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BACKGROUND Outcomes of left lateral segment (LLS) grafts in pediatric recipients were compared between living (LD-LLS) and deceased donor (DD-LLS) grafts. METHODS 195 LLS grafts (99DD-LLS-96LD-LLS) were analyzed with a median follow-up of 9.1years. The primary endpoints were overall patient/graft survival. RESULTS LD-LLS grafts were younger (0.9vs.1.4years, p = 0.039), more likely to have a fulminant liver failure (17.9%vs.5.3%,p = 0.002), less likely to have a metabolic disorder (6.3%vs.25.5%,p = 0.002), and less likely to be undergoing retransplantation (5.3% vs.16.2%,p = 0.015). There was a trend toward decreased hepatic artery thrombosis in LD-LLS grafts (6.6% vs. 15.5%,p = 0.054). No differences in the overall biliary complications occurred. The LD-LLS group had prolonged survival compared to the DD-LLS group with 10-year survival rates of 81%, and 74% (p = 0.005), respectively. LD-LLS grafts had longer graft survival compared to DD-LLS grafts (10-year graft survival 85%vs.67%,p = 0.005). Recipient age >1year (HR 2.39,p = 0.026), aortic reconstruction (HR 2.12,p = 0.046) and vascular complication (HR 3.12,p

The growing burden of liver fibrosis and lack of effective antifibrotic therapies highlight the need for identification of pathways and complementary model systems of hepatic fibrosis. A rare, monogenic disorder in which children with mutations in mannose phosphate isomerase (MPI) develop liver fibrosis led us to explore the function of MPI and mannose metabolism in liver development and adult liver diseases. Herein, analyses of transcriptomic data from three human liver cohorts demonstrate that MPI gene expression is down-regulated proportionate to fibrosis in chronic liver diseases, including nonalcoholic fatty liver disease and hepatitis B virus. Depletion of MPI in zebrafish liver in vivo and in human hepatic stellate cell (HSC) lines in culture activates fibrotic responses, indicating that loss of MPI promotes HSC activation. We further demonstrate that mannose supplementation can attenuate HSC activation, leading to reduced fibrogenic activation in zebrafish, culture-activated HSCs, and in ethanol-activated HSCs. Conclusion: These data indicate the prospect that modulation of mannose metabolism pathways could reduce HSC activation and improve hepatic fibrosis.

The aim of this document is to provide a concise scientific review of the currently available COVID-19 vaccines and those in development, including mRNA, adenoviral vectors, and recombinant protein approaches. The anticipated use of COVID-19 vaccines in patients with chronic liver disease (CLD) and liver transplant (LT) recipients is reviewed and practical guidance is provided for health care providers involved in the care of patients with liver disease and LT about vaccine prioritization and administration. The Pfizer and Moderna mRNA COVID-19 vaccines are associated with a 94%-95% vaccine efficacy compared to placebo against COVID-19. Local site reactions of pain and tenderness were reported in 70%-90% of clinical trial participants, and systemic reactions of fever and fatigue were reported in 40%-70% of participants, but these reactions were generally mild and self-limited and occurred more frequently in younger persons. Severe hypersensitivity reactions related to the mRNA COVID-19 vaccines are rare and more commonly observed in women and persons with a history of previous drug reactions for unclear reasons. Because patients with advanced liver disease and immunosuppressed patients were excluded from the vaccine licensing trials, additional data regarding the safety and efficacy of COVID-19 vaccines are eagerly awaited in these and other subgroups. Remarkably safe and highly effective mRNA COVID-19 vaccines are now available for widespread use and should be given to all adult patients with CLD and LT recipients. The online companion document located at https://www.aasld.org/about-aasld/covid-19-resources will be updated as additional data become available regarding the safety and efficacy of other COVID-19 vaccines in development.

Liver fibrosis is the excessive accumulation of extracellular matrix that can progress to cirrhosis and failure if untreated (1). The mechanisms of fibrogenesis are multi-faceted and remain elusive with no approved antifibrotic treatments available (2). Here we use single-cell RNA sequencing (scRNA-seq) of the adult zebrafish liver to study the molecular and cellular dynamics of the liver at a single-cell level and demonstrate the value of the adult zebrafish as a model for studying liver fibrosis. scRNA-seq reveals transcriptionally unique populations of hepatic cell types that comprise the zebrafish liver. Joint clustering with human liver scRNA-seq data demonstrates high conservation of transcriptional profiles and human marker genes in zebrafish cell types. Human and zebrafish hepatic stellate cells (HSCs), the driver cell in liver fibrosis (3), specifically show conservation of transcriptional profiles and we uncover Colec11 as a novel, conserved marker for zebrafish HSCs. To demonstrate the power of scRNA-seq to study liver fibrosis, we performed scRNA-seq on our zebrafish model of a pediatric liver disease with characteristic early, progressive liver fibrosis caused by mutation in mannose phosphate isomerase (MPI) (4–6). Comparison of differentially expressed genes from human and zebrafish MPI mutant HSC datasets demonstrated similar activation of fibrosis signaling pathways and upstream regulators. CellPhoneDB analysis revealed important receptor-ligand interactions within normal and fibrotic states. This study establishes the first scRNA-seq atlas of the adult zebrafish liver, highlights the high degree of similarity to the human liver, and strengthens its value as a model to study liver fibrosis.Significance StatementTo our knowledge, this is the first single-cell characterization of the adult zebrafish liver, both in a normal physiologic state and in the setting of liver fibrosis. We identify transcriptionally distinct zebrafish liver cell populations and a high degree of transcriptional conservation between human and zebrafish cells across the majority of hepatic cell types. Furthermore, using this scRNA transcriptome, we identify key signaling pathways in zebrafish HSCs that are replicated in human HSCs and implicated in the regulation of liver fibrosis. Our work provides a useful resource that can be used to aid research using the zebrafish liver and asserts the usefulness of the adult zebrafish to study liver fibrosis.

Crohn's disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn's disease1,2, and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment3. The risk alleles with the highest effect on Crohn's disease are loss-of-function mutations in NOD24,5, which increase the risk of stricturing6. However, the mechanisms that underlie pathogenicity driven by NOD2 mutations and the pathways that might rescue a lack of response to anti-TNF treatment remain largely uncharacterized. Here we use direct ex vivo analyses of patients who carry risk alleles of NOD2 to show that loss of NOD2 leads to dysregulated homeostasis of activated fibroblasts and macrophages. CD14+ peripheral blood mononuclear cells from carriers of NOD2 risk alleles produce cells that express high levels of collagen, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. The enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages suggested that gp130 blockade might rescue the activated program in NOD2-deficient cells. We show that post-treatment induction of the STAT3 pathway is correlated with a lack of response to anti-TNF treatment in patients, and demonstrate in vivo in zebrafish the amelioration of the activated myeloid-stromal niche using the specific gp130 inhibitor bazedoxifene. Our results provide insights into NOD2-driven fibrosis in Crohn's disease, and suggest that gp130 blockade may benefit some patients with Crohn's disease-potentially as a complement to anti-TNF therapy.

The severe acute respiratory syndrome coronavirus 2 pandemic has drastically altered all facets of clinical care and research. Clinical research in hepatology has had a rich tradition in several domains, including the discovery and therapeutic development for diseases such as hepatitis B and C and studying the natural history of many forms of chronic liver disease. National Institutes of Health, foundation, and industry funding have provided important opportunities to advance the academic careers of young investigators while they strived to make contributions to the field. Instantaneously, however, all nonessential research activities were halted when the pandemic started, forcing those involved in clinical research to rethink their research strategy, including a shift to coronavirus disease 2019 research while endeavoring to maintain their preexisting agenda. Strategies to maintain the integrity of ongoing studies, including patient follow-up, safety assessments, and continuation of investigational products, have included a shift to telemedicine, remote safety laboratory monitoring, and shipping of investigational products to study subjects. As a revamp of research is being planned, unique issues that face the research community include maintenance of infrastructure, funding, completion of studies in the predetermined time frame, and the need to reprogram career path timelines. Real-world databases, biomarker and long-term follow up studies, and research involving special groups (children, the homeless, and other marginalized populations) are likely to face unique challenges. The implementation of telemedicine has been dramatically accelerated and will serve as a backbone for the future of clinical research. As we move forward, innovation in clinical trial design will be essential for conducting optimized clinical research.

Objectives Coping with patient death among pediatric liver transplant teams has received little attention despite general recognition of the potentially negative emotional consequences associated with such loss. The purpose of this study was to investigate the ways in which members of pediatric liver transplant teams cope with the death of patients on the waitlist and post-transplant and the institutional resources available to facilitate this coping. Methods Participants included 120 physicians, nurses, and mental health professionals from multiple transplant centers across the United States. Participants completed an online questionnaire that assessed the availability of formal coping resources at their institutions, informal sources of support used to cope with patient death, and as indices of coping, bereavement, and emotional exhaustion symptoms experienced. Results Debriefing, the most commonly offered support, was available to about half (55.8%) of the sample; yet, nearly all respondents (98.3%) indicated that debriefing would be useful. On average, bereavement and emotional exhaustion levels were comparable to normative data, but patterns of coping varied based on participants' position within the transplant team. For participants who reported that debriefing was available at their institutions, emotional exhaustion was lower. Conclusions Overall, formal supports were inconsistently offered to pediatric transplant team members. Team members expressed high acceptability for debriefing, which has been associated with benefits in other populations, and findings indicated better coping in the transplant setting when it was offered.

Zebrafish (Danio rerio) larvae are a uniquely powerful model system which investigate the effects of toxicant exposure on liver development and function. Manufacturing processes and development of new synthetic compounds increased rapidly since the middle of the twentieth century, resulting in widespread exposure to environmental toxicants. This is compounded by the shift in the global burden of disease from infectious agents to chronic disease, particularly in industrialized nations, which increases the need to investigate the long-term and transgenerational effects of environmental exposures on human health. Zebrafish provide an excellent model to investigate the mechanisms of action of environmental pollutants given their large-scale embryo production and rapid development, which allow for short-term assessment of toxicity in a whole animal system. Here we describe methods for the use of zebrafish to study hepatotoxicity and liver disease induced by chemical toxicants. Many of the genetic, molecular, and cellular processes are conserved between zebrafish and mammals, enabling translation to human populations and diseases.

Small bowel obstruction in a pediatric patient following liver transplant often results from adhesions, hernias, or post-transplant lymphoproliferative disease. Here, we present an unusual and previously unreported entity - Roux-en-Y intussusception in an eight-yr-old female several years after liver transplantation. Although a rare complication, Roux-en-Y intussusception should be considered as a potential etiology in the patient presenting with bowel obstruction, with specific attention to acute presentation accompanying jaundice.

The trappc11 mutation in zebrafish causes a stressed UPR, leading to fatty liver disease. This phenotype is not due to a trafficking defect but instead results from N-glycosylation defects. Hypoglycosylation and lipid accumulation are also found in patient cells with knockdown or mutated TRAPPC11 genes, suggesting a common etiology with zebrafish., Activation of the unfolded protein response (UPR) can be either adaptive or pathological. We term the pathological UPR that causes fatty liver disease a “stressed UPR.” Here we investigate the mechanism of stressed UPR activation in zebrafish bearing a mutation in the trappc11 gene, which encodes a component of the transport protein particle (TRAPP) complex. trappc11 mutants are characterized by secretory pathway defects, reflecting disruption of the TRAPP complex. In addition, we uncover a defect in protein glycosylation in trappc11 mutants that is associated with reduced levels of lipid-linked oligosaccharides (LLOs) and compensatory up-regulation of genes in the terpenoid biosynthetic pathway that produces the LLO anchor dolichol. Treating wild-type larvae with terpenoid or LLO synthesis inhibitors phenocopies the stressed UPR seen in trappc11 mutants and is synthetically lethal with trappc11 mutation. We propose that reduced LLO level causing hypoglycosylation is a mechanism of stressed UPR induction in trappc11 mutants. Of importance, in human cells, depletion of TRAPPC11, but not other TRAPP components, causes protein hypoglycosylation, and lipid droplets accumulate in fibroblasts from patients with the TRAPPC11 mutation. These data point to a previously unanticipated and conserved role for TRAPPC11 in LLO biosynthesis and protein glycosylation in addition to its established function in vesicle trafficking.

Deferesirox (DFX), an oral chelating agent, is used to treat chronic iron overload in several hematological diseases such as β-thalassemia, sickle cell disease, and myelodysplastic anemia. DFX is generally well tolerated with the exception of gastrointestinal disturbances and rash, although cases of renal toxicity, as well as acute and chronic liver failure, have been reported in adults and children. Here we describe a 3-year-old girl with β-thalassemia undergoing treatment with DFX who presented with acute liver failure and Fanconi's syndrome. It is important for pediatric gastroenterologists, hepatologists, and hematologists to be aware that the commonly used drug DFX can lead to acute liver failure in children, and liver function should be monitored closely in all patients taking DFX.

Zebrafish (Danio rerio) larvae are a uniquely powerful model system which investigate the effects of toxicant exposure on liver development and function. Manufacturing processes and development of new synthetic compounds increased rapidly since the middle of the twentieth century, resulting in widespread exposure to environmental toxicants. This is compounded by the shift in the global burden of disease from infectious agents to chronic disease, particularly in industrialized nations, which increases the need to investigate the long-term and transgenerational effects of environmental exposures on human health. Zebrafish provide an excellent model to investigate the mechanisms of action of environmental pollutants given their large-scale embryo production and rapid development, which allow for short-term assessment of toxicity in a whole animal system. Here we describe methods for the use of zebrafish to study hepatotoxicity and liver disease induced by chemical toxicants. Many of the genetic, molecular, and cellular processes are conserved between zebrafish and mammals, enabling translation to human populations and diseases.

Genome-wide association studies have identified over 200 genomic loci associated with inflammatory bowel disease (IBD). High-effect risk alleles define key roles for genes involved in bacterial response and innate defense. More high-throughput in vivo systems are required to rapidly evaluate therapeutic agents. We visualize, in zebrafish, the effects on epithelial barrier function and intestinal autophagy of one-course and repetitive injury. Repetitive injury induces increased mortality, impaired recovery of intestinal barrier function, failure to contain bacteria within the intestine and impaired autophagy. Prostaglandin E2 (PGE2) administration protected against injury by enhancing epithelial barrier function and limiting systemic infection. Effects of IBD therapeutic agents were defined: mesalamine showed protective features during injury, whereas 6-mercaptopurine displayed marked induction of autophagy during recovery. Given the highly conserved nature of innate defense in zebrafish, it represents an ideal model system with which to test established and new IBD therapies targeted to the epithelial barrier. This article has an associated First Person interview with the first author of the paper., Summary: As IBD attempts to enter the era of precision medicine, our models provide an opportunity for the rapid and sophisticated determination of time course, cellular contributions and mechanisms of new drugs.

Hemophagocytic lymphohistiocytosis (HLH), a rare condition characterized by immune dysfunction with uncontrolled activation of macrophages and hypersecretion of cytokines, has only been reported in a small number of pediatric patients following solid organ transplant (SOT). The diagnosis of HLH after SOT is especially difficult, as several of the diagnostic criteria, including fever, splenomegaly, and cytopenias, are nonspecific and can be seen with other post-transplant complications. Autoimmune hemolytic anemia (AIHA) has also been reported after pediatric SOT and is thought to be related to immunosuppression, specifically tacrolimus. Although HLH and AIHA have been separately described following SOT, there have been no reports of them occurring together in post-liver transplant (LT) patients. We report the first case of autoimmune hemolysis as the presenting symptom of HLH in a pediatric post-LT patient.

Liver transplantation (LT) in children with biliary atresia (BA) is often performed because of poor bile drainage, complications of biliary cirrhosis, or recurrent cholangitis. Poor bile drainage after a Kasai hepatoportoenterostomy is the primary driver for LT in infancy. The aim of the present study was to compare the clinical characteristics and outcome of first isolated liver transplantation for infants with BA who underwent transplant before 2 years of age (transplanted at infancy [TAI]) with children transplanted later in life (age 2-18 years = transplanted at childhood [TAC]).Children with BA who underwent LT between 2002 and 2012 were identified from the United Network for Organ Sharing Standard Transplant Analysis and Research data set files.A total of 1818 children underwent first isolated liver transplantation for BA (TAI 1408 [77.4%]; TAC 410 [22.6%]). One and 5-year patient survival of the TAI and TAC patients was 95.2%, 93.8%, and 97.8 %, 97.1%, respectively (P 0.01 for both periods). One and 5-year graft survival of the TAI and TAC patients was 87.6%, 84.6 % and 93.2%, 90.7%, respectively (P 0.01 for both periods). Removal from the waitlist for disease progression or death was significantly higher for TAI compared with TAC (120 patients [6.3%] vs 21 [3.7%], P = 0.02). Cold ischemic time was found to be the prognostic factor for death after LT in TAI, whereas being on life support was a poor prognostic factor in TAC by multivariate risk factor analysis.The vast majority of transplants for BA occur in children2 years of age. Younger patients with BA had significantly higher waitlist and posttransplant mortality. Given the consistently poorer outcomes, there is an urgent need to find methods to improve bile drainage after the Kasai hepatoportoenterostomy.

IgG4 sclerosing cholangitis (IgG4-SC) is an immune-mediated process that results in inflammation and fibrosis of the pancreatobiliary tract. Although IgG4-SC is predominantly associated with autoimmune pancreatitis, IgG4-SC as its own entity can be difficult to diagnose. Patients with IgG4-SC are typically men over the age of 60, and present clinically with obstructive jaundice, abdominal pain, and weight loss. The diagnosis of IgG4-SC may be difficult to differentiate from primary sclerosing cholangitis (PSC) or cholangiocarcinoma. IgG4-SC is morphologically characterized by dense lymphoplasmacellular infiltration, particularly IgG4+ plasma cells and CD4+ T cells, extensive fibrosis in bile duct walls, and obliterative phlebitis. In contrast to PSC, those with IgG4-SC often have elevated serum IgG4 and can be successfully treated with immunosuppression. Here, we present the first reported case of IgG4-SC in a pediatric patient with asymptomatic elevation in liver enzymes, bile duct strictures on imaging, characteristic pathology findings, elevated serum IgG4, and excellent response to corticosteroids. Pediatric gastroenterologists and hepatologists, as well as pediatric hepatopathologists, need to be aware of IgG4-SC as a disease entity. Although certain clinical and imaging findings mimic PSC, diagnosis of IgG4-SC and its appropriate treatment with corticosteroids often lead to remission and reversal of disease.

EBV-SMT are a rare entity following organ transplantation. Given the rarity of the tumor, there is no standard approach to diagnosis and treatment. A literature search identified 28 reported cases of EBV-SMT in addition to our own experience with one case. The aim of this review is to summarize the existing data regarding pathogenesis, diagnosis, and treatment.

Rapid cellular proliferation in early development and cancer depends on glucose metabolism to fuel macromolecule biosynthesis. Metabolic enzymes are presumed regulators of this glycolysis-driven metabolic program, known as the Warburg effect; however, few have been identified. We uncover a previously unappreciated role for Mannose phosphate isomerase (MPI) as a metabolic enzyme required to maintain Warburg metabolism in zebrafish embryos and in both primary and malignant mammalian cells. The functional consequences of MPI loss are striking: glycolysis is blocked and cells die. These phenotypes are caused by induction of p53 and accumulation of the glycolytic intermediate fructose 6-phosphate, leading to engagement of the hexosamine biosynthetic pathway (HBP), increased O-GlcNAcylation, and p53 stabilization. Inhibiting the HBP through genetic and chemical methods reverses p53 stabilization and rescues the Mpi-deficient phenotype. This work provides mechanistic evidence by which MPI loss induces p53, and identifies MPI as a novel regulator of p53 and Warburg metabolism. DOI: http://dx.doi.org/10.7554/eLife.22477.001

As manufacturing processes and development of new synthetic compounds increase to keep pace with the expanding global demand, environmental health, and the effects of toxicant exposure are emerging as critical public health concerns. Additionally, chemicals that naturally occur in the environment, such as metals, have profound effects on human and animal health. Many of these compounds are in the news: lead, arsenic, and endocrine disruptors such as bisphenol A have all been widely publicized as causing disease or damage to humans and wildlife in recent years. Despite the widespread appreciation that environmental toxins can be harmful, there is limited understanding of how many toxins cause disease. Zebrafish are at the forefront of toxicology research; this system has been widely used as a tool to detect toxins in water samples and to investigate the mechanisms of action of environmental toxins and their related diseases. The benefits of zebrafish for studying vertebrate development are equally useful for studying teratogens. Here, we review how zebrafish are being used both to detect the presence of some toxins as well as to identify how environmental exposures affect human health and disease. We focus on areas where zebrafish have been most effectively used in ecotoxicology and in environmental health, including investigation of exposures to endocrine disruptors, industrial waste byproducts, and arsenic.

Gastric variceal bleeding is associated with high morbidity and mortality. Balloon-occluded retrograde transvenous obliteration is a relatively new treatment used to control bleeding gastric varices that involves transvenous sclerosis of gastric varices through a spontaneous gastrorenal shunt. Here, we report on a 14-yr-old patient that underwent balloon-occluded retrograde transvenous obliteration for refractory bleeding fundal varices in the setting of esophageal varices and cirrhosis, which did not respond to medical management or endoscopic injection. This case report serves as a reminder that balloon-occluded retrograde transvenous obliteration can successfully control fundal variceal bleeding in pediatric patients and may serve as a bridge to liver transplantation.

Summary Individuals with congenital disorders of glycosylation (CDG) have recessive mutations in genes required for protein N-glycosylation, resulting in multi-systemic disease. Despite the well-characterized biochemical consequences in these individuals, the underlying cellular defects that contribute to CDG are not well understood. Synthesis of the lipid-linked oligosaccharide (LLO), which serves as the sugar donor for the N-glycosylation of secretory proteins, requires conversion of fructose-6-phosphate to mannose-6-phosphate via the phosphomannose isomerase (MPI) enzyme. Individuals who are deficient in MPI present with bleeding, diarrhea, edema, gastrointestinal bleeding and liver fibrosis. MPI-CDG patients can be treated with oral mannose supplements, which is converted to mannose-6-phosphate through a minor complementary metabolic pathway, restoring protein glycosylation and ameliorating most symptoms, although liver disease continues to progress. Because Mpi deletion in mice causes early embryonic lethality and thus is difficult to study, we used zebrafish to establish a model of MPI-CDG. We used a morpholino to block mpi mRNA translation and established a concentration that consistently yielded 13% residual Mpi enzyme activity at 4 days post-fertilization (dpf), which is within the range of MPI activity detected in fibroblasts from MPI-CDG patients. Fluorophore-assisted carbohydrate electrophoresis detected decreased LLO and N-glycans in mpi morphants. These deficiencies resulted in 50% embryonic lethality by 4 dpf. Multi-systemic abnormalities, including small eyes, dysmorphic jaws, pericardial edema, a small liver and curled tails, occurred in 82% of the surviving larvae. Importantly, these phenotypes could be rescued with mannose supplementation. Thus, parallel processes in fish and humans contribute to the phenotypes caused by Mpi depletion. Interestingly, mannose was only effective if provided prior to 24 hpf. These data provide insight into treatment efficacy and the broader molecular and developmental abnormalities that contribute to disorders associated with defective protein glycosylation.

Autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are progressive immune-mediated inflammatory diseases that may require liver transplant (LT). Outcomes in children undergoing LT for these diseases are poorly studied in the pediatric end-stage liver disease era. We aimed to characterize the outcome of LT in children with AIH and PSC. Children 18 years or younger with PSC or AIH who had a first, isolated LT from 2002 to 2012 were identified from the United Network for Organ Sharing database. Graft and patient outcomes were studied. A total of 174 children with AIH and 113 with PSC were transplanted in the study period. One-year patient survival was 95.4% for AIH and 97.3% for PSC. Five-year patient survival was 91.4% for AIH and 92.9% for PSC. Patient survival was not significantly different between the 2 groups. Forty-four (25.2%) children with AIH were listed as status 1 for transplant (fulminant hepatic failure at presentation or acute-on-chronic disease). Patients transplanted as status 1 had significantly lower patient survival compared with patients transplanted with AIH and end-stage liver disease. The one- and five-year graft survival rates were not significantly different between patients with AIH and PSC. Children with AIH transplanted as status 1 had significantly lower patient survival rates but similar graft survival rates to children with chronic AIH. Children transplanted for AIH versus PSC showed no significant differences in patient or graft survival at both 1 and 5 years.

Chu J, Kerkar N, Miloh TA, Rodriguez-Laiz G, Lewis B, Stangl A, Newton KP, Iyer K, Arnon R. Roux-en-Y loop varices in children with portal hypertension after liver transplantation: An unusual cause of “obscure” gastro intestinal bleeding. Pediatr Transplantation 2011: 15: E156–E161. © 2010 John Wiley & Sons A/S. Abstract: PHALT may result from graft dysfunction, portal vein thrombosis, arterio-venous fistulas and can lead to GIB, commonly from bleeding esophageal varices. We present three children with GIB requiring multiple blood transfusions that were diagnosed with RY Loop bleeding. Routine EGD, colonoscopy, and CE failed to reveal the bleeding source. However, enteroscopy revealed large varices at the site of hepaticojejunostomy anastomosis in all. Our experience demonstrates that RY loop varices in children with PHALT are a rare and treatable cause of obscure GI bleeding.

Acute iron poisoning may lead to life-threatening hepatotoxicity. We present the cases of two pediatric patients with hepatotoxicity following intentional iron ingestion that progressed rapidly to fulminant hepatic failure despite treatment with deferoxamine. Liver transplantation was lifesaving in both patients. These cases emphasize the need for a high index of suspicion for iron ingestion, close monitoring for liver toxicity, and timely consideration for liver transplantation.

NH is the most common identifiable cause of ALF in the neonate. LT is the definitive treatment for neonates with NH who have failed medical therapy. Our aim was to determine the outcomes of LT in infants with NH. Patients (less than one yr of age) with NH who were listed for LT and patients who underwent LT between 1994 and 2013 were identified from the UNOS database for analysis. Risk factors for death and graft loss were analyzed by multivariate logistic regression. Thirty-eight infants with NH with a total of 43 transplants were identified. One- and five-yr patient and graft survival were 84.2%, 81.6%, 71.1%, and 68.4%, respectively. The outcomes for NH were not significantly different when compared to the same age-matched recipients with other causes of ALF. There were no statistically significant risk factors identified for graft loss or death. Ninety infants with NH were listed for LT. Reasons for removal included transplanted (49%), death (27%), too sick to transplant (7%), and improved status (13%). LT for infants with NH has a high rate of graft loss and death; however, outcomes are comparable to the same age-matched recipients with other causes of ALF.

Objective The study tested the hypothesis that females who sustain stress fractures of cancellous bone have decreased bone density. Design A retrospective, controlled, cross-sectional study. Setting The setting of the study was a tertiary care center for Women's Sports Medicine. Patients 20 female patients under the age of 40 who had suffered a stress fracture and who had a positive diagnostic study (radiograph, bone scan, or magnetic resonance imaging) were included in the study. Interventions Patients who had a positive diagnostic study (radiograph, bone scan, or magnetic resonance imaging) for the diagnosis of stress fracture also underwent dual energy X-ray absorptiometry (DEXA) scans. Main outcome measure Bone density measured by the DEXA scan, as defined by the World Health Organization criteria for osteopenia (greater than one standard deviation from the standard age-matched control). Results 8 of 9 patients with cancellous stress fractures had DEXA scans indicating osteopenia while only 3 of 11 patients with stress fractures of cortical bone had a scan indicating osteopenia (p = 0.01). Conclusions A cancellous stress fracture in a female may be a warning sign of early onset osteopenia. We recommend that young females who have documented stress fractures of cancellous bone or cortical bone (with risk factors for osteopenia) undergo bone density evaluation.

Objectives Children with nonalcoholic fatty liver disease (NAFLD) experience compromised quality of life (QOL) akin to those with other chronic disease. Our objectives were to examine the association between NAFLD and QOL as well as other psychosocial outcomes, to compare psychosocial outcomes to obese children without known NAFLD, and to determine whether present standard care for NAFLD results in weight loss and improvement in psychosocial outcomes longitudinally. Methods Children with NAFLD between 8 and 18 years and obese control children without known NAFLD were consented to complete a brief psychosocial battery examining depression (Children's Depression Inventory), QOL (Pediatric Quality of Life Inventory; PedsQL), and effect of weight on self-esteem (Body-Esteem Scale for Adolescents and Adults) at baseline; and additionally for the NAFLD group after at least 6 months. Results A total of 48 children with NAFLD and 40 obese control children were enrolled. The PedsQL scores were not significantly different but the CDI total score and subscales of negative mood, ineffectiveness, and negative self-esteem as well as all of the 3 subscales of BESAA, appearance, attribution, and weight were worse in the NAFLD group compared with obese controls. The PedsQL scores also did not change after standard care in the 33 patients with NAFLD who completed the follow-up evaluations, but the CDI score differed between those whose body mass index improved or not. Conclusions Children with NAFLD have higher levels of depression than obese controls. Outcomes did not improve with standard care. Larger longitudinal studies and appropriate interventions are required in this area.

Socioeconomic status influences health outcomes, although its impact on liver transplantation (LT) in children with biliary atresia (BA) is unknown. We hypothesized that governmental insurance [public insurance (PU)], rather than private insurance (PR), would be associated with poorer outcomes for children with BA. Children with BA who underwent first isolated LT between January 2003 and June 2011 were identified from United Network for Organ Sharing Standard Transplant Analysis and Research files. We identified 757 patients with PR and 761 patients with PU. The race/ethnicity distribution was significantly different between the groups (65% white, 12% black, and 10% Hispanic in the PR group and 33% white, 26% black, and 29% Hispanic in the PU group, P 0.01). Wait-list mortality was higher for the PU group versus the PR group [46/1654 (2.7%) versus 29/1895 (1.5%), P 0.01]. PR patients were older than PU patients at transplant (2.4 ± 4.5 versus 1.5 ± 3.0 years, P 0.01). The donor types differed between the groups: 165 children (21.8%) in the PR group received living donor grafts, whereas 79 children (10.4%) in the PU group did (P 0.01). The 1- and 5-year posttransplant patient survival rates were greater for the PR group versus the PU group (98.0% versus 94.1% at 1 year, P 0.01; 97.8% versus 92.2% at 5 years, P 0.01). Cox proportional hazards models revealed that the insurance type (PU), the donor type (deceased), and life support were significant risk factors for death. A separate analysis of deceased donor LT revealed that the PU group still had significantly worse patient and graft survival. In conclusion, PU coverage is an independent risk factor for significantly increased wait-list and posttransplant mortality in children with BA. Further studies are needed to unearth the reasons for these important differences in outcomes.

This is a case report of the first patient with Alagille syndrome (AGS) to undergo a partial internal biliary diversion (PIBD) for the treatment of symptoms refractory to medical therapy. Alagille syndrome is a hereditary disease resulting in chronic cholestasis and hypercholesterolemia that can lead to severe and intractable pruritus and disfiguring and debilitating xanthomas. PIBD has proven to be an effective treatment option for other causes of cholestatic liver disease. This report reviews the immediate and 2-year follow-up of a patient after this surgical procedure. The results suggest that PIBD has potential to provide relief of intractable symptoms and improve the quality of life in patients with AGS while avoiding an external stoma. It does not, however, appear to prevent the progression of liver disease. Long-term follow-up is still needed.

Although UHRF1 is essential for many epigenetic marks, the mechanism that regulates UHRF1 is not understood. This study shows that a key component of the cell cycle machinery—cyclin-dependent kinase 2/cyclin A2—phosphorylates UHRF1 and that this phosphorylation is essential for early zebrafish development., Ubiquitin-like, containing PHD and RING finger domains 1 (uhrf1) is regulated at the transcriptional level during the cell cycle and in developing zebrafish embryos. We identify phosphorylation as a novel means of regulating UHRF1 and demonstrate that Uhrf1 phosphorylation is required for gastrulation in zebrafish. Human UHRF1 contains a conserved cyclin-dependent kinase 2 (CDK2) phosphorylation site at Ser-661 that is phosphorylated in vitro by CDK2 partnered with cyclin A2 (CCNA2), but not cyclin E. An antibody specific for phospho-Ser-661 recognizes UHRF1 in both mammalian cancer cells and in nontransformed zebrafish cells, but not in zebrafish bearing a mutation in ccna2. Depleting Uhrf1 from zebrafish embryos by morpholino injection causes arrest before gastrulation and early embryonic death. This phenotype is rescued by wild-type UHRF1, but not by UHRF1 in which the phospho-acceptor site is mutated, demonstrating that UHRF1 phosphorylation is essential for embryogenesis. UHRF1 was detected in the nucleus and cytoplasm, whereas nonphosphorylatable UHRF1 is unable to localize to the cytoplasm, suggesting the importance of localization in UHRF1 function. Together, these data point to an essential role for UHRF1 phosphorylation by CDK/CCNA2 during early vertebrate development.

PHALT may result from graft dysfunction, portal vein thrombosis, arterio-venous fistulas and can lead to GIB, commonly from bleeding esophageal varices. We present three children with GIB requiring multiple blood transfusions that were diagnosed with RY Loop bleeding. Routine EGD, colonoscopy, and CE failed to reveal the bleeding source. However, enteroscopy revealed large varices at the site of hepaticojejunostomy anastomosis in all. Our experience demonstrates that RY loop varices in children with PHALT are a rare and treatable cause of obscure GI bleeding.