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To evaluate oral health conditions in pediatric liver transplant recipients, with special focus on caries, green staining of the teeth, gingival bleeding, and gingival overgrowth. 40 patients (mean age 11.6 years) were examined at a routine follow-up visit, 6 months to 16 years after liver transplantation at the Swiss Center for Liver Disease in Children. After the medical examination, participants were further examined for the presence of dental caries, periodontal disease, GE, and GTC. The mean decay, missing, and filled teeth (dmft/DMFT) score was 3.8. 45% of the participants presented at least one carious lesion. Two-third of the participants had more than 20% of sites with the presence of plaque and gingival inflammation. Signs of GE were found in 18% and GTC in 30% of the participants. A positive correlation was identified between GTC and peak serum bilirubin (P

Liver biopsy (LB) is still the criterion standard procedure for obtaining liver tissue for histopathological examination and a valuable tool in the diagnosis, prognosis, and management of many parenchymal liver diseases. The aim of this position paper is to summarise the present practice of paediatric LB and make recommendations about its performance. Although histological evaluation of the liver is important in assessing prognosis and exploring treatment, noninvasive techniques (ie, imaging, laboratory markers) may replace use of liver histology. The indications for LB are changing as present knowledge of aetiologies, pathomechanism, and therapeutic options in paediatric liver disease is evolving. Adult and paediatric literature was reviewed to assess the existing clinical practice of LB with focus on the technique, indications, risk of complications, and contraindications in paediatrics. This position paper presents types of LB, indications, complications, contraindications, and an essential checklist for paediatric LB.

Paediatric hepatic neoplasias are rare, accounting for 1-4% of all solid childhood tumors. Liver tumors in children can be classified into benign or malignant; some of the benign lesions can have the potential of malignant transformation. Two-thirds of liver tumors in children are malignant. Hepatoblastoma accounts for two-thirds of malignant liver tumors in children. Other liver malignancies in children include sarcomas, germ cell and rhabdoid tumours, and hepatocellular carcinoma. Benign tumors of the liver in children include vascular tumours, hamartomas, adenomas, and focal nodular hyperplasia. The histology and anatomy of a paediatric liver tumour guides the treatment and prognosis. Although benign and malignant liver masses share some clinical manifestations, treatment and prognosis differ.

Abnormalities in primary cilia lead to diseases called ciliopathies. Multiple organ involvement is the norm since primary cilia are present in most cells. When cholangiocyte cilia are abnormal, ductal plate malformation ensues leading to such conditions as congenital hepatic fibrosis, Caroli disease or syndrome, or other fibrocystic disease.

OBJECTIVES Obesity has been associated with increased bone mass, but the mechanisms involved are still poorly understood. We aimed to explore the relation between bone mineral density and factors known to influence bone formation in obese and lean adolescents. METHODS We recruited 24 obese and 25 lean adolescents in a case-control study. Total body bone mineral density (TB-BMD) z scores and body composition were determined using dual-energy x-ray absorptiometry. We measured 25-hydroxyvitamin D (25-OH-D), glucose, insulin, and leptin concentrations. Physical activity (PA) level was quantified using accelerometer. RESULTS TB-BMD z score was higher, whereas 25-OH-D and PA levels were lower in obese compared with lean subjects (TB-BMD z score 1.06 ± 0.96 vs 0.26 ± 0.91, P = 0.004; 25-OH-D 9.9 ± 6.4 vs 18.5 ± 7.4 ng mL, P

The presence of elevated aminotransferases on routine blood tests can reveal liver diseases of various severities. In children, etiologies are more numerous and complex than those usually considered in adults. Information derived from family and personal history, physical examination and basic laboratory data are necessary to reach a timely and correct diagnosis. A stepwise approach is proposed to guide the timing of more specific investigations that are often required.

Combined liver-kidney transplantation (CLKT) in children is uncommon and outcomes have not been well defined. Using the Scientific Registry of Transplant Recipients, data were analyzed on 152 primary pediatric CLKTs performed from October 1987 to February 2011, to determine their outcome in the largest series reported to date. Patient survival was 86.8%, 82.1% and 78.9% at 1, 5 and 10 years, liver graft survival was 81.9%, 76.5% and 72.6%, and kidney graft survival was 83.4%, 76.5% and 66.8%. By way of comparison, the Registry was queried for pediatric patient survival following isolated liver transplantation (LT) during the same time frame: 86.7%, 81.2% and 77.4% and following isolated kidney transplant (KT): 98.2%, 95.4% and 90% at 1, 5 and 10 years. In patients having undergone CLKT, primary hyperoxaluria was associated with reduced patient (p = 0.01), liver graft (p = 0.01) and kidney graft survival (p = 0.01). Furthermore, graft outcome following CLKT improved over the past decade (p = 0.04 for liver, p = 0.02 for kidney), but this did not translate into improved patient outcome (p = 0.2). All in all, our results confirmed that survival following LT was less than following KT, and that CLKT offered similar patient survival to isolated LT.

Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle defect. Thromboembolic complications have not heretofore been linked with this diagnosis. We describe four patients with neonatal-onset OTC deficiency who developed vascular thromboses. One patient had arterial thrombosis; the rest developed venous thromboses. Multiple pro-thrombotic risk factors were identified. Low plasma arginine levels were observed in all patients at the time of thrombosis. Arginine deficiency and the resultant nitric oxide insufficiency may contribute to thrombotic risk. Careful normalization of plasma arginine and citrulline levels and increased surveillance for thrombotic complications should be considered in patients with OTC deficiency.

Psychomotor development in pediatric liver transplant (LT) recipients depends on several factors. Our aim was to evaluate the importance of parental involvement and family dynamics on psychomotor development by assessing (i) children and parents individually, (ii) the parent-child relationship, and (iii) the correlation between parental functioning and patient outcome, all before and after LT. Age-appropriate scales were used before and after LT. Twenty-one patients, 19 mothers, and 16 fathers were evaluated. Developmental quotient (DQ): No subjects scored in the "very good" range. The proportion of children with deficits increased from LT to two yr: 17.6% vs. 28.6%. Subjects 0-2 yr were more likely to have normal DQ at transplant (66.7% vs. 50% for older children). Abnormal DQ was more prevalent two yr post-LT in children older at LT (p = 0.02). The mother-child relationship was normal in 59% of families pre-LT and in 67% at two yr. The relationship was more favorable when the child received a transplant as an infant (p = 0.014 at 12 months post-LT). Normal DQ was associated with higher maternal global functioning score pre-LT (p = 0.03). Paternal performance scores were higher than maternal scores. Children transplanted after two yr of age suffer greater long-term deficits than those transplanted as infants.

Making endocrine pancreas cells at will is one of the major goals of cellular based therapies for diabetes. The experimentally induced conversion of hepatocytes into pancreatic cells, using a modified version of the transcription factor Pdx-1, may provide an alternative to stem cell approaches.

Varicella can have a severe course in immunosuppressed patients. Although prevention is fundamental, live-attenuated varicella-zoster (VZV) vaccine is not currently recommended in transplant recipients. Our aims were to (1) evaluate VZV immunity in pediatric liver transplant (LT) recipients; (2) immunize (two doses) seronegative patients post-LT; (3) monitor vaccine safety, (4) assess B and T cell vaccine responses. All patients followed at the Swiss National Pediatric LT Center were approached and 77/79 (97.5%) were enrolled (median age 7.8 years). Vaccine safety was monitored by standardized diary cards and phone calls. VZV-specific serology and CD4(+) T cells were assessed before and after immunization. Thirty-nine patients (51.1%) were seronegative including 14 children immunized pre-LT. Thirty-six of 39 seronegative patients were immunized post-LT (median 3.0 years post LT). Local (54.8%) and systemic (64.5%) reactions were mild and transient. The frequency of VZV-specific CD4(+) T cells and antibody titers increased significantly (respectively from 0.085% to 0.16%, p = 0.04 and 21.0 to 1134.5 IU/L, p < 0.001). All children reached seroprotective titers and 31/32 (97%) patients assessed remained seroprotected at follow-up (median 1.7 years). No breakthrough disease was reported during follow-up (median 4.1 years). Thereby, VZV vaccine appears to be safe, immunogenic and provide protection against disease in pediatric LT patients.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adolescents in the United States, and most probably also in the rest of the industrialized world.As the prevalence of NAFLD in childhood increases with the worldwide obesity epidemic, there is an urgent need for diagnostic standards that can be commonly used by pediatricians and hepatologists. To this end, we performed a PubMed search of the adult and pediatric literature on NAFLD diagnosis through May 2011 using Topics and/or relevant Authors as search words. According to the present literature, NAFLD is suspected based on the association of fatty liver combined with risk factors (mainly obesity), after the exclusion of other causes of liver disease. The reference but imperfect standard for confirming NAFLD is liver histology. The following surrogate markers are presently used to estimate degree of steatosis and liver fibrosis and risk of progression to end-stage liver disease: imaging by ultrasonography or magnetic resonance imaging, liver function tests, and serum markers of liver fibrosis.NAFLD should be suspected in all of the overweight or obese children and adolescents older than 3 years with increased waist circumference especially if there is a NAFLD history in relatives. The typical presentation, however, is in children ages 10 years and older. The first diagnostic step in these children should be abdominal ultrasound and liver function tests, followed by exclusion of other liver diseases. Overweight/obese children with normal ultrasonographic imaging and normal liver function tests should still be monitored due to the poor sensitivity of these tests at a single assessment.Indications for liver biopsy include the following: to rule out other treatable diseases, in cases of clinically suspected advanced liver disease, before pharmacological/surgical treatment, and as part of a structured intervention protocol or clinical research trial.

Objectives: Little is known about pancreatic fat accumulation and its possible associations with metabolic syndrome (MetS) and glucose metabolism. The aim of the present study was to quantify pancreatic fat fraction (PFF) in lean and obese adolescents and explore its relation to metabolic parameters. Methods: We recruited 25 lean and 24 obese adolescents. PFF and visceral adipose tissue (VAT) were determined using magnetic resonance imaging. We measured blood pressure, fasting glucose, insulin, liver enzymes, leptin, and lipid levels. Obese subjects underwent an oral glucose tolerance test. Results: PFF was significantly higher in obese than in lean subjects (4.8 � 1.2 vs 3.6 � 0.9; P < 0.001) and was associated with VAT, g-glutamyltransferase, triglycerides, high-density lipoprotein cholesterol, leptin concentrations, and MetS (P < 0.05 for all). None of the obese subjects had glucose intolerance, but when adjusted for VAT, the following 3 parameters correlated negatively with PFF: fasting and 30minute and 120-minute insulin levels. We divided subjects into 3 groups: group I, lean without MetS; group II, obese without MetS; and group III, obese with MetS, and observed that PFF increased gradually among groups (I: 3.56% � 0.88%; II: 4.70% � 1.06%; III: 5.34% � 1.49%; P < 0.001). Conclusions: Obese adolescents accumulate fat in the pancreas. PFF correlates with the presence of MetS. Even in the absence of glucose intolerance, pancreatic fat deposition is associated with impaired insulin response to glucose overload. This suggests that b-cell dysfunction may already be present in nondiabetic obese adolescents, mirroring what has been shown in adults, and that pancreatic fat accumulation may participate in obesity-associated pancreatic endocrine dysfunction.

Background Psycho-social outcome in children after liver transplantation (LT) is known to be inferior to age-related peers. Yet, when children and their parents are questioned by their nurse or physician about the child’s psycho-social well-being, the answers usually are very positive. We hypothesized that patients and their parents after LT report their psycho-social well-being too enthusiastically when enquired by their personal care takers. Methods Inclusion criteria: LT at the Children’s University Hospital of Geneva 1992–2007, age >3 years, 2 years. Children and their parents were questioned by their well-known, familiar nurse at the annual follow up visit about their personal well-being. To allow for evaluation of answers, scores (good, medium, bad) were attributed to the different questions. 46 children were included in the study. Results Mean age at enquiry was 9.7 years (SD 4 years), mean time after LT was 7.5 years (SD 4.2 years). The different themes were reported as good for: parent–child relationship (83%), relationship with peers (98%), relation with siblings (39%), sport activities (54%), play activities (78%), school performance (87%), expression skills (67%), and general behavior (89%). Conclusion Most of our LT children and their parents consider, during a personal interview with a closely related, familiar nurse, that the child’s psycho-social outcome is good. Yet, it is generally acknowledged that children after LT have negatively altered psycho-social outcomes. Thus, emotionally influenced reports about psycho-social outcome in children after LT must be looked at with care.

As pediatric liver transplant (LT) recipients come of age, additional insight into long-term medical complications of immunosuppression is warranted. The aims of this study were to estimate the prevalence of elevated blood pressure (BP) in long-term survivors of pediatric LT using the data from the Studies in Pediatric Liver Transplantation (SPLIT) database and to identify predictive factors. Patients enrolled in the BP arm of the SPLIT cohort participated in the study. All patients were of at least 5 years but ≤10 years post-LT. Automated BP measurements were obtained at anniversary visits. BP measures were classified as normal, borderline or elevated according to standard criteria. Patients taking antihypertensive medications were classified as "elevated." Eight hundred and fifteen patients participated. The prevalence of elevated BP measurements 5 to 10 years post-LT was 17.5 to 27.5%. Of total 62.5% patients presented with at least one additional elevated BP at a later follow up visit. Multivariate analysis revealed the following parameters to be predictive of elevated BP: age at transplant, steroid use at last BP measurement and cGFR at last BP measurement. Pediatric LT patients show a high prevalence of elevated BP measurements 5 to 10 years following LT, which is related to age at LT, decreased cGFR and recent steroid use.

Internal hernias are an extremely rare complication after pediatric liver transplantation, and its presentation with cholestasis has not been described to date. We report the case of a 12-yr-old boy who presented with moderate abdominal pain 11 yr after split liver transplantation and biliary-enteric anastomosis. He developed severe jaundice within 24 h of initial presentation. Imaging studies revealed ascites, dilation of the intrahepatic bile ducts, a dilated Roux-en-Y-loop, with the loop truncated at the level of the mesenteric artery, which performed a narrow right-to-left loop. At laparotomy, a transmesenteric internal hernia at the root of the jejunal mesentery was identified, originating from the creation of the Y-loop; the Roux-en-Y-loop and its adjacent intestinal loops had slipped through the opening. The Roux-en-Y loop was ischemic from strangulation, and the rest of the intestine well perfused. No surgical resection was necessary following reduction. The patient recovered completely. We discuss diagnosis and management of internal hernias, and review radiological signs. Internal transmesenteric hernias can occur at any time after liver transplantation and prompt diagnosis and surgical treatment are vital.

s 307 Objective/Purpose: In order to better characterize the presentation and progression of LAL D, we have conducted a multinational observational study in children and adults with LAL Deficiency (n5 48). Methods: Data was compiled by performing a retrospective chart review of subjects with documented LAL Deficiency. Results: The median age (range) of first symptoms was 5.8 (0.0 to 42.0) years and the median age at diagnosis was 9.5 (1.2 to 46.1) years. The median age at which dyslipidemia or elevated transaminases was reported was 8.4 and 8.2 years, respectively. 44 of the 48 patients had an ALT above the upper limit of normal (median 80.5 U/L) at the first recorded assessment (on study), and almost all remained abnormal. (follow-up interval 3 to 24 months). The median highest reported total cholesterol, LDL and triglycerides were 316 mg/dL, 239 mg/dL, and 219 mg/dL respectively and the median lowest HDL was 26.5 mg/dL. 67% of patients had dietary interventions during the course of their disease and 65% had received lipid lowering therapy. Although improvements in serum lipids were observed in some patients, these interventions seemed to have a limited effect on controlling the liver disease. Six of the 48 patients underwent liver transplant: 4 patients were under the age of 18 at the time of transplant, while 2 were over the age of 40 and both developed end-stage liver disease rather precipitously. Conclusion: Disease appears to be progressive in some patients despite restriction of dietary fat or lipid lowering therapy. End-stage hepatic complications may develop rapidly and without apparent warning. In conclusion, this study confirms that dyslipidemia and hepatic dysfunction are common in LAL D children, although the diagnosis is often delayed because of non-specific presentation. Supplementary Figure Summary of results of patients sequenced* for pathogenic mutations and variants of unknown pathogenicity in LDLR, APOB, PCSK9, and LDRAP1. 115 Gene Sequencing in US Patients with Severe Clinical Familial Hypercholesterolemia* Marisa Schoen, BA, Emil deGoma, MD, Martianne Stef, PhD, Marina Cuchel, MD, PhD, Daniel Rader, MD, (Philadelphia, PA) Lead Author’s Financial Disclosures: None Study Funding: Yes Funding Sources: Genetic sequencing was performed at no cost by Progenika Biopharma SA. Background/Synopsis: Familial hypercholesterolemia (FH) is characterized by increased plasma levels of lowdensity lipoprotein (LDL) cholesterol, tendon xanthoma, and premature atherosclerotic cardiovascular disease. FH, also called autosomal dominant hypercholesterolemia, can result from mutations in the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB), or the proprotein convertase subtilisin/kexin type 9 gene (PCSK9). Gene sequencing for molecular diagnosis of FH is rarely performed clinically in the US. Objective/Purpose: To determine the specific mutations in patients with clinical and laboratory characteristics of severe clinical FH. Methods: DNA samples of research subjects with clinical and laboratory characteristics of FH were sent to PROGENIKA Inc for genetic sequencing. Next-generation sequencing was performed using SEQPRO LIPO v1, which is designed to detect mutations in the three known genes causing autosomal dominant hypercholesterolemia (i.e., LDLR, APOB, and PCSK9) and in the LDRAP1 gene causing autosomal recessive hypercholesterolemia. It also analyses copy number variations in the LDLR associated with FH. Results: Under an IRB-approved protocol, DNA samples from 25 patients meeting MEDPED (Make Early Diagnosis-Prevent Early Death) criteria for definite FH (mean LDL-C 406 mg/dL) were sequenced for LDLR, APOB, PCSK9, and LDLRAP1. 17 (68%) subjects were found to have a heterozygous pathogenic mutation in LDLR; 2 (8%) subjects were found to have a heterozygous variant of unknown pathogenicity in LDLR; and 6 (24%) subjects had no pathogenic mutations detected. Of the 6 without a detectable mutation, the mean LDL-C was 416 mg/dL (range 242 to 519 mg/dL) and 2 are on LDL apheresis. Conclusion: Our findings show that while pathogenic mutations or variants of unknown significance in LDLR were detected in 76% of patients selected for severe clinical FH phenotypes, no disease-causing mutations were found in 6 (24%) subjects. These findings suggest that other causes of severe FH phenotype may be present and highlight the need for further evaluation to improve diagnosis and management of these patients.

The IRIS was initially described in HIV-positive patients as a sudden clinical deterioration after the introduction of highly active retroviral therapy. It is believed that IRIS is caused by a restored and exaggerated inflammatory immune response to different infectious or non-infectious triggers. This abnormal response is the consequence of an imbalance between pro-inflammatory and anti-inflammatory states. Recently, IRIS has also been reported in adult SOT recipients, causing local and systemic manifestations, and compromising long-term graft function and patient survival. However, IRIS has to date not been reported in pediatric SOT recipients. Here we review what is known and speculated about the pathogenesis of IRIS and propose that children may be relatively protected from IRIS.

FoxF genes are essential for visceral mesoderm development from Drosophila to human. However, part of the difficulty of studying the visceral mesoderm is its relative inaccessibility during early development. Owing to its external development Xenopus laevis presents considerable advantages for the study of visceral mesoderm formation, yet FoxF2 has not been identified in this system. Here, we describe the cloning and expression pattern of XFoxF2 during embryonic development, metamorphosis and adulthood, and compare and contrast it to the expression of FoxF1 in Xenopus laevis and FoxF2 in mouse.

The gastrointestinal (GI) tract forms from the endoderm (which gives rise to the epithelium) and the mesoderm (which develops into the smooth muscle layer, the mesenchyme, and numerous other cell types). Much of what is known of GI development has been learned from studies of the endoderm and its derivatives, because of the importance of epithelial biology in understanding and treating human diseases. Although the necessity of epithelial-mesenchymal cross talk for GI development is uncontested, the role of the mesoderm remains comparatively less well understood. The transformation of the visceral mesoderm during development is remarkable; it differentiates from a very thin layer of cells into a complex tissue comprising smooth muscle cells, myofibroblasts, neurons, immune cells, endothelial cells, lymphatics, and extracellular matrix molecules, all contributing to the form and function of the digestive system. Understanding the molecular processes that govern the development of these cell types and elucidating their respective contribution to GI patterning could offer insight into the mechanisms that regulate cell fate decisions in the intestine, which has the unique property of rapid cell renewal for the maintenance of epithelial integrity. In reviewing evidence from both mammalian and nonmammalian models, we reveal the important role of the visceral mesoderm in the ontogeny of the GI tract.

The complement system is the central component of innate immunity and an important player in the adaptive immunity of vertebrates. We analyzed the expression patterns of several key members of the complement cascade during Xenopus development. We found extensive expression of these molecules already during gastrula/early neurula stage. Remarkably, several genes also showed an organ-specific expression pattern during early organogenesis. Early expression is notable for two different expression patterns in the neuroectoderm. In one group, there is early strong neural plate and neural precursor expression. This is the case of properdin, C1qA, C3 and C9. The second pattern, seen with C1qR and C6, is noteworthy for its expression at the periphery of the neural plate, in the presumptive neural crest. Two genes stand out for their predominantly mesodermal expression. C3aR, the message for the cognate receptor for C3 in the complement cascade, is expressed at the same time as C3, but in a complementary, reciprocal pattern in the mesoderm. C1qA expression also predominates in somites, pronephros, visceral mesoderm and ventral blood islands. Finally, several genes are characterized by later expression in developing organs. C1qR displays a reticular pattern consistent with expression in the developing vasculature. The late expression of C1qA and C3bC4b is strongest in the pronephros. Finally, the expression of properdin in the hindbrain and in the developing lens are novel findings. The expression patterns of these molecules suggest that these components of the complement system may have in Xenopus a so far undefined developmental role.

Since its advent, cyclosporine nephrotoxicity has been a major concern to pediatricians attending to liver transplant recipients. The aims of this study were to examine glomerular and tubular function after orthotopic liver transplantation (OLT) in children, their correlation to CsA, and how they differed according to the underlying disease. Patients and methods: Glomerular and tubular function was examined in 28 patients aged 7 months to 14 yr at the time of transplantation (mean 4.0 +/- 3.6), retrospectively examining creatinine clearance, tubular phosphate reabsorption (TRP), calcium/creatinine ratio, sodium excretion fraction, and protein/creatinine ratio. The group with metabolic disease and an underlying tubulopathy was compared with the group with liver disease only. The effect of CsA trough levels and cumulated dose on these indices was examined, as was the effect of antihypertensives on creatinine clearance. Both glomerular and tubular functions improved significantly following liver transplantation. In patients on CsA (n = 21), CrCl decreased significantly at 1 month post-OLT (42.6 +/- 26.6 mL/min/1.73 m(2)) when compared with pretransplantation, and 3, 12 and 60 months post-OLT (p < 0.05). It improved between 12 and 60 months post-OLT (p < 0.05). It was correlated with cyclosporine trough levels (p < 0.03), and with total dose of CsA at 12 months. This was not true for patients on tacrolimus (n = 7). Overall pretransplant TRP was below normal (73.7% +/- 19.6), which was significantly lower than the values at years 2, 3, and 5 post-OLT (p < 0.05), owing mainly to the metabolic group which recovered normal proximal tubular function by the end of the second week post-OLT. Calcium/creatinine ratio was significantly worse in the group with liver disease only (p < 0.01). Protein/creatinine ratio normalized rapidly in both groups. Urinary sodium excretion fraction (FENa) was very abnormal in the early postoperative phase, normalizing thereafter in both groups. Kidney function improved after liver transplantation in patients with and without pre-existing kidney dysfunction. Overall, creatinine clearance was correlated to CsA trough levels suggesting CsA did not have an irreversible 'sclerosing' effect in the medium term. Combined antihypertensive therapy using nifedipine and enalapril may be the optimal choice for patients requiring medical management of their hypertension, although the observed effect on creatinine clearance did not reach statistical significance in this study. Tubular dysfunction is frequent in both groups of patients, pre- and post-transplant, and may contribute to bone mineral density as well as to metabolic disturbances in this population.

Keywords: CIBM-AIT Reference EPFL-CONF-177240View record in Web of Science Record created on 2012-05-18, modified on 2017-05-12

Biliary atresia (BA) is a congenital malformation or an evolutive inflammatory process which, without treatment, leads to cirrhosis, hepatic failure and death within two years of birth. The literature gives a survival rate of 60% at five years and 25% to adulthood after an initial operation performed for BA. 30% of children do not survive beyond two years of age. BA has become the most frequent indication for liver transplantation (LT) in children. With LT, survival expectancy is 90%. Results of the operation designed for BA remain unsatisfactory, and seem to depend on the age of the infants, as well as on other factors such as liver histology, and centre experience. Since 1989, onset of the paediatric hepatic transplantation program in Geneva, to July 2000, 20 children have been referred for initial treatment of BA, and 26 for possible hepatic transplantation after initial treatment done in another centre. The aim of the current study is to analyse our own results of the initial operation and to present the results of liver transplantation in this particular group of patients. All the patients with a BA are included in this study. The initial operation for BA yielded 43% favourable outcome at five years and the survival in this group following LT reached 91.3% survival. The importance of the age of the patient at time of initial operation is underlined.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, neonatally lethal developmental disorder of the lung with defining histologic abnormalities typically associated with multiple congenital anomalies (MCA). Using array CGH analysis, we have identified six overlapping microdeletions encompassing the FOX transcription factor gene cluster in chromosome 16q24.1q24.2 in patients with ACD/MPV and MCA. Subsequently, we have identified four different heterozygous mutations (frameshift, nonsense, and no-stop) in the candidate FOXF1 gene in unrelated patients with sporadic ACD/MPV and MCA. Custom-designed, high-resolution microarray analysis of additional ACD/MPV samples revealed one microdeletion harboring FOXF1 and two distinct microdeletions upstream of FOXF1, implicating a position effect. DNA sequence analysis revealed that in six of nine deletions, both breakpoints occurred in the portions of Alu elements showing eight to 43 base pairs of perfect microhomology, suggesting replication error Microhomology-Mediated Break-Induced Replication (MMBIR)/Fork Stalling and Template Switching (FoSTeS) as a mechanism of their formation. In contrast to the association of point mutations in FOXF1 with bowel malrotation, microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, probably due to haploinsufficiency for the neighboring FOXC2 and FOXL1 genes. These differences reveal the phenotypic consequences of gene alterations in cis.

C57BL/6 mice are the most widely used strain of laboratory mice. Using in vivo proton Magnetic Resonance Spectroscopy (1H MRS), we have repeatedly observed an abnormal neurochemical profile in the brains of both wild-type and genetically modified mice derived from the C57BL/6J strain, consisting of a several fold increase in cerebral glutamine and two fold decrease in myo-inositol. This strikingly abnormal neurochemical “phenotype” resembles that observed in chronic liver disease or portosystemic shunting and appeared to be independent of transgene, origin or chow and was not associated with liver failure. As many as 25% of animals displayed the abnormal neurochemical profile, questioning the reliability of this model for neurobiology. We conducted an independent study to determine if this neurochemical profile was associated with portosystemic shunting. Our results showed that 100% of the mice with high brain glutamine displayed portosystemic shunting by concomitant portal angiography while all mice with normal brain glutamine did not. Since portosystemic shunting is known to cause alterations in gene expression in many organs including the brain, we conclude that portosystemic shunting may be the most significant problem associated with C57BL/6J inbreeding both for its effect on the central nervous system and for its systemic repercussions.

We describe four infants with ornithine transcarbamylase (OTC) deficiency, who developed arterial and venous thromboses prior to undergoing liver transplantation. These patients prompted a retrospective chart review of children with inborn errors of metabolism associated with hyperammonemia seen at our institution between 1998 and 2008; no additional cases with thrombosis were detected. Data abstracted from medical records include patient demographics, details about thrombus, treatment, associated risk factors and metabolic abnormalities. OTC deficiency was diagnosed during the first week of life in all patients (median age – 4 days; age range 1–7 days). Thrombotic complications developed prior to liver transplant in all patients (median age - 63 days; age range 6–71 days). One patient had arterial thrombus; the rest developed venous thromboses. Possible risk factors for thrombosis are summarized in the table below. Risk factors Patient 1 Patient 2 Patient 3 Patient 4 Indwelling catheter at the site of thrombus Yes Yes Yes Yes Hyperammonemia (>94 mmol/L) Yes No Yes Yes Low plasma arginine ( Table 1. Patient characteristics that are potential risk factors for thrombosis * AT III - Anti-thrombin III Multiple pro-thrombotic risk factors were present. Hyperammonemia was seen in 3 patients and low plasma arginine level was present in all patients around the time of thrombosis. As L-arginine is a substrate for nitric oxide synthesis, arginine deficiency leads to low nitric oxide levels. Recent studies have linked nitric oxide insufficiency to platelet hyperaggregability, thrombosis and endothelial damage. Infants with OTC deficiency, indwelling vascular catheters, hyperammonemia and low plasma arginine may be at increased risk for thrombosis. Further studies in patients with OTC deficiency, to evaluate the role of hyperammonemia and low plasma arginine in thrombogenesis are warranted.

Congenital portosystemic shunts are increasingly recognized in several settings and at any age. The following are some of the most common presentations: prenatal ultrasound, neonatal cholestasis, incidental finding on abdominal imaging, or systemic complications such as unexplained cardiopulmonary or neurological disease, or the presence of liver nodules in a noncirrhotic liver. The purpose of the present review is to summarize clinical presentation and current recommendations for management, and highlight areas of future research. Illustrative examples from the veterinary literature complement our current lack of knowledge of this rare malformation often masquerading as a multisystem disease.

Type C hepatic encephalopathy (type C HE) is increasingly suspected in children with chronic liver disease (CLD), and believed to underlie long-term neurocognitive difficulties. The molecular underpinnings of type C HE in both adults and children are incompletely understood. In the present study we combined the experimental advantages of in vivo high field 1H magnetic resonance spectroscopy with immunohistochemistry to follow longitudinally over 8 weeks the neurometabolic changes in the hippocampus of animals having undergone bile duct ligation as pups. Rats who develop CLD early in life displayed pronounced neurometabolic changes in the hippocampus characterized by a progressive increase in glutamine concentration which correlated with plasma ammonia levels and a rapid decrease in brain myo-inositol. Other neurometabolic findings included a decrease in other organic osmolytes (taurine, choline-containing compounds and creatine), ascorbate and glutamate. At the cellular level, we observed an increase in glial fibrillary acidic protein (GFAP) and aquaporin 4 (AQP4) expression in the hippocampus at 4 weeks post bile duct ligation (BDL), together with astrocytic morphological alterations. These findings differ from observations in the brain of adult rats following BDL, and are in keeping with the commonly accepted theory of age-dependent vulnerability.

Background & Aims: The sequence of events in hepatic encephalopathy (HE) remains unclear. Using the advantages of in vivo 1H-MRS (9.4T) we aimed to analyse the time-course of disease in an established model of type C HE by analysing the longitudinal changes in a large number of brain metabolites together with biochemical, histological and behavioural assessment. We hypothesized that neurometabolic changes are detectable very early, and that these early changes will offer insight into the primary events underpinning HE. Methods: Wistar rats underwent bile-duct ligation (BDL) and were studied before BDL and at post-operative weeks 2, 4, 6 and 8 (n = 26). In vivo short echo-time H-1-MRS (9.4T) of the hippocampus was performed in a longitudinal manner, as were biochemical (plasma), histological and behavioural tests. Results: Plasma ammonium increased early after BDL and remained high during the study. Brain glutamine increased (+47%) as early as 2-4 weeks post-BDL while creatine (-8%) and ascorbate (-12%) decreased. Brain glutamine and ascorbate correlated closely with rising plasma ammonium, while brain creatine correlated with brain glutamine. The increases in brain glutamine and plasma ammonium were correlated, while plasma ammonium correlated negatively with distance moved. Changes in astrocyte morphology were observed at 4 weeks. These early changes were further accentuated at 6-8 weeks post-BDL, concurrently with the known decreases in brain organic osmolytes. Conclusion: Using a multimodal, in vivo and longitudinal approach we have shown that neurometabolic changes are already noticeable 2 weeks after BDL. These early changes are suggestive of osmotic/oxidative stress and are likely the premise of some later changes. Early decreases in cerebral creatine and ascorbate are novel findings offering new avenues to explore neuroprotective strategies for HE treatment. Lay summary: The sequence of events in chronic hepatic encephalopathy (HE) remains unclear, therefore using the advantages of in vivo proton magnetic resonance spectroscopy at 9.4T we aimed to test the hypothesis that neurometabolic changes are detectable very early in an established model of type C HE, offering insight into the primary events underpinning HE, before advanced liver disease confounds the findings. These early, previously unreported neurometabolic changes occurred as early as 2 to 4 weeks after bile-duct ligation, namely an increase in plasma ammonium and brain glutamine, a decrease in brain creatine and ascorbate together with behavioural and astrocyte morphology changes, and continued to progress throughout the 8-week course of the disease. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V.