In a multinational study of children with acute liver failure, we found that incorporating diagnostic test recommendations into electronic medical record order sets accessed at time of admission reduced the percentage with an indeterminate diagnosis that may have reduced liver transplants without increasing mortality. Widespread use of this approach could significantly enhance care of acute liver failure in children.

Background & Aims No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. Methods We performed a double-masked trial of 169 children with NAFLD Activity Scores ≥ 4 at 10 centers. From June 2012 to January 2014, the patients were randomly assigned to receive CBDR or placebo twice daily (300 mg for ≤65 kg, 375 mg for >65–80 kg, 450 mg for >80 kg) for 52 weeks. The primary outcome from the intention to treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in NAFLD Activity Score ≥ 2 points without worsening fibrosis; patients without biopsies from week 52 (17 in the CBDR group and 6 in the placebo group) were considered non-responders. We calculated relative risks (RR) of improvement using stratified Cochran-Mantel-Haenszel analysis. Results There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% CI, 0.8–2.1; P=.34). However, children receiving CBDR had significant changes in pre-specified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction of 53±88 U/L vs a reduction of 8±77 U/L in the placebo group; P=.02) and aspartate aminotransferase (reduction of 31±52 vs a reduction of 4±36 U/L in the placebo group; P=.008), and a larger proportion had reduced lobular inflammation (in 36% of patients in the CBDR group vs placebo 21% of patients in the placebo group; RR, 1.8; 95% CI, 1.1–2.9; P=.03). In a post-hoc analyses, of children ≤65 kg, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3–12.3; P=.005). Conclusions In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR did, however, have significant reductions in serum levels of aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.

Purpose Fetal hydrops arises from multiple disease processes and can portend a grim prognosis. We reviewed our experience with hydropic fetuses to understand relevant antenatal anatomic and physiologic predictors of survival. Methods We reviewed fetal ultrasounds and echocardiograms of hydropic fetuses evaluated from 1996-2013. Results Overall neonatal survival in 167 fetuses was 44% (range, 0-75%) and was influenced by the underlying disease process. The anatomic distribution of fluid varied and was not significantly different between survivors and non-survivors. Univariate analysis indicated that resolution of hydrops and delivery at a later gestational age were predictive of survival (OR:5.7 (95% CI:2.5-13.2) and OR:1.3 (95% CI:1.1-1.4), respectively). Fetal intervention also improved survival in some diseases. Echocardiograms were reviewed to group fetuses with similar cardiac physiology and defined categories with high or low/normal cardiothoracic ratio (CTR). Among patients with a high CTR, the cardiovascular profile score was predictive of survival (p=0.009). Conclusion Survival in hydrops depends on the underlying disease, available fetal therapies to resolve hydrops, and the gestational age of delivery and not on the specific anatomic manifestations of hydrops. In hydropic fetuses with high CTRs, the cardiovascular profile score may be a useful prognostic indicator.

The presence of maternal cells in offspring may promote tolerance to noninherited maternal antigens (NIMAs). Children with biliary atresia (BA) have increased maternal cells in their livers, which may impact tolerance. We hypothesized that patients with BA would have improved outcomes when receiving a maternal liver. We reviewed all pediatric liver transplants recorded in the SRTR database from 1996 to 2010 and compared BA and non-BA recipients of maternal livers with recipients of paternal livers for the incidences of graft failure and retransplantation. Rejection episodes after parental liver transplantation were examined for patients transplanted at our institution. BA patients receiving a maternal graft had lower rates of graft failure compared to those receiving a paternal graft (3.7% vs. 10.5%, p = 0.02) and, consequently, fewer episodes of retransplantation (2.7% vs. 7.5%, p = 0.04). These differences were not seen among non-BA patients or among BA patients who received female deceased donor grafts. In patients transplanted at our institution, paternal liver transplantation was associated with an increased incidence of refractory rejection compared to maternal liver transplantation only in BA. Our data support the concept that maternal cells in BA recipients promote tolerance to NIMAs and may be important in counseling BA patients who require liver transplantation.

BackgroundCongenital diaphragmatic hernia (CDH) represents a spectrum of lung hypoplasia and consequent pulmonary hypertension is an important cause of postnatal morbidity and mortality. We studied biomarkers at the maternal-fetal interface to understand factors associated with the persistence of pulmonary hypertension.MethodsMaternal and cord blood samples from fetuses with CDH and unaffected controls were analyzed using a human 39plex immunoassay kit. Cellular trafficking between the mother and the fetu was quantified using quantitative real-time PCR for non-shared alleles. Biomarker profiles were then correlated with CDH severity based on the degree of pulmonary hypertension.ResultsCord blood levels of epidermal growth factor, platelet-derived growth factor, and several inflammatory mediators increased significantly as the severity of CDH increased, while maternal levels growth factors and mediators decreased significantly with CDH severity. Maternal cells were increased in fetuses with severe CDH compared to controls, with elevated levels of the chemokine CXCL-10 in patients with the highest trafficking.ConclusionPatients with CDH demonstrate pro-inflammatory and chemotactic signals in fetal blood at the time of birth. Since some of these molecules have been implicated in the development of pulmonary hypertension, prenatal strategies targeting specific molecular pathways may be useful adjuncts to current fetal therapies.