., (© 2021 Wiley Periodicals LLC.)

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.)

Mesenteric plexiform neurofibroma is a subtype of plexiform neurofibroma that involves the mesentery and causes a variety of gastrointestinal complaints. Plexiform neurofibroma is classically found in patients with neurofibromatosis type 1, although genetic contributions to plexiform neurofibroma pathogenesis are heterogeneous. We report the first case of mesenteric plexiform neurofibroma in a patient with a YPEL3 pathogenic variant. This patient presented with growth failure, generalized abdominal pain and chronic diarrhea. She was confirmed to have mesenteric plexiform neurofibroma on histopathology and targeted sequencing on affected tissue confirmed that there were no neurofibromatosis type 1 variants present. Given that this patient's mesenteric plexiform neurofibroma is associated with YPEL3 dysfunction, she is unlikely to benefit from MEK inhibitors, which are the newly approved treatment for inoperable plexiform neurofibroma in patients with neurofibromatosis type 1., Competing Interests: The authors report no funding and conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)