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Objectives To identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere. Study design The Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected. Results We enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score. Conclusions Portal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.

Objectives To prospectively assess the value of serum total bilirubin (TB) within 3 months of hepatoportoenterostomy (HPE) in infants with biliary atresia as a biomarker predictive of clinical sequelae of liver disease in the first 2 years of life. Study design Infants with biliary atresia undergoing HPE between June 2004 and January 2011 were enrolled in a prospective, multicenter study. Complications were monitored until 2 years of age or the earliest of liver transplantation (LT), death, or study withdrawal. TB below 2 mg/dL (34.2 μM) at any time in the first 3 months (TB Results Fifty percent (68/137) of infants had TB P P P P P = .0002), LT (OR 12.4, 95% CI 5.3-28.7, P P Conclusions Infants whose TB does not fall below 2.0 mg/dL within 3 months of HPE were at high risk for early disease progression, suggesting they should be considered for LT in a timely fashion. Interventions increasing the likelihood of achieving TB Trial registration ClinicalTrials.gov: NCT00061828 and NCT00294684.

We report a 2.5-month-old infant with bilateral adrenal neuroblastoma, stage 4S(M), with liver metastases and chemotherapy-induced veno-occlusive disease leading to cirrhosis requiring liver transplantation. Despite unknown tumour histology and MYCN-amplification status, we proceeded with liver transplant. This decision was based on clinical suspicion that our patient was MYCN-negative due to significant tumour regression, and was supported by evidence indicating that MYCN-amplification is rare in infants with favourable-stage neuroblastoma. This is the second case report of neuroblastoma requiring liver transplantation; however, in the previously reported case, the diagnosis of neuroblastoma was not established until after transplantation. We discuss this unique case to justify the potential use of life-saving liver transplants in infants with neuroblastoma.

CNI use can cause hyperlipidemia and new onset diabetes, and obesity may have adverse effects on allograft and patient survival, but the mechanisms are unclear. Design: We assessed if CNI or rapamycin (Rapa) use correlated with the metabolic status of children (n = 62) with stable, long-term liver (26 M, 27 F) or kidney (6 M, 3 F) allografts, and if being overweight or obese (Ow/Ob) was associated with impaired Treg phenotype or function. Results: Most patients had CNI (39) or Rapa (9) monotherapy, though 12 received CNI (8) or Rapa (4) plus MMF, Aza or steroids. 45 children had normal weight, but 7 were overweight and 10 were obese. The CNI group had more Ow/Ob patients (p=0.045) and higher BMI-for age percentile (BMI) than the Rapa group (61.7 vs. 42.9, p=0.047). CNI dose correlated with BMI (0.521, p=0.013), while Rapa use negatively correlated with BMI (-0.888, p=0.044). Also, Ow/Ob patients had reduced Treg suppressive function compared to patients with normal weight (153 vs. 100 units for autologous CD4 responders, 166 vs. 92 for standard CD4 responders, 114 vs. 43 for CD8 responders, p=0.031), and BMI was negatively correlated with CTLA-4 expression in Tregs (-0.555, p=0.011). Conclusions: CNI use is associated with being overweight or obese post-Tx, and the latter are associated with impaired Treg function and phenotype. The metabolic consequences of being overweight or obese post-Tx may include disruption of immune regulation and favor a pro-inflammatory phenotype.