Paediatric autoimmune liver disease is characterized by inflammatory liver histology, circulating autoantibodies, and increased levels of IgG, in the absence of a known etiology. Three conditions ...have a likely autoimmune pathogenesis: autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis, and de novo AIH after liver transplantation. Two types of pediatric AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (AIH-1) or liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibodies (AIH-2).Pertinent issues addressing the diagnosis, treatment, and long-term follow-up were formulated by a core group of ESPGHAN members. They have commissioned the first authors with execution of this project. Initially, they have performed a systematic literature search on MEDLINE, ResearchGate, and Mendeley databases during the last 30 years and produced a document focusing on prospective and retrospective studies in children. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique.
Background. To date, there is no commercially available vaccine to prevent infectious mononucleosis, a disease frequently induced by Epstein-Barr virus (EBV) infection in adolescents or adults devoid ...of preexisting immunity to the virus. Methods. A total of 181 EBV-seronegative, healthy, young adult volunteers were randomized in a double-blind fashion to receive either placebo or a recombinant EBV subunit glycoprotein 350 (gp350)/aluminum hydroxide and 3-O-desacyl-4′-monophosphoryl lipid A (AS04) candidate vaccine in a 3-dose regimen. Results. The vaccine had demonstrable efficacy (mean efficacy rate, 78.0% 95% confidence interval {CI}, 1.0%–96.0%) in preventing the development of infectious mononucleosis induced by EBV infection, but it had no efficacy in preventing asymptomatic EBV infection. One month after receipt of the final dose of gp350 vaccine, 98.7% of subjects showed seroconversion to anti-gp350 antibodies (95% CI, 85.5%–97.9%), and they remained anti-gp350 antibody positive for >18 months. Furthermore, there were no concerns regarding the safety or reactogenicity of the gp350/AS04 vaccine. Conclusion. These data support the clinical feasibility of using an EBV vaccine to prevent infectious mononucleosis. Trial registration. ClinicalTrials.gov identifier: NCT00430534.
In 2017, the European Medicines Agency and the Food and Drug Administration approved the use of the fixed-dose combination of ledipasvir/sofosbuvir and of the combination of sofosbuvir and ribavirin ...for treatment of adolescents (12-17 years or weighing >35 kg) with chronic hepatitis C virus (HCV) genotype 1, 4, 5, and 6 and genotype 2 and 3 infections, respectively. Although trials with direct-acting antivirals are ongoing for younger children, the only available treatment in the United States and Europe for those <12 years is still the dual therapy of pegylated interferon and ribavirin. There is currently a lack of a systematic approach to the care of these patients. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition developed an evidence-based position paper for the management of chronic HCV infection in children.
A systematic literature search and meta-analysis were performed using MEDLINE and Embase from June 1, 2007 to June 1, 2017. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. European Society of Pediatric Gastroenterology, Hepatology and Nutrition Committee members voted on each recommendation, using the nominal voting technique.
The efficacy of the different direct-acting antivirals combinations tested was higher, the relapse and the treatment discontinuation rates lower when compared to pegylated interferon and ribavirin.
This position paper addresses therapeutic management issues including goals, endpoints, indications, contraindications, and the optimal treatment regimen in children with chronic HCV infection.
Progressive familial intrahepatic cholestasis (PFIC) can cause intense pruritus that is refractory to medical therapy. Surgical biliary diversion techniques, including partial internal biliary ...diversion (PIBD), have been developed over the years to relieve pruritus without requiring liver transplantation. No clinical or genetic features can currently predict postoperative pruritus response. We present three PFIC type 2 (PIFC 2) patients who underwent transient endoscopic nasobiliary drainage (NBD) prior to PIBD surgery. Two patients repeatedly responded to NBD and presented with complete pruritus resolution after subsequent PIBD. NBD failed technically in the third patient, and PIBD was partially successful. Mild post-endoscopic biological pancreatitis occurred in 2/6 NBD procedures and resolved spontaneously. The only adverse effect observed within 7 years post-PIBD was very mild transient osmotic diarrhea.
Conclusion
: Our limited data suggest that NBD is a safe and effective way to predict pruritus response before performing permanent biliary diversion surgery in PFIC patients.
What is Known:
•
Surgical biliary diversion techniques have been developed to relieve intractable pruritus in progressive familial intrahepatic cholestasis (PFIC).
•
No clinical or genetic features can currently predict pruritus response to surgery.
What is New:
•
Our data suggest that nasobiliary drainage could be a safe and effective tool to predict pruritus response to biliary diversion and avoid unnecessary surgery in PFIC patients.
Background
Given the widespread use of Point-of-Care UltraSound (PoCUS) in clinical practice, with ultrasound machines becoming more portable and affordable, recommendations and position statements ...from ultrasound societies now promote teaching PoCUS in the undergraduate curriculum. Nevertheless, surveys about PoCUS teaching in European medical schools are lacking. This survey aims to overview the current and future undergraduate PoCUS courses in the European Union (EU).
Results
A questionnaire was sent to medical schools in 26 of the 27 countries of the EU; Luxembourg is the only country without a medical school. The survey was completed by the dean or a member of the medical school with knowledge of the medical curriculum. Of the 58 medical schools from 19 countries that responded to the survey, 18 (31.0%) from 13 (68.4%) EU countries reported the existence of an undergraduate PoCUS curriculum and a further 16 (27.6%) from 12 (41.4%) EU countries intended to offer it in the future. No significant difference was observed between the current and future PoCUS curricula regarding its content and purpose. Less than 40 h of theoretical teaching is provided in all the medical schools and less than 40 h of practical training is provided in 12 (75%) of the 16 medical schools which answered this specific question. Of the 40 (69%) surveyed medical schools that do not currently teach PoCUS, 20 (50%) intend to offer PoCUS courses in the future.
Conclusion
Although the lack of teaching hours in curricula suggests that most PoCUS courses are introductory in nature and that medical students are possibly not trained to become autonomous in clinical practice, evaluating the feasibility and impact of PoCUS teaching on clinical practice should be promoted. The medical schools that intend to develop this curriculum should be encouraged to implement validated tools to objectively assess their programs and students’ performances.
Background
Pediatric LT are at particular risk of HAT, and its management still constitutes a matter of debate. Our purpose was to study predisposing factors and outcome of HAT post‐LT, including the ...impact of surgical revisions on survival and biliary complications.
Methods
Among 882 primary pediatric LT performed between 1993 and 2015, 36 HAT were encountered (4.1%, 35 fully documented). Each HAT case was retrospectively paired with a LT recipient without HAT, according to diagnosis, age at LT, type of graft, and era.
Results
Five‐year patient survivals were 77.0% versus 83.9% in HAT and non‐HAT paired groups, respectively (P = .321). Corresponding graft survivals were 20.0% versus 80.5% (P < .001), and retransplantation rates 77.7% versus 10.7%, respectively (P < .001). One‐year biliary complication‐free survivals were 16.6% versus 83.8% in the HAT and non‐HAT groups, respectively (P < .001). Regarding chronology of surgical re‐exploration, only HAT cases that occurred within 14 days post‐LT were re‐operated, fourteen of them being explored within 7 days post‐LT (revascularization rate: 6/14), versus two beyond 7 days (no revascularization). When revascularization was achieved, graft and biliary complication‐free survival rates at 1 year were 33.3% and 22.2%, respectively, both rates being 0.0% in case of failure.
Conclusions
The pejorative prognosis associated with HAT in terms of graft survival is confirmed, whereas patient survival could be preserved through retransplantation. Results suggest that HAT should be re‐operated if occurring within 7 days post‐LT, but not beyond.
The management of esophageal varices (EV) in children experiencing biliary atresia (BA) remains controversial. Recent studies in children proposed initiating a prophylactic treatment in patients with ...severe (grade III) EV and/or EV associated with red color signs. Our study was aimed at assessing the risk of bleeding from EV in a series of patients with BA, identifying risk factors for bleeding to develop a predictive model of bleeding.
This was a retrospective study including 83 eligible patients with BA. Clinical, ultrasonographic, endoscopic, and laboratory parameters were studied from the beginning of medical management up to the occurrence of upper gastrointestinal bleeding. In patients not presenting any bleeding, data were analyzed until liver transplantation, endoscopic treatment of EV was performed, or last follow-up. Risk factors were investigated using univariate and multivariate statistical analyses.
Seventeen of 83 patients (20%) presented gastrointestinal bleeding, with a median age of 9.5 months (6-50 months). In univariate and multivariate analyses, high-grade EV, red color signs on endoscopic examination, and low fibrinogen levels, at first endoscopy, were identified as risk factors for bleeding. When tested in >10,000 different models, these 3 variables appeared to play the most significant role in predicting bleeding.
Our study confirmed that grade III EV and red color signs are risk factors for bleeding in patients followed up for BA. We identified low fibrinogen levels as an additional risk factor. The relevance of these 3 factors to predict bleeding from EV requires validation in a prospective study.
The phenotypic homology of fibroblasts and mesenchymal stem cells (MSCs) has been recently described. Our study investigated the in vitro potential of human skin fibroblasts to differentiate into ...mesodermal (osteocyte and adipocyte) and endodermal (hepatocyte) cell lineages by comparison with human bone marrow (hBM) MSCs. The endodermal potential of fibroblasts was then explored in vivo in a mouse model of liver injury. Fibroblasts were able to acquire osteocyte and adipocyte phenotypes as assessed by cytochemistry and gene expression analyses. After exposure to a specific differentiation cocktail, these cells presented hepatocyte‐like morphology and acquired liver‐specific markers on protein and gene expression levels. Furthermore, these fibroblast‐derived hepatocyte‐like cells (FDHLCs) displayed the ability to store glycogen and synthesize small amounts of urea. By gene expression analysis, we observed that fibroblasts remained in a mesenchymal‐epithelial transition state after hepatocyte differentiation. Moreover, FDHLCs lost their hepatocyte‐like phenotype after dedifferentiation. In vivo, human fibroblasts infused directly into the liver of hepatectomized severe combined immunodeficient (SCID) mice engrafted in situ and expressed hepatocyte markers (albumin, alpha‐fetoprotein, and cytokeratin 18) together with the mesodermal marker fibronectin. Despite lower liver‐specific marker expression, the in vitro and in vivo differentiation profile of fibroblasts was comparable to that of mesenchymal‐derived hepatocyte‐like cells (MDHLCs). In conclusion, our work demonstrates that human skin fibroblasts are able to display mesodermal and endodermal differentiation capacities and provides arguments that these cells share MSCs features both on the phenotypic and functional levels. (HEPATOLOGY 2007;46:1574–1585.)
Mesenchymal stem cell (MSC) transplantation is a fast-developing therapy in regenerative medicine. However, some concerns have been raised regarding their safety and the infusion-related ...pro-coagulant activity. The aim of this study is to analyze the induced thrombogenic risk and the safety of adding anticoagulants during intraportal infusions of liver-derived MSCs (HepaStem), in patients with Crigler-Najjar (CN) and urea cycle disorders (UCD).
Eleven patients (6 CN and 5 UCD patients) were included in this partially randomized phase 1/2 study. Three cell doses of HepaStem were investigated: low (12.5 × 10
cells/kg), intermediate (50 × 10
cells/kg), and high doses (200 × 10
cells/kg). A combination of anticoagulants, heparin (10 I.U./5 × 10
cells), and bivalirudin (1.75 mg/kg/h) were added during cell infusions. The infusion-related thrombogenic risk and anticoagulation were evaluated by clinical monitoring, blood sampling (platelet and D-dimer levels, activated clotting time, etc.) and liver Doppler ultrasound. Mixed effects linear regression models were used to assess statistically significant differences.
One patient presented a thrombogenic event such as a partial portal vein thrombus after 6 infusions. Minor adverse effects such as petechiae, epistaxis, and cutaneous hemorrhage at the site of catheter placement were observed in four patients. A significant decrease in platelet and increase in D-dimer levels were observed at the end of the infusion cycle, normalizing spontaneously after 7 days. No significant and clinically relevant increase in portal vein pressure could be observed once the infusion cycle was completed.
The safety- and the infusion-related pro-coagulant activity remains a concern in MSC transplantation. In our study, a combination of heparin and bivalirudin was added to prevent the thrombogenic risk induced by HepaStem infusions in 11 patients. A significant decrease in platelet and increase in D-dimer levels were observed, suggesting the activation of coagulation in these patients; however, this was spontaneously reversible in time. We can conclude that adding this combination of anticoagulants is safe and limits infusion-related thrombogenesis to subclinical signs in most of the patients.
ClinicalTrials.gov identifier: NCT01765283-January 10, 2013.
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