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Chronic liver disease (CLD) is a serious condition where various toxins present in the blood affect the brain leading to type C hepatic encephalopathy (HE). Both adults and children are impacted, while children may display unique vulnerabilities depending on the affected window of brain development.We aimed to use the advantages of high field proton Magnetic Resonance Spectroscopy (1H MRS) to study longitudinally the neurometabolic and behavioural effects of Bile Duct Ligation (animal model of CLD-induced type C HE) on rats at post-natal day 15 (p15) to get closer to neonatal onset liver disease. Furthermore, we compared two sets of animals (p15 and p21-previously published) to evaluate whether the brain responds differently to CLD according to age onset.We showed for the first time that when CLD was acquired at p15, the rats presented the typical signs of CLD, i.e. rise in plasma bilirubin and ammonium, and developed the characteristic brain metabolic changes associated with type C HE (e.g. glutamine increase and osmolytes decrease). When compared to rats that acquired CLD at p21, p15 rats did not show any significant difference in plasma biochemistry, but displayed a delayed increase in brain glutamine and decrease in total-choline. The changes in neurotransmitters were milder than in p21 rats. Moreover, p15 rats showed an earlier increase in brain lactate and a different antioxidant response. These findings offer tentative pointers as to which neurodevelopmental processes may be impacted and raise the question of whether similar changes might exist in humans but are missed owing to 1H MRS methodological limitations in field strength of clinical magnet.

Type C hepatic encephalopathy (HE) is a neuropsychiatric disease caused by chronic liver disease. Management of type C HE remains an important challenge because treatment options are limited. Both the antibiotic rifaximin and probiotics have been reported to reduce the symptoms of HE, but longitudinal studies assessing their effects on brain metabolism are lacking and the molecular mechanisms underpinning their effects are not fully understood. Therefore, we evaluated in detail the effects of these different treatments on the neurometabolic changes associated with type C HE using a multimodal approach including ultra-high field in vivo 1H MRS. We analyzed longitudinally the effect of rifaximin alone or in combination with the probiotic Vivomixx on the brain metabolic profile in the hippocampus and cerebellum of bile duct ligated (BDL) rats, an established model of type C HE. Overall, while rifaximin alone appeared to induce no significant effect on the neurometabolic profile of BDL rats, its association with the probiotic resulted in more attenuated neurometabolic alterations in BDL rats followed longitudinally (i.e. a smaller increase in Gln and milder decrease in Glu and Cr levels). Given that both rifaximin and some probiotics are used in the treatment of HE, the implications of these findings may be clinically relevant.

Brain metabolism evolves rapidly during early post-natal development in the rat. While changes in amino acids, energy metabolites, antioxidants or metabolites involved in phospholipid metabolism have been reported in the early stages, neurometabolic changes during the later post-natal period are less well characterized. Therefore, we aimed to assess the neurometabolic changes in male Wistar rats between post-natal days 29 and 77 (p29-p77) using longitudinal magnetic resonance spectroscopy (MRS) in vivo at 9.4 Tesla. 1 H MRS was performed in the hippocampus between p29 and p77 at 1-week intervals (n = 7) and in the cerebellum between p35 and p77 at 2-week intervals (n = 7) using the SPECIAL sequence at ultra-short echo-time. NOE enhanced and 1 H decoupled 31 P MR spectra were acquired at p35, p48 and p63 (n = 7) in a larger voxel covering cortex, hippocampus and part of the striatum. The hippocampus showed a decrease in taurine concentration and an increase in glutamate (with more pronounced changes until p49), seemingly a continuation of their well-described changes in the early post-natal period. A constant increase in myo-inositol and choline-containing compounds in the hippocampus (in particular glycero-phosphocholine as shown by 31 P MRS) was measured throughout the observation period, probably related to membrane metabolism and myelination. The cerebellum showed only a significant increase in myo-inositol between p35 and p77. In conclusion, this study showed important changes in brain metabolites in both the hippocampus and cerebellum in the later post-natal period (p29/p35-p77) of male rats, something previously unreported. Based on these novel data, changes in some neurometabolites beyond p28-35, conventionally accepted as the cut off for adulthood, should be taken into account in both experimental design and data interpretation in this animal model.

Case Presentation A 13-year-old male was referred after incidental finding of cardiomegaly on chest radiograph and signs of pulmonary hypertension on subsequent cardiology consult. He was diagnosed with idiopathic pulmonary hypertension, and came to our center for a second opinion. He was born from consanguineous parents. He reported to be asymptomatic in his daily life. He was not on medications. Family history was not contributive.

Background The cellular infiltrate in protocol liver biopsies (PB) following pediatric liver transplantation remains mostly uncharacterized, yet there is increasing concern about the role of inflammation and fibrosis in long-term liver allografts. We aimed to define cell types in PB and to analyze their relationship with donor-specific antibodies (DSA) and histological phenotype. Methods PB were performed at least 1 year after transplantation. We identified 4 phenotypes: normal, fibrosis, inflammation, inflammation with fibrosis. Cell types were counted after immunostaining for CD3, CD4, CD8, CD68, CD20, MUM1, and FoxP3. Results Forty-four patients underwent 1 PB between 2000 and 2015. Eleven percent (5/44) of PB displayed normal histology, 13.6% (6/44) fibrosis, 34.1% (15/44) inflammation, and 40.9% (18/44) inflammation and fibrosis. The main cell types in the portal tracts and lobules were CD3+ and CD68+ cells. Frequency of de novo DSA was 63% (27/44). The presence of CD8+ cells in the lobules was associated with fibrosis. Inflammation and fibrosis in PB were associated with the presence of circulating de novo DSA, number of de novo DSA, and C1q binding activity when compared to other phenotypes. Conclusions T cells (CD3+) and macrophages (CD68+) were the most prevalent cell-types in PB. In the presence of inflammation, portal tracts were enriched in CD3+, CD20+ but displayed fewer CD68+. This coincided with the presence and number of de novo DSA. How these cellular and humoral actors interact is unclear, but peripheral DSA may be a marker of immune cellular activity in the seemingly quiescent allograft.

Aims and background Ophthalmic abnormalities are amongst the five major criteria required for a diagnosis of Alagille syndrome (ALGS), of which embryotoxon, pseudo-papilledema, and hypopigmented retinopathy are the most common. Papilledema with or without intracranial hypertension (ICHT) is rarely described. We report nine pediatric cases of ALGS with bilateral papilledema, five of which were diagnosed with ICHT. Methods The ophthalmic data from 85 patients with clinically and/or genetically (n = 37) proven ALGS were reviewed. The study inclusion criteria were a positive diagnosis of ALGS and availability of ophthalmic follow-up data. Ophthalmic data from 40 patients after liver transplantation for other indications were also analyzed. Results Nine (13.0%) of the 69 patients meeting the inclusion criteria had papilledema. The neurological and neuroimaging results in all nine patients were normal. These nine patients were categorized into four groups: (1) a non-transplant group (n = 1), (2) a group with pretransplant papilledema persistent after liver transplantation (LT) (n = 2), (3) a group with papilledema occurring after LT with spontaneous resolution (n = 2), and (4) a group with papilledema and signs of ICHT after LT (n = 5). The patients with ICHT were treated with steroids alone (n = 1) or with acetazolamide (n = 4). A ventriculoperitoneal shunt was placed in two of the five cases because of progressive visual loss. Pseudopapilledema was present in 10 additional patients (14.5%, 10/69). One (2.5%) of the 40 patients without ALGS developed papilledema after LT. Conclusions True ICHT may be underdiagnosed in patients with ALGS. Our findings underscore the need for close ophthalmic follow-up before and after LT in these patients.

Type C hepatic encephalopathy (HE) is a complex neuropsychiatric disorder occurring as a consequence of chronic liver disease. Alterations in energy metabolism have been suggested in type C HE, but $\textit{in vivo}$ studies on this matter remain sparse and have reported conflicting results. Here, we propose a novel preclinical $^{18}$F-FDG PET methodology to compute quantitative 3D maps of the regional cerebral metabolic rate of glucose (CMR$_{glc}$) from a labelling steady-state PET image of the brain and an image-derived input function. This quantitative approach shows its strength when comparing groups of animals with divergent physiology, such as HE animals. PET CMR$_{glc}$ maps were registered to an atlas and the mean CMR$_{glc}$ from the hippocampus and the cerebellum were associated to the corresponding localized $^{1}$H MR spectroscopy acquisitions. This study provides for the first time local and quantitative information on both brain glucose uptake and neurometabolic profile alterations in a rat model of type C HE. A 2-fold lower brain glucose uptake, concomitant with an increase in brain glutamine and a decrease in the main osmolytes was observed in the hippocampus and in the cerebellum. These novel findings are an important step towards new insights into energy metabolism in the pathophysiology of HE., 30 pages, 6 figures

Patients who have a prolonged stay in the intensive care unit (ICU) are often excluded for organ donation because of supposed deleterious effects of a lengthy ICU stay. We aimed to determine the effects of a prolonged donor stay in the ICU on the outcome of liver transplantation (LT) in children.Retrospective review of 89 pediatric LT patients, age 0-18 years, period 2003-2018, including patients having undergone whole organ or in situ split LT. The patients were divided into two groups according to the donor length of stay in the ICU. A prolonged stay was defined as5 days. Recipient, graft, and donor characteristics were compared; outcome parameters included recipient and graft survival rates and postoperative complications.Group short (donor ICU stay5 days) included 75 patients, group long (donor ICU stay5 days) 14 patients. Baseline characteristics between recipients did not differ. Donors in group long had significantly more infectious complications and a higher gamma glutamyl transferase (gGT) the day of organ recovery. Incidence of biliary complications post-LT was significantly higher in group long (p = .029). Patient and graft survival rates did not differ significantly between groups.Donors with a prolonged stay in the ICU should still be considered for liver donation if they fulfill most other selection criteria. Recipients from donors having stayed in ICU5 days may be at increased risk of biliary complications.

Type C hepatic encephalopathy (HE) is a complex neuropsychiatric disorder occurring as a consequence of chronic liver disease. Alterations in energy metabolism have been suggested in type C HE, but in vivo studies on this matter remain sparse and have reported conflicting results. Here, we propose a novel preclinical

Background: Children with biliary atresia rapidly develop liver fibrosis secondary to inflammatory destruction of the biliary tract. Noninvasive detection of liver fibrosis in neonatal/infantile cholestasis is an additional criterion for the diagnosis of biliary atresia, leading to prompt surgical exploration. Objective: To assess the value of US with acoustic radiation force impulse (ARFI) elastography to detect biliary atresia in the workup of neonatal/infantile cholestasis. Materials and methods: In this retrospective study, 20 children with cholestasis suspected of having biliary atresia were investigated by US and ARFI. We evaluated the association between US findings and the diagnosis of biliary atresia and with two scores of liver fibrosis obtained from liver biopsy. Results: In univariate analyses, gallbladder size, triangular cord sign, spleen size and ARFI values were found to be associated with biliary atresia, though only the triangular cord sign remained significant when elevated gamma glutamyltransferase (GGT) was included as a predictor. In contrast, spleen size and ARFI correlated with the degree of liver fibrosis on biopsy (r > 0.70, P

That children present with hepatic encephalopathy (HE) in the setting of acute liver failure (ALF) is accepted and a recognized prognostic factor for survival [1,2]. What is less understood is the impact of chronic liver disease (CLD) on the neuro-cognitive and -psychiatric development and outcomes of children with chronic liver disease early in life. Much is extrapolated from the adult literature or from work in experimental models. But what distinguishes children is that central nervous system development, characterized by massive brain growth, is ongoing at the time of liver disease, arguably exposing them to unique risks, something which cannot be extrapolated from adults. The purpose of this brief review is to summarize what is distinctive about the neurocognition of children with CLD or having presented CLD or portosystemic bypass in childhood.

Summary Objective Pediatric recipients of liver transplantation (LT) often report lower Health-Related Quality of Life (HRQOL) than healthy controls when assessed on generic HRQOL measurement tools. The recent addition of the Pediatric Liver Transplant Quality of Life (PeLTQL), a novel disease-specific HRQOL instrument for pediatric LT recipients, into the clinical armamentarium of tools now routinely available to clinical care teams, provides the unique opportunity to identify disease-related challenges in children who have undergone this life-saving intervention. This study assesses HRQOL in pre-adolescent aged patients with a primary diagnosis of biliary atresia (BA) who underwent LT as an infant, using both generic and disease-specific HRQOL instruments validated for children. We also examined modifiable factors associated with HRQOL after pediatric LT. Methods HRQOL was the primary outcome of this study assessed using the disease-specific PeLTQL and the generic Pediatric Quality of Life Inventory 4.0 (PedsQL). Exposure variables of interest included medication status (e.g., monotherapy, dual therapy) and participation in sports. Results A total of 70 (56% female, mean age 9.89 ± 1.25 years) pediatric LT recipients (mean interval since LT was 9.0 ± 1.26 years) comprised the study cohort. LT recipients reported significantly lower PedsQL Scores relative to the general population. Immunosuppression monotherapy was associated with higher patient-reported PeLTQL Scores, and sports participation was associated with higher parent-reported PedsQL Scores. Conclusions Pre-adolescents who underwent LT as an infant with BA, self-report low HRQOL on both disease-specific and generic HRQOL tools. Further research targeting sports participation and simplifying immunosuppression may further optimize quality of life years restored by life-saving LT.

We report an unusual case of intermittent episodes of cholestasis in a young patient. The cholestatic attacks were preceded in each case by an infection and subsequent antibiotic therapies. After ruling out many possible causes of cholestatic hepatitis, the differential diagnoses were a benign recurrent intrahepatic cholestasis or a drug-induced liver injury. We discuss here the diagnostic approach and interpretation of the genetic analysis.

Objectives: We aimed to investigate national allocation policies for pediatric liver transplantation (LT).Method: A survey was prepared by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Hepatology Committee in collaboration with the North American Studies of Pediatric Liver Transplantation consortium. The survey was sent to pediatric hepatologists and transplant surgeons worldwide. National data were obtained from centrally based registries.Results: Replies were obtained from 15 countries from 5 of the world continents. Overall donation rate varied between 9 and 35 per million inhabitants. The number of pediatric LTs was 4 to 9 per million inhabitants younger than 18 years for 13 of the 15 respondents. In children younger than 2 years mortality on the waiting list (WL) varied between 0 and 20%. In the same age group, there were large differences in the ratio of living donor LT to deceased donor LT and in the ratio of split liver segments to whole liver. These differences were associated with possible discrepancies in WL mortality.Conclusions: Similarities but also differences between countries were detected. The described data may be of importance when trying to reduce WL mortality in the youngest children.

OBJECTIVES The aim of this study was to analyze if contrast-enhanced echocardiography (CEE) is as reliable as lung perfusion scintigraphy (LPS) to detect intrapulmonary shunting (IPS) in children with portal hypertension (PHTN) or congenital/surgical portosystemic shunts (PSS) and to define the number of cardiac cycles required to exclude intrapulmonary shunting. METHODS Inclusion criteria for this cross-sectional study were: (1) presence of PHTN or PSS diagnosed on abdominal ultrasound, (2) technically valid saline contrast echocardiography, (3) lung perfusion scintigraphy within 6 months of CEE. The number of cardiac cycles between right atrial opacification and the arrival of contrast in the left atrium were counted. We analyzed our CEE data at three and five cardiac cycles and compared them with LPS results. RESULTS The study population was composed of 78 children (38 girls, 49%) ages 2.1-18.8 years (mean 9.8). Sixty-nine patients had PHTN (88%), and nine had a PSS (11%). Eleven subjects (14%) presented evidence of IPS on LPS. Peripheral oxygen saturation was lower in the subjects with IPS detected on LPS (95.3 ± 1.7% vs 99.0 ± 1.4%; P

Autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are rare indications for liver transplantation (LT) in children. The aim of the present retrospective multicenter study was to evaluate long-term outcome after LT for autoimmune liver disease in childhood.Retrospective data from 30 children who underwent a first LT from 1988 to 2018 were collected.The study population consisted of 18 girls and 12 boys, transplanted for AIH type 1 (n=14), AIH type 2 (n=7) or PSC (n=9). Mean age at LT was 11.8±5.2 years. The main indications for LT were acute (36.7%) or chronic end-stage liver failure (63.3%). Graft rejection occurred in 19 patients (63.3%); 6 pts required retransplantation for chronic rejection. Recurrence of initial disease was observed in 6 patients (20.0%), all of them with type 1 AIH, after a median time of 42 months, requiring retransplantation in 2 cases. Overall patient survival rates were 96.4%, 84.6%, 74.8%, 68.0%, 68.0%, 68.0% and 68.0% at 1, 5, 10, 15, 20, 25 and 30 years, respectively. Age at LT1year (p0.0001), LT for fulminant failure (p=0.023) and LT for type 2 AIH (p=0.049) were significant predictive factors of death.Long-term outcome after LT for pediatric autoimmune liver disease is impaired in patients with AIH because of consistent complications such as rejection and disease recurrence.

International audience; Introduction: Liver transplantation (LT) is the therapeutic option for end-stage liver disease associated with alpha1 antitrypsin (A1AT) deficiency. The aim of the present retrospective study was to report on long-term outcomes following LT for A1AT deficiency.Methods: The medical records of 90 pediatric and adult patients transplanted between 1982 and 2017 in France and Geneva (Switzerland) were reviewed.Results: The study population consisted of 32 adults and 58 children; median age at transplant was 13.0 years (range: 0.2-65.1), and 65 were male (72.2%). Eighty-two patients (94.8% of children and 84.4% of adults) had the PI*ZZ genotype/phenotype and eight patients (8.9%) had the Pi*SZ genotype/phenotype. Eighty-four patients (93.3%) were transplanted for end-stage liver disease and six (all Pi*ZZ adults) for HCC. Median follow-up after LT was 13.6 years (0.1-31.7). The overall cumulative patient survival rates post-transplant were 97.8% at 1 year, and 95.5%, 95.5%, 92.0%, 89.1% at 5, 10, 15, 20 years respectively. The overall cumulative graft survival rates were 92.2% at 1 year, and 89.9%, 89.9%, 84.4%, 81.5% at 5, 10, 15 and 20 years, respectively.Conclusions: In a representative cohort of patients having presented with end-stage-liver disease or HCC secondary to A1AT, liver transplantation offered very good patient and graft survival rates.

Chronic liver disease leads to neuropsychiatric complications called hepatic encephalopathy (HE). Current treatments have some limitations in their efficacy and tolerability, emphasizing the need for alternative therapies. Modulation of gut bacterial flora using probiotics is emerging as a therapeutic alternative. However, knowledge about how probiotics influence brain metabolite changes during HE is missing. In the present study, we combined the advantages of ultra-high field in vivo 1H MRS with behavioural tests to analyse whether a long-term treatment with a multistrain probiotic mixture (VIVOMIXX) in a rat model of type C HE had a positive effect on behaviour and neurometabolic changes. We showed that the prophylactic administration of this probiotic formulation led to an increase in gut Bifidobacteria and attenuated changes in locomotor activity and neurometabolic profile in a rat model of type C HE. Both the performance in behavioural tests and the neurometabolic profile of BDL + probiotic rats were improved compared to the BDL group at week 8 post-BDL. They displayed a significantly lesser increase in brain Gln, a milder decrease in brain mIns and a smaller decrease in neurotransmitter Glu than untreated animals. The clinical implications of these findings are potentially far-reaching given that probiotics are generally safe and well-tolerated by patients.

We read with great interest the report by Uchida et al on the long-term outcomes of liver transplantation for congenital porto-systemic shunts (CPSS). We are in full agreement with the authors that there is an era effect in this report as we now know that most of the indications for liver transplantation in this series can be corrected by endovascular or surgical closure: hyperammonemia, hepatopulmonary syndrome, non-malignant nodules. The other notable feature of this report is the young age of patients at transplant with 19/26 patients having undergone transplantation before the age of 9 years, and 14/26 before the age of 5 years, of which two were for portopulmonary hypertension (POPH).

International audience; Mannose phosphate isomerase MPI-CDG (formerly CDG-1b) is a potentially fatal inherited metabolic disease which is readily treatable with oral D-mannose. We retrospectively reviewed long-term outcomes of patients with MPI-CDG, all but one of whom were treated with D-mannose. Clinical, biological, and histological data were reviewed at diagnosis and on D-mannose treatment. Nine patients were diagnosed with MPI-CDG at a median age of 3 months. The presenting symptoms were diarrhea (n = 9), hepatomegaly (n = 9), hypoglycemia (n = 8), and protein loosing enteropathy (n = 7). All patients survived except the untreated one who died at 2 years of age. Oral D-mannose was started in eight patients at a median age of 7 months (mean 38 months), with a median follow-up on treatment of 14 years 9 months (1.5-20 years). On treatment, two patients developed severe portal hypertension, two developed venous thrombosis, and 1 displayed altered kidney function. Poor compliance with D-mannose was correlated with recurrence of diarrhea, thrombosis, and abnormal biological parameters including coagulation factors and transferrin profiles. Liver fibrosis persisted despite treatment, but two patients showed improved liver architecture during follow-up. This study highlights (i) the efficacy and safety of D-mannose treatment with a median follow-up on treatment of almost 15 years (ii) the need for life-long treatment (iii) the risk of relapse with poor compliance, (iii) the importance of portal hypertension screening (iv) the need to be aware of venous and renal complications in adulthood.

Background Mutations in the melanocortin-4 receptor (MC4R) represent the most common cause of monogenic obesity. Treatment options are limited but glucagon-like peptide-1 receptor agonists (GLP-1 RA) may be of use to induce weight loss. Methods Exome of the patient was captured using the Agilent SureSelect QXT Human All Exon V5 kit and sequenced on Illumina. Clinical findings and results We report obesity-associated diabetes and cirrhosis in a 13-year girl born from consanguineous parents of Afghan origin. Past medical history revealed mild mental retardation and excessive weight gain since infancy. Linear growth was normal. Her father was obese and no diabetes was found in the family. The girl was initially investigated for hoarseness and found to have pulmonary hypertension, later accepted to be secondary to cirrhosis and portal hypertension. Physical examination revealed obesity (BMI 34.9kg/m2) and acanthosis nigricans. Blood exams showed leucopenia and thrombocytopenia without anemia, compatible with portal hypertension. Chest CT revealed important dilatation of the pulmonary arteries, a nodular liver and splenomegaly. Liver biopsy confirmed cirrhosis. An extensive workup including whole exome sequencing identified a homozygous MC4R variant [NM_005912.2 (MC4R): c.63_64del, p.(Tyr21*)], classified as pathogenic according to the ACMG guidelines. Both parents were heterozygous for this variant. An endocrinological workup showed insulin resistance with a HOMA-IR index of 7.27 and diabetes with peak blood glucose of 11.5mmol/l. HbA1c was 5.1% (32mmol/mol). Thyroid tests, leptin, proinsulin levels (3.5pmol/l, n The mutation being homozygous with a predicted complete loss of function (https://www.mc4r.org.uk/), no treatment with a MC4R agonist was tried. At the age of 15 years (BMI 36.0kg/m2), the patient underwent liver transplantation because of progressive portal hypertension and to halt the progression of pulmonary hypertension. At the age of 16 years (BMI 33.2kg/m2, HbA1c 4.9% (30.0 mmol/mol), HOMA-IR 5.3) a treatment with GLP-1 RA (liraglutide) was started at a dosage of 0.6mg and progressively increased to 3mg, in an attempt to induce weight loss, avoid the accumulation of liver fat and to protect the graft. GLP-1 RA is supposed to exerts its effects on appetite independently of the MC4R pathway. 2 months after liraglutide introduction, no side effects, a weight loss of 4kg and a decrease of appetite were observed (BMI 31.6kg/m2, HbA1c 4.5% (26mmol/mol), HOMA-IR 3.14). Conclusion Obesity-associated MCR4 mutations, in homozygous state, may lead to diabetes, liver cirrhosis and porto-pulmonary hypertension. Treatment options are scarce, but GLP-1 RA seem to have a rapid, positive effect on weight and metabolic control. Would earlier treatment have prevented progression to end-stage-liver disease and need for liver transplantation?

Brain metabolism evolves rapidly during early post-natal development in the rat. While changes in amino acids, energy metabolites, antioxidants or metabolites involved in phospholipid metabolism have been reported in the early stages, neurometabolic changes during the later post-natal period are less well characterized. Therefore, we aimed to assess the neurometabolic changes in male Wistar rats between post-natal days 29 and 77 (p29-p77) using longitudinal magnetic resonance spectroscopy (MRS) in vivo at 9.4 Tesla.

Despite growing interest about the impact of donor-specific HLA antibodies (DSA) in LT limited data are available for pediatric recipients. Our aim was to perform a retrospective single-center chart review of children (0-16 years) having undergone LT between January 1, 2005 and December 31, 2017, to characterize DSA, to identify factors associated with the development of de novo DSA, and to analyze potential associations with the diagnosis of TCMR. Information on patient- and donor-characteristics and LB reports were analyzed retrospectively. Serum obtained before LT and at LB was analyzed for presence of recipient HLA antibody using Luminex® technology. MFI > 1000 was considered positive. In 63 pediatric LT recipients with a median follow-up of 72 months, the overall prevalence of de novo DSA was 60.3%. Most were directed against class II antigens (33/38, 86.8%). Preformed DSA were present in 30% of patients. Twenty-eight (28/63) patients (44.4%) presented at least one episode of TCMR, mostly (12/28, 43%) moderate (Banff 6-7). De novo DSA were significantly more frequent in patients with TCMR than in patients without (75% vs 48.6%, P = .03), and patients with preformed and de novo DSA had a significantly higher rate of TCMR than patients without any DSA (66.7% vs 20%, P = .02). Neither preformed DSA nor de novo DSA were associated with frequency or severity of TCMR. Recipients with lower weight at LT developed de novo DSA more frequently (P = .04). De novo DSA were highly prevalent in pediatric LT recipients. Although associated with the development of TCMR, they did not appear to impact the frequency or severity of TCMR or graft survival. Instead, de novo DSA may suggest a state of insufficient IS.

Summary Portopulmonary hypertension is a rare but serious complication of portal hypertension or portosystemic shunting. Portopulmonary hypertension is an indication for liver transplantation or shunt closure. However, liver transplantation is contraindicated in patients with severe pulmonary arterial hypertension. Reported mortality rates are high in children with portopulmonary hypertension and there are scarce recommendations on its management. Our aim was to report on our real-world experience of managing portopulmonary hypertension in a specialised centre. We describe a series of 6 children with portopulmonary hypertension. Their median age at diagnosis was 13 years (range 10–15). The underlying liver conditions were cirrhosis of unknown origin (1), congenital portocaval shunts (3), biliary atresia (1), and portal vein cavernoma with surgical mesenterico-caval shunt (1). Median mean pulmonary arterial pressure was 47 mmHg (range 32–70), and median pulmonary vascular resistance was 6.6 Wood units (range 4.3–15.4). All patients except one were treated with a combination of pulmonary arterial hypertension-specific therapy (phosphodiesterase type 5 inhibitors and/or endothelin receptor antagonists and/or prostacyclin analogues). Three patients then benefited from shunt closure and the others underwent liver transplantation. Five patients showed improvement or stabilisation of pulmonary arterial hypertension with no deaths after a mean follow-up of 39 months. Based on our limited experience, early and aggressive treatment with a combination of pulmonary arterial hypertension-specific therapy significantly improves patients' haemodynamic profile and enables the performance of liver transplantation and shunt closure with satisfactory outcomes.

Immunosuppressive therapy must be guided by therapeutic drug monitoring (TDM) in paediatric liver (LT) and kidney transplantation (KT) patients to prevent under- and overdosing, which have clinical consequences.The purpose of our study was to analyse TDM results in our institutions and evaluate factors associated with blood level stabilisation after LT and KT.Blood levels of immunosuppressants were measured by immunoassay analysis. We compared blood level stabilisation between LT and KT, and evaluated associated factors in a retrospective study in two Swiss university hospitals.Forty-six patients (27 LT [median age 1.0 y], 19 KT [15.1 y]) were included. During the first month after transplantation, 32.8% (LT) and 41.2% (KT) of tacrolimus, and 22.1% (KT) of ciclosporin trough levels (measured before the next dose) were within target. In KT, trough levels stabilised earlier for tacrolimus than for ciclosporin (p = 0.02). Intensive care and hospital discharge occurred earlier in KT patients (plt;0.001). Living-donor LT was associated with an earlier intensive care discharge compared with deceased donor (5.5 vs 11 days, p = 0.02). Primary metabolic disease and graft/recipient weight-ratioge;0.03 was associated with earlier tacrolimus level stabilisation (14 vs 18 days, p = 0.01 and 15 vs 22 days, p = 0.05, respectively). In KT, recipient age (ge;15.1 years) and weight (ge;39.4 kg) were associated with an earlier trough level stabilisation (both 13 days vs not reached, plt;0.001), and age with earlier hospital discharge (10 vs 14 days, p = 0.02).Immunosuppressant trough levels were often outside the target range in the first month after LT and KT. Organ-specific factors were associated with trough stabilisation.

As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications. Copyright © 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Detection of subclinical hepatic encephalopathy in children is difficult. We aimed to assess the changes in imaging of the central nervous system in children with chronic liver disease using MR imaging, diffusion, and 1H -spectroscopy. Forty three children with chronic liver disease and/or porto-systemic shunting (111.4±56.9 months) and 24 controls (72.0±51.8 months) underwent brain MRI/spectroscopy on a 1.5T to examine T1, T2, ADC, Cho/Cr, ml/Cr, Glx/Cr ratio spectroscopy in the globus pallidus. Patients were divided into 3 groups according to the ratios of globus pallidus/putamen T1 signal : isointense (i), hyperintense (h), much more hyperintense (h+). The relationship with clinical and biological data was analyzed. T1 signal intensity and ml/Cr were significantly different between controls and group h+ (p=0.001). ADC did not differ significantly between groups. Age correlated strongly with the presence of a T1 signal ratio (p > 0.001). There was no correlation between imaging findings and biological parameters. In children with chronic liver disease and/or porto-systemic shunting, the presence of a hyperintense T1 signal in the globus pallidus correlated strongly with age. Biological and clinical parameters were not predictive of these changes. MRI may become a useful screening tool for hepatic encephalopathy in children. • Children with chronic liver disease should undergo brain MRI during their follow-up • T1 hyperintensity of globus pallidus is suggestive of liver-related CNS involvement • MRS mI/Cr is decreased in children with chronic liver disease • Biological parameters (ammonium) were not predictive of hepatic encephalopathy • Duration of chronic liver disease may be causative the hepatic encephalopathy

Chickenpox is a highly contagious vaccine-preventable disease that can lead to severe complications, especially in immunocompromised patients. Varicella-zoster virus (VZV) vaccine appears to be safe and immunogenic in pediatric solid organ transplant recipients, but there are few data on the long-term vaccine-induced seroprotection.In this prospective interventional study, we offered 2 doses of VZV vaccine to all eligible and nonseroprotected children seen 1 year after liver transplant. Vaccine responses were measured 1 month later and yearly thereafter. Vaccine safety was closely monitored. A supplementary dose was administered if protective levels were not reached/maintained.Among 121 enrolled patients, 49 were vaccinated and followed during 5.5 years (interquartile range, 3.7-8.0). Their seroconversion rate reached 100% (97.5% confidence interval [CI], 92.7-100). Low VZV-antibody concentration (≤400 UI/L) after the first 1-2 dose/s was associated with the need for a supplementary dose (odds ratio, 15.0; 95% CI, 3.4-67.0, P = 0.001) and was given to 31% (15/47) of children at 1.1 year (interquartile range, 0.9-3.9). Although antibody concentrations declined during follow-up, 96% (95% CI, 86.0-99.5) of patients maintained protective antibody concentrations at a median of 5.5 years after vaccination. One breakthrough disease was identified.VZV immunization of pediatric solid organ transplant recipients confers sustained seroprotection.

Introduction Hepatoportoenterostomy (HPE) is the first-line treatment for biliary atresia (BA) patients. This study aims to describe perioperative complications after HPE and to analyze their impact on outcome. Materials and Methods Patients with HPE (Swiss National Biliary Atresia Registry, 1994–2017) were retrospectively analyzed. Perioperative complications were defined as complications occurring up to 30 days after surgery. Surgical complications were defined as directly related to the surgical act; medical complications were defined as any other deviation from the uneventful postoperative course. Results Sixty-two patients were included. Median age at HPE was 63 days (18–126). Twenty six patients out of 62 (42%) had ≥ 1 complications: 6/62 (10%) surgical, 24/62 (39%) medical, that is, we observed 7 surgical and 28 medical complications. As for medical complications, cholangitis was the most frequent: 19/28 (68%). Lower gestational age at birth correlated with more overall complications (p = 0.02). Age, weight at HPE, syndromic BA, and postoperative steroid administration were not significantly correlated. There were no perioperative deaths. Perioperative complications did not correlate with overall survival (p = 0.14) and survival with native liver (p = 0.55). Conclusion HPE is often associated with perioperative medical complications. Lower gestational age at birth was significantly associated with more complications. Perioperative complications had no impact on overall outcome.

Pediatric acute liver failure (ALF) is life threatening with genetic, immunologic, and environmental etiologies. Approximately half of all cases remain unexplained. Recurrent ALF (RALF) in infants describes repeated episodes of severe liver injury with recovery of hepatic function between crises. We describe bi-allelic RINT1 alterations as the cause of a multisystem disorder including RALF and skeletal abnormalities. Three unrelated individuals with RALF onset A or G>T) in trans with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del) in RINT1. ALF episodes are concomitant with fever/infection and not all individuals have complete normalization of liver function testing between episodes. Liver biopsies revealed nonspecific liver damage including fibrosis, steatosis, or mild increases in Kupffer cells. Skeletal imaging revealed abnormalities affecting the vertebrae and pelvis. Dermal fibroblasts showed splice-variant mediated skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay. Fibroblasts also revealed decreased RINT1 protein, abnormal Golgi morphology, and impaired autophagic flux compared to control. RINT1 interacts with NBAS, recently implicated in RALF, and UVRAG, to facilitate Golgi-to-ER retrograde vesicle transport. During nutrient depletion or infection, Golgi-to-ER transport is suppressed and autophagy is promoted through UVRAG regulation by mTOR. Aberrant autophagy has been associated with the development of similar skeletal abnormalities and also with liver disease, suggesting that disruption of these RINT1 functions may explain the liver and skeletal findings. Clarifying the pathomechanism underlying this gene-disease relationship may inform therapeutic opportunities.

Live-attenuated vaccines are currently contraindicated in solid-organ transplant recipients. However, the risk of vaccine-preventable infections is lifelong, and can be particularly severe after transplantation. In this prospective interventional national cohort study, 44 pediatric liver transplant recipients with measles IgG antibodies 1 year posttransplantation, low immunosuppression, lymphocyte count ≥0.75 G/L), inducing seroprotection in most subjects. (Clinicaltrials.gov number NCT01770119).

Summary Background During the past decade, mTOR inhibitors (mTORi), everolimus and sirolimus, have been increasingly used after adult liver transplantation (LT). The aim of the present study was to describe the use of mTORi in pediatric LT recipients. Methods All pediatric LT recipients who received mTORi before December 2017 from 4 European pediatric LT centers were included and analyzed. Results The present retrospective study included 30 patients; 21 were male (70%), median age was 9.3 years (range: 1.2–17.1 years) at mTORi introduction. Main indications for mTORi introduction were pre-existing liver malignancy (43.3%), calcineurin inhibitor (CNI) nephrotoxicity (26.7%), or rejection (23.4%). At last follow-up, mTORi CNIs were withdrawn in 10 patients (10/29, 34.5%). The median dose of mTORi was 1.8 mg/day (range: 0.3–5.0) or 0.058 mg/kg/day (range: 0.01–0.26), and the median trough level was 5.1 μg/L (range: 1.0–15.5). After a median follow-up of 2.8 years (range: 0.2–10.0), 50.0% of the patients presented with at least one adverse event. The main adverse events included hyperlipidemia, proteinuria, dermatitis, and mucitis. Overall mTORi discontinuation rate was 23.3% (10.0% because of adverse event). Introduction of mTORi had no significant impact on renal function. Conclusion Our results suggest that mTORi can be used in pediatric LT recipients in different clinical situations, both to reinforce immunosuppressive therapy, and to reduce CNI and related toxicity.

Pediatric liver transplantation (LT) differs widely from adult liver transplantation. A pediatric team experienced in LT is central to the care of these patients both pre- and post-LT. Centers of reference with a multidisciplinary team especially trained in LT improve patient outcomes. A standardized protocol is the foundation of successful short-term and long-term management of LT recipients. Nonetheless, protocols should be adapted to the individual needs of patients. In this chapter, a practical approach to pretransplant, transplant, and posttransplant care will be provided. Recommendations for pretransplant assessment, listing for transplant, and management during the pretransplant period are described in the first section. The second part will focus on a practical approach of early postoperative management and complications together with suggested diagnostic and therapeutic protocols. A suggested long-term follow-up schedule and complications surveillance will be provided in the third part of the chapter. These protocols are designed to be as comprehensive as possible and should be adapted to local resources.

Background: Hepatitis E virus (HEV) is endemic in large parts of the developing world. Waterborne transmission of genotypes 1 or 2 commonly causes acute hepatitis, which is usually self-limited in healthy individuals. In addition, acute HEV infections also occur outside endemic areas, mostly related to foodborne transmission of HEV genotype 3. A growing number of publications in the last decade have reported chronic infection progressing to cirrhosis in immunosuppressed patients. It has also been suggested that HEV transmission may occur via contaminated blood products. This publication aims to provide recommendations for diagnosis, prevention, and treatment of HEV infection, particularly in children after solid organ transplantation.Methods: A systematic PubMed literature search on HEV infection from 1990 to January 2016 was performed focusing on pediatric studies. The existing body of evidence was reviewed and recommendations were agreed upon following discussion and unanimous agreement by all members of the ESPGHAN Hepatology Committee during a consensus meeting in January 2016. In the absence of randomized controlled studies these recommendations were considered to be expert opinions.Key Recommendations: Immunocompetent children with increased transaminases and/or extrahepatic manifestations should be considered for testing for evidence of HEV infection. Immunocompromised children with increased aminotransferases should be repeatedly tested for HEV and may require therapeutic intervention.

Hyperammonemia can be caused by various acquired or inherited disorders such as urea cycle defects. The brain is much more susceptible to the deleterious effects of ammonium in childhood than in adulthood. Hyperammonemia provokes irreversible damage to the developing central nervous system: cortical atrophy, ventricular enlargement and demyelination lead to cognitive impairment, seizures and cerebral palsy. The mechanisms leading to these severe brain lesions are still not well understood, but recent studies show that ammonium exposure alters several amino acid pathways and neurotransmitter systems, cerebral energy metabolism, nitric oxide synthesis, oxidative stress and signal transduction pathways. All in all, at the cellular level, these are associated with alterations in neuronal differentiation and patterns of cell death. Recent advances in imaging techniques are increasing our understanding of these processes through detailed in vivo longitudinal analysis of neurobiochemical changes associated with hyperammonemia. Further, several potential neuroprotective strategies have been put forward recently, including the use of NMDA receptor antagonists, nitric oxide inhibitors, creatine, acetyl-L-carnitine, CNTF or inhibitors of MAPKs and glutamine synthetase. Magnetic resonance imaging and spectroscopy will ultimately be a powerful tool to measure the effects of these neuroprotective approaches.